\r\n\r\nThe publication of this book was supported by Nagoya University, the 21st COE program "Micro- and NanoMechatronics for Information-Based Society," and the global COE program “COE for Education and Research of Micro-Nano Mechatronics.”\r\n',isbn:null,printIsbn:"978-953-51-1104-7",pdfIsbn:"978-953-51-4246-1",doi:"10.5772/55984",price:139,priceEur:155,priceUsd:179,slug:"micro-nano-mechatronics-new-trends-in-material-measurement-control-manufacturing-and-their-applications-in-biomedical-engineering",numberOfPages:378,isOpenForSubmission:!1,isInWos:1,isInBkci:!0,hash:"4c4d9bcf3fcabbf90f5fd91e54af8cc1",bookSignature:"Toshio Fukuda, Tomohide Niimi and Goro Obinata",publishedDate:"June 5th 2013",coverURL:"https://cdn.intechopen.com/books/images_new/3740.jpg",numberOfDownloads:10222,numberOfWosCitations:10,numberOfCrossrefCitations:0,numberOfCrossrefCitationsByBook:null,numberOfDimensionsCitations:0,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:10,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"January 28th 2013",dateEndSecondStepPublish:"February 18th 2013",dateEndThirdStepPublish:"May 25th 2013",dateEndFourthStepPublish:"August 23rd 2013",dateEndFifthStepPublish:"September 22nd 2013",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7,8",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"168330",title:"Dr.",name:"Chikara",middleName:null,surname:"Nagai",slug:"chikara-nagai",fullName:"Chikara Nagai",profilePictureURL:"https://mts.intechopen.com/storage/users/168330/images/system/168330.jpg",biography:"Chikara Nagai received the M.S. and Ph. 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\n\t\t\t
1. Introduction
\n\t\t\t
Diabetes mellitus is characterized by chronically elevated serum glucose levels resulting in damage of several tissues (e. g. retina, kidney, nerves) due to higher protein glycation, retardation of wound healing, impaired insulin secretion, enhanced insulin resistance, cell apoptosis, and increased oxidative stress. Type 2 diabetes (T2DM), representing 90-95 % of all diabetic cases, is a multifactorial disease where impaired insulin secretion and the development of insulin resistance ultimately leads to hyperglycemia (Hengesh, 1995). The end of the 20th century has witnessed a dramatic increase in the number of patients diagnosed with diabetes worldwide. The predicted number for the year 2025 is well over 300 million representing a 4-5 % yearly increase of the population above 20 years of age (Treadway et al., 2001). This striking prevalence can even be an underestimate due to methodological uncertainties as well as undiagnosed cases (Green et al., 2003). The highest increases are expected in the developing countries of Africa, Asia, and South America, while European populations seem to be less affected (Diamond, 2003). T2DM has been considered as the adult- or late-onset variant, however, the recent decade has seen the appearance and spreading of the disease among young people including children: this forecasts severe economic and health service burdens in the near future (Alberti et al., 2004; Ehtisham & Barrett, 2004).
\n\t\t\t
The epidemic of T2DM is in conjunction with genetic susceptibility: evidence for a genetic component to the disease are accumulating, and the potential of these factors in the treatment and prevention of diabetes has been reviewed (Barroso, 2005; Bonnefond et al., 2010; Sladek et al., 2007; Toye & Gauguier, 2003). A similarly high contribution to this epidemic may originate from behavioral factors such as sedentary lifestyle, overly rich nutrition, and obesity (Bloomgarden, 2004).
\n\t\t\t
Especially due to its long term complications (Brownlee, 2001) like retinopathy, neuropathy, nephropathy, and in particular cardiovascular diseases, as well as significantly higher risk of myocardial infarction, stroke, gangrene, and limb amputation diabetes has become one of the largest contributors to disability and mortality. Although several pathomechanisms (Lowell & Shulman, 2005; Panunti et al., 2004; Stumvoll et al., 2005) are under investigation, no firm understanding of the molecular origins (Ross et al., 2004) of the disease exists. Thereby, all available and investigational treatments are symptomatic. As the complications can first of all be attributed to the high blood glucose levels, current antidiabetic therapies (Table 1) aim at reaching normoglycemia. However, most of the applied oral hypoglycemic agents (Cheng & Fantus, 2005; Krentz & Bailey, 2005; Mizuno et al., 2008; Padwal et al., 2005; Rendell, 2004; Uwaifo & Ratner, 2005) have several side effects and are inadequate for 30-40 % of the patients (Wagman & Nuss, 2001). On the other hand, their efficacy is lost over the time, and several concerns exist regarding their safety (Israili, 2011).
Main types of current therapeutic agents for T2DM and their major side effects (Israili, 2011; Moller, 2001)
\n\t\t\t
The complexity of T2DM offers many potential points of intervention for pharmacotherapy for which the main molecular targets and strategies such as insulin secretagogues, insulin sensitizers, hormones, inhibitors of PTP-1B, GSK3, and hepatic glucose production, methods for altering lipid metabolism, combination therapies, etc. have been reviewed in details (Israili, 2011;\n\t\t\t\tMorral, 2003; Nourparvar et al., 2004; Wagman et al., 2004).
\n\t\t\t
Among the numerous methods used to treat type 2 diabetes and investigated to find new therapeutic possibilities there are several approaches which apply carbohydrate (especially glucose) derivatives as well as compounds mimicking the properties of sugars. Based on our experience in the chemistry of carbohydrates and glycomimetics, in this survey we summarize the roles of such compounds in combatting type 2 diabetes relying on the review literature and very recent primary scientific papers.
\n\t\t
\n\t\t
\n\t\t\t
2. Inhibitors of α-glucosidase enzymes
\n\t\t\t
Starch and sucrose are the most important dietary carbohydrates but they are not directly available for the cells. They are digested in the gastrointestinal tract to monosaccharides which can be absorbed to the circulation to raise the serum concentration (Hanhineva et al., 2010). The normal blood glucose level (3.6–5.8 mM) fluctuates throughout the day, is usually lowest in the morning, before the first meal of the day, and rises after meals for an hour or two.
\n\t\t\t
A medically applied treatment of diabetes is to retard the absorption of glucose by inhibition of the carbohydrate hydrolyzing enzymes α-amylase and α-glucosidase in the digestive tract. In humans the digestion of starch, maltodextrins, and maltooligosaccharides includes several stages: degradation of the polymeric substrates results in shorter oligomers which are than cleaved by α-amylase into smaller oligosaccharides. This mixture is broken down to monosaccharides by α-glucosidase from the non-reducing end of the oligosaccharides. By inhibition of these enzymes the rate of glucose production can be reduced that contributes to diminishing the blood glucose levels, too (Tundis et al., 2010). Such inhibitors decrease postprandial hyperglycaemia and hyperinsulinaemia, thereby may improve sensitivity to insulin and release the stress on β-cells (Scheen, 2003).
\n\t\t\t
Glycosidases are a long known and studied class of glycoenzymes for which an enormous number of compounds have been tested as inhibitors (El Ashry et al., 2000a; El Ashry et al., 2000b; El Ashry et al., 2000c; Lillelund et al., 2002). Analogues of monosaccharides in which the ring oxygen is replaced by a nitrogen atom are known as iminosugars (or less properly azasugars) comprising both natural and synthetic molecules (Table 2) which, as the most potent inhibitors of glycosidases, have high pharmacological potential not only in the context of T2DM (Asano, 2009; Compain & Martin, 2007).
\n\t\t\t
The naturally occurring salacinol and analogous sugar mimics with a 4-thiofuranoid type ring (Table 2) belong to a growing class of zwitterionic glycosidase inhibitors, which attract great interest both as synthetic targets and applications for α-glucosidase inhibition (Praly & Vidal, 2010).
\n\t\t\t
The positive charge on the sulfur atom in the thiosugar derivatives and in the iminosugar-based glycosidase inhibitors at physiological pH is facilitating the binding in the active sites of glycosidase enzymes as a mimicry of the charge of the oxocarbeniumion-like transition state formed during hydrolysis of the natural enzyme substrate (Zechel & Withers, 2000). The stabilizing electrostatic interactions between the ammonium (protonated nitrogen) or sulfonium (positively charged sulfur) moieties and an active-site carboxylate residue are considered to be a possible mechanism of action of these inhibitors (Mohan & Pinto, 2007).
\n\t\t\t
Three competitive inhibitors of α-glucosidases: acarbose, miglitol, and voglibose (de Melo et al., 2006) (Table 3) are used as drugs in the treatment of T2DM under various brand names. These compounds are known to inhibit a wide range of glycosidases. In the absence of specificity and because of the known serious side effects, the applications of these first generation iminosugar drugs are limited. Current investigations aim at discovering safer, more specific, and effective iminosugar based derivatives not only as hypoglycemic agents but for several other purposes among others in oncology, as antivirals, and against cystic fibrosis as reviewed in (Home et al., 2011).
\n\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t
Table 2.
\n\t\t\t
Select iminosugar and thiosugar type inhibitors and their effect againstα-glucosidases originating from mammalian gastrointestinal tract
\n\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Name
\n\t\t\t\t\t\t
Structure
\n\t\t\t\t\t\t
Side-effect
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Acarbose Approved in 1995
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
Flatulence (78% of the patients) Diarrhea (14% of the patients)
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Miglitol Approved in 1996
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
Diarrhea, gas, soft stools, stomach pain
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Voglibose Approved in 1997
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
Diarrhea, stool loss, meteorism, upset stomach
\n\t\t\t\t\t
\n\t\t\t\t
Table 3.
α-Glucosidase inhibitors in the clinical practice against T2DM
\n\t\t
\n\t\t
\n\t\t\t
3. Inhibitors of renal sodium-glucose cotransporters
\n\t\t\t
The mammalian kidney plays an important role in the maintenance of energy balance of the organism. In healthy individuals 180 g/day of D-glucose is filtered from plasma through the glomerulus, which is completely reabsorbed in the renal proximal tubules to the blood-stream, thereby preventing the loss of glucose in the urine (Wright, 2001). This reabsorption process is mediated by two sodium dependent glucose cotransporters (SGLTs). SGLT1 is a high-affinity, low-capacity glucose/galactose transporter located predominantly in the small intestine, but is also present in the S3 segment of the proximal tubule in the kidney, as well as in the heart. The primary function of SGLT1 is the absorbtion of dietary glucose in the intestine, however it shares in the renal glucose transport in the kidney and regulates cardiac glucose transport in the heart, as well. SGLT2 is a low affinity, high capacity glucose transporter specifically expressed in the S1 segment of the proximal convoluted tubule. SGLT2 is responsible for ~90 % of renal glucose reabsorption, while SGLT1 plays only an auxiliary role in this process (Boldys & Okopien, 2009; Idris & Donnelly, 2009; Washburn, 2009b). Genetic studies demonstrated that defects of SGLT2 but in a lesser extent of SGLT1 genes had neither adverse effects on kidney function as well as carbohydrate metabolism, nor hypoglycaemia (Handlon, 2005; Santer & Calado, 2010; Wright, 2001).
\n\t\t\t
Nowadays sodium-glucose cotransporters have received remarkable attention as new drug targets for the treatment of diabetes (Bailey, 2011). Considering the exclusive expression of SGLT2 in the kidney and its predominant role in renal glucose recovery, most pharmaceutical investigations have focused primarily on selective SGLT2 inhibition to facilitate benign glucosuria (Santer & Calado, 2010; Washburn, 2009b). In contrast to the currently applied diabetic therapies most of which aim at insulin resistance and insulin deficiency, targeting SGLT2 is an insulin-independent strategy based on enhanced renal glucose excretion and, consequently, lowering plasma glucose levels without severe side effects (Isaji, 2007).
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t R = H unless indicated otherwise
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Entry
\n\t\t\t\t\t\t
R’
\n\t\t\t\t\t\t
Entry
\n\t\t\t\t\t\t
R’
\n\t\t\t\t\t\t
Entry
\n\t\t\t\t\t\t
R’
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
1.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
2.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
3.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Phlorizin 35.6* (Meng et al., 2008) 18.6** (Katsuno et al., 2007)
\n\t\t\t\t\t\t
T-1095 R = COOMe (prodrug form) T-1095A R = H (active form) 50 (Handlon, 2005) 6.6* (Meng et al., 2008)
\n\t\t\t\t\t\t
Sergliflozin R = COOEt (prodrug form) Sergliflozin-A R = H (active form) 9.2* (Meng et al., 2008) 2.39** (Katsuno et al., 2007)
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
4.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
5.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
6.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
0.1 (Handlon, 2005)
\n\t\t\t\t\t\t
Remogliflozin etabonate R = COOEt (prodrug form) Remogliflozin R = H (active form) 12.4** (Fujimori et al., 2008)
\n\t\t\t\t\t\t
BI 44847 (Washburn, 2009b)
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
7.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
8.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
9.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
3 (Handlon, 2005)
\n\t\t\t\t\t\t
8 (Handlon, 2005)
\n\t\t\t\t\t\t
20 (Handlon, 2005)
\n\t\t\t\t\t
\n\t\t\t\t
Table 4.
Selected O-glucopyranoside type inhibitors of SGLT2 (IC50, EC50\n\t\t\t\t\t\t*, Ki\n\t\t\t\t\t\t ** values [nM])
\n\t\t\t
The first class of potential SGLT2 inhibitors to be explored was the O-glucosides derived from the structure of phlorizin (Table 4, Entry 1) of natural origin isolated from the root bark of the apple tree (Ehrenkranz et al., 2005). Phlorizin lowers plasma glucose levels and improves insulin resistance by increasing renal glucose excretion (Isaji, 2007). However, it is not considered as an antidiabetic drug because of its nonselective inhibition against SGLTs as well as its metabolic instability due to hydrolysis by glucosidase enzymes in the intestinal tract that prevented oral administration (Washburn, 2009a). In addition, enzymatic release of the aglycone phloretin, a micromolar inhibitor of sodium-independent facilitative glucose transporters (GLUTs), could potentially inhibit GLUT-mediated cellular uptake of glucose (Ehrenkranz et al., 2005; Washburn, 2009a). Because of the poor bioavailability and the aforementioned undesirable effects of phlorizin, initial efforts entailed exploring more stable and selective O-glucoside analogues of this compound.
\n\t\t\t
T-1095 (Table 4, Entry 2) is a methyl carbonate prodrug which, after oral administration, is rapidly converted to an active metabolite, T-1095A showing high affinity and plausible selectivity against human SGLT2 (Handlon, 2005). Development of T-1095 reached phase II clinical trials but was subsequently discontinued (Isaji, 2007).
\n\t\t\t
The β-D-glucosides in which the aglycone moiety is a phenyl ring substituted in ortho position by a benzyl group represent a promising type of O-glucoside candidates (Entries 3 and 4). Sergliflozin (Entry 3), an ethyl carbonate prodrug, emerged from this series to enter clinical trials (Isaji, 2007). According to the in vitro assay, its active form is a highly potent and 296-fold more selective inhibitor for human SGLT2 over SGLT1 (Katsuno et al., 2007).
\n\t\t\t
Heteroaromatic O-glucosides are the next potent series of SGLT2 inhibitors. Among pyrazole derivatives remogliflozin (Entry 5) showed a reassuring 365-fold selectivity for SGLT2 versus SGLT1 in vitro (Fujimori et al., 2008), and reached clinical developments (Isaji, 2007). In addition, an analogue of remogliflozin (Entry 6) presumably entered clinical trials as BI 44847 (Washburn, 2009b). 2-Pyridyl-O-glucoside (Entry 7) with a potency of 3 nM against human SGLT2 represent an additional highly active compound of this class (Handlon, 2005).
\n\t\t\t
Efficacy of a series of benzofused heterocyclic derivatives was also investigated and, for example, benzotriazole and indole O-glucosides (Entries 8 and 9, respectively) were found to strongly inhibit human SGLT2 (Handlon, 2005).
\n\t\t\t
Susceptibility of O-glucosides to enzymatic degradation by glucosidases impacted bioavailability and duration of action (Washburn, 2009b). Therefore, remarkable attention has been paid to metabolically more stable C-glucopyranosyl derivatives.
\n\t\t\t
Compounds containing a diarylmethane aglycone represent the first type of this class (Table 5). According to the SAR the benzyl substituent in meta position of the central aryl ring is more favourable compared to the ortho attached derivatives of high activity in case of O-glucosides (Washburn, 2009a; Washburn, 2009b). At present, dapagliflozin (Entry 1) with considerable in vitro as well as in vivo activity is the most advanced SGLT2 inhibitor in phase III clinical trials and has become a leading structure for further inhibitor design (Washburn, 2009a; Washburn, 2009b).
\n\t\t\t
Additional SAR exploration revealed that introduction of an appropriate ortho substituent at the proximal phenyl ring adjacent to the glycosidic bond is beneficial in respect of inhibitory efficiency (Entry 2) (Washburn, 2009a). For example, propargyl ether derivative (Entry 3) exhibited sub-nanomolar activity and a more than 3300-fold selectivity for SGLT2 (Xu et al., 2010).
\n\t\t\t
Replacement of the distal phenyl group with fused rings resulted in a new potent inhibitor type. For example, 1:1 choline complex of azulene (Entry 4) as well as 1:1 L-proline complex of benzothiophene (Entry 5) derivatives appeared as clinical candidates (Washburn, 2009b).
\n\t\t\t
Modification of dapagliflozin by replacing the distal aryl ring by heterocycles led to the discovery of canagliflozin (Entry 6) which obtained the second highest interest in clinical developments (\n\t\t\t\t\tNomura et al., 2010\n\t\t\t\t).
\n\t\t\t
Recently, along this line, the structure of dapagliflozin was modified by other heterocycles such as thiazole (Song et al., 2011), 1,3,4-thiadiazole (Lee et al., 2010b), pyridazine (Kim et al., 2010), and pyrimidine (Lee et al., 2010a) moieties. Among them, the thiazole derivative
\n\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Entry
\n\t\t\t\t\t\t
R
\n\t\t\t\t\t\t
Entry
\n\t\t\t\t\t\t
R
\n\t\t\t\t\t\t
Entry
\n\t\t\t\t\t\t
R
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
1.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
2.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
3.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Dapagliflozin BMS-512148 1.1* (Meng et al., 2008) 0.49 (Song et al., 2011) 6.7 (Xu et al., 2010) 1.4 (Robinson et al., 2010)
\n\t\t\t\t\t\tC-glucopyranosyl compounds as SGLT2 inhibitors (IC50, EC50\n\t\t\t\t\t\t* values [nM])
\n\t\t\t
(Entry 7) displayed the best result, however, according to its in vitro (IC50 = 0.72 nM) as well as in vivo activity, it was less potent than dapagliflozin (IC50 = 0.49 nM) (Song et al., 2011).
\n\t\t\t
From C-glucosyl hetarenes containing a central heterocyclic ring such as pyrazine, indole, benzisothiazole, and benzothiophenes (Entries 8-12, respectively) the latter two proved most efficient (Washburn, 2009b).
\n\t\t\t
\n\t\t\t\tN-Glucopyranosides represent an other series of SGLT2 inhibitors with probably higher metabolic stability as compared to O-glucopyranosides. Among these derivatives benzylated aniline-, pyrrole-, and indole N-glucosides (Table 6, Entries 1-4, respectively) are potent orally active SGLT2 inhibitors (Washburn, 2009b).
\n\t\t\t
\n\t\t\t\tO-Spiroketal C-arylglucosides (Entries 5 and 6) which combine the character of both O-glucosides and C-glucosyl derivatives, show good inhibitory activity (Lv et al., 2009) and high selectivity (Washburn, 2009b) for SGLT2 which can be attributed, in part, to a greater conformational constraint imposed by the spiro-annelated ring system.
\n\t\t\t
In the quest of new candidates for SGLT2 inhibition the modification of the sugar part of the molecules is a further possibility. Replacement of the ring oxygen by a sulfur atom provided new potent 1,5-anhydro-1-thio-D-glucitol derivatives (Table 7, Entries 1-3) (Washburn, 2009b). TS-071 (Entry 1) showed excellent urinary glucose excretion in dogs and is currently undergoing phase II clinical trials (Kakinuma et al., 2010). Modification of the glucose moiety by substituting the hydroxyl groups attached to either C-4 or C-6 with fluorine (Entries 4 and 5) also resulted in effective molecules (Washburn, 2009b). Replacement of the hydroxymethyl side chain of the glucose part with a methyl- or methylsulfanyl group (Entries 6 and 7, respectively) provided molecules with good inhibitory effect, from which LX4211 (Entry 7) is a clinical candidate (Washburn, 2009b). Further transformation of the
\n\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Entry
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
Entry
\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
1.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
2.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
2.9 (Washburn, 2009b)
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
1.1 (Washburn, 2009b)
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
3.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
4.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
0.9 (Washburn, 2009b)
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
2.3 (Washburn, 2009b)
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
5.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
6.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
1.5 (Washburn, 2009b)
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
0.3 (Lv et al., 2009)
\n\t\t\t\t\t
\n\t\t\t\t
Table 6.
Select compounds of N-glucopyranosides, N-glucopyranosyl heterocycles, and anomeric spirocycles (IC50 [nM])
\n\t\t\t
side chain of the sugar moiety as in the C-5-spirocyclic analogues (Entries 8 and 9) as well as removal of the 4-OH from the glucose ring (Entry 10) furnished compounds exhibiting SGLT2 inhibitory effect in the low nanomolar range (Robinson et al., 2010).
\n\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Entry
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
Entry
\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
1.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
2.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
TS-071 2.26 (Kakinuma et al., 2010)
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
10 (Washburn, 2009b)
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
3.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
4.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
12 (Washburn, 2009b)
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
5 (Washburn, 2009b)
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
5.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
6.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
31 (Washburn, 2009b)
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
2.4 (Robinson et al., 2010)
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
7.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
8.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
LX4211 (Washburn, 2009b)
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
3.4 (Robinson et al., 2010)
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
9.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
10.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
3.0 (Robinson et al., 2010)
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
21 (Robinson et al., 2010)
\n\t\t\t\t\t
\n\t\t\t\t
Table 7.
Miscalleneous compounds with modifications in the glucose unit as inhibitors of SGLT2 (IC50, [nM])
\n\t\t
\n\t\t
\n\t\t\t
4. Glucose analogue inhibitors of glycogen phosphorylase
\n\t\t\t
The liver accounts for ~90 % of the body\'s endogenous glucose production. Hepatic glucose is formed via two pathways: glycogenolysis (release of monomeric glucose from the glycogen polymer storage form) and gluconeogenesis (de novo synthesis of glucose from C-3 precursors). Hepatic glucose output is elevated in type 2 diabetic patients, therefore, modulation (mostly inhibition) of one or more of the respective biochemical pathways may contribute to diminishing blood sugar levels. Targets for this can be the glucagon receptor (enhances hepatic glucose output), GCK (catalyzes the first step of glycolysis), 6PF-2-K/F-2,6-P2ase (regulator of glycolytic and gluconeogenic rates through production of F-2,6-P2), G-6-Pase (catalyzes the last step of gluconeogenesis), F-1,6-P2ase (regulates gluconeogenic rates), GSK3 (inhibits glycogen synthase), and glycogen phosphorylase (GP, catalyzes the conversion of glycogen to glucose-1-phosphate monomers) (Morral, 2003). Current evidence indicates that glycogenolysis is an important contributor (~75 %) to the production of glucose by the liver. Furthermore, a substantial portion of glucose formed by gluconeogenesis is cycled through the glycogen pool prior to efflux from the liver cells (Andersen et al., 1999). As GP is the rate determining enzyme of glycogen breakdown (Kurukulasuriya et al., 2003; Ross et al., 2004) its pharmacological inhibition has been regarded as an effective therapeutic approach to treating diseases caused by abnormalities in glycogen metabolism, such as type 2 diabetes (Oikonomakos, 2002; Somsák et al., 2003; Somsák et al., 2005), myocardial ischemia (Tracey, W. et al., 2003; Tracey, W. R. et al., 2004), cerebral ischemia (Sun & Xu, 2010), and tumors (Geschwind et al., 2004; Schnier et al., 2003).
\n\t\t\t
Glycogen phosphorylases (existing as ‘muscle’, ‘brain’, or ‘liver’ isoforms) are allosterically regulated enzymes consisting of a dimeric arrangement of two identical subunits related to each other by a C2 symmetry. Protein crystallographic studies (Chrysina, 2010; Oikonomakos, 2002) revealed the existence of six binding sites in GP (Fig. 1): the catalytic, the inhibitor, the allosteric, the glycogen storage, and the new allosteric sites, as well as the newly discovered benzimidazole site (Chrysina et al., 2005). Each binding site can be targeted by small molecules, and a large variety of inhibitors were tested as described in recent reviews (Loughlin, 2010; Oikonomakos & Somsák, 2008; Somsák et al., 2008).
\n\t\t\t
Physiological investigations with glycogen phosphorylase inhibitors in the context of T2DM have recently been reviewed (Agius, 2010).
\n\t\t\t
Under physiological conditions glucose (Fig. 2) serves as a regulator of GP since the less active T state of the enzyme is stabilized (Board et al., 1995) by its weak binding to the catalytic centre. This has raised the possibility to search for glucose derivatives with much higher affinity to the active site. A large variety of glucose based compounds were synthesized and tested mainly against the prototype of the GP enzymes, the best available rabbit muscle GP (Chrysina, 2010).
The studied O-, and S-glucopyranosides proved very weak inhibitors with Ki values in the 2000-25000 μM and 650-21100 μM, respectively (Somsák et al., 2003; Somsák et al., 2005).
\n\t\t\t
Extensive investigation of N-glucopyranosylamide type compounds (Table 8, Entries 1-4) revealed that a) the NHCONHCO linker between the sugar and the aromatic part of the
\n\t\t\t
Figure 1.
A schematic diagram of the muscle GPb dimeric molecule viewed down the molecular dyad. (The positions are shown for the catalytic, allosteric, glycogen storage, inhibitor, new allosteric, and benzimidazole sites. The catalytic site, marked by 2-β-D-glucopyranosyl benzimidazole, is buried at the center of the subunit and is accessible to the bulk solvent through a 15 Å-long channel. Binding of the competitive inhibitor benzimidazole promotes the less active T state through stabilization of the closed position of the 280s loop (shown in white). The allosteric site, which binds the activator AMP (indicated in the figure), is situated at the subunit–subunit interface some 30 Å from the catalytic site. The inhibitor site or caffeine binding site, which binds purine compounds such as caffeine and flavopiridol (indicated) is located on the surface of the enzyme some 12 Å from the catalytic site and, in the T state, obstructs the entrance to the catalytic site tunnel. The glycogen storage site (with bound maltopentaose) is on the surface of the molecule some 30 Å from the catalytic site, 40 Å from the allosteric site and 50 Å from the new allosteric inhibitor site. The new allosteric or indole binding site, located inside the central cavity, formed on association of the two subunits, binds indole-2 carboxamide analogs, N-benzoyl-N’-β-D-glucopyranosyl urea, and benzimidazole (indicated). The novel binding site with bound benzimidazole, also located on the surface of the molecule, is some 31 Å from the catalytic site, 32 Å from the allosteric site, and 32 Å from the indole site. (Figure by courtesy of N. G. Oikonomakos and E. D. Chrysina.)
\n\t\t\t
Figure 2.
Structure of α- and β-D-glucose and their inhibition constants with RMGPb.
\n\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Entry
\n\t\t\t\t\t\t
Compound
\n\t\t\t\t\t\t
R
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
A
\n\t\t\t\t\t\t
B
\n\t\t\t\t\t\t
C
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
(Somsák, 2011; Somsák et al., 2008)
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
1.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
CH3 32
\n\t\t\t\t\t\t
81
\n\t\t\t\t\t\t
10
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
2.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
H 140
\n\t\t\t\t\t\t
18
\n\t\t\t\t\t\t
5.2
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
3.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
-
\n\t\t\t\t\t\t
4.6
\n\t\t\t\t\t\t
0.35
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
4.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
-
\n\t\t\t\t\t\t
21
\n\t\t\t\t\t\t
-
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
(Gimisis, 2010)
\n\t\t\t\t\t\t
-CH3
\n\t\t\t\t\t\t
-(CH2)2SCH3
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
5.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
510
\n\t\t\t\t\t\t
1200
\n\t\t\t\t\t\t
350
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
(Alexacou et al., 2010; Deleanu et al., 2008)
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
6.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
33
\n\t\t\t\t\t\t
5.7
\n\t\t\t\t\t\t
28
\n\t\t\t\t\t
\n\t\t\t\t
Table 8.
Inhibition of RMGPb by N-glucopyranosidic derivatives (Ki [μM])
\n\t\t\t
compounds and b) a large hydrophobic substituent (compare columns B and C) make the best inhibitor (Entry 3C), actually the first glucose analogue in the nanomolar inhibition range. Other structures, e. g. those in Entries 1-2A, are much less efficient. For further detailed analysis of structure-activity relationships of analogous compounds see (Somsák et al., 2008). N-Glucopyranosylamides incorporating natural L-amino acids (Entry 5) proved weaker inhibitors (Gimisis, 2010), although the hydrophobicity of the appendage seems to play an important role in this series, as well (compare Entries 5A and 5B to 5C). Very recently thiosemicarbazone type inhibitors (Entry 6) have been published with inhibitory efficiency in the low micromolar range (Alexacou et al., 2010; Deleanu et al., 2008).
\n\t\t\t
Among 1-glucopyranosyl-1,2,3-triazoles (Table 9, Entries 1-3), which can be regarded as non-classical bioisosteres of N-glucopyranosylamides (Table 8, Entry 1), some low micromolar inhibitors were found (Somsák, 2011) which again show the preference for a
\n\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Entry
\n\t\t\t\t\t\t
Compound
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
R
\n\t\t\t\t\t\t
Ki [μM]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
(Somsák, 2011)
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
1.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
151
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
2.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
16
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
3.
\n\t\t\t\t\t\t
-CH2OH
\n\t\t\t\t\t\t
14
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
(Gimisis, 2010; Praly & Vidal, 2010)
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
4.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
310
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
5.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
170
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
6.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
OH
\n\t\t\t\t\t\t
6.1
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
7.
\n\t\t\t\t\t\t
F
\n\t\t\t\t\t\t
3460
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
8.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
OH
\n\t\t\t\t\t\t
5.5
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
9.
\n\t\t\t\t\t\t
F
\n\t\t\t\t\t\t
3670
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
10.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
OH
\n\t\t\t\t\t\t
7.7
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
11.
\n\t\t\t\t\t\t
F
\n\t\t\t\t\t\t
4010
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
12.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
46
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
13.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
76
\n\t\t\t\t\t
\n\t\t\t\t
Table 9.
Inhibition of RMGPb by N-glucopyranosyl heterocycles
\n\t\t\t
large aromatic moiety (compare Entries 1 and 2 in Table 9). Interestingly, a polar appendage also led to an inhibitor of similar efficiency (Entry 3). N-Glucopyranosyl derivatives of the well known nucleobases were also tested towards GP (Gimisis, 2010): while the purine derivatives (Entries 4 and 5) proved modest inhibitors, pyrimidines in Entries 6, 8, and 10 showed binding in the low micromolar range. Modification of the glucose moiety by replacing the 3-OH of these compounds by fluorine (Entries 7, 9, and 11) weakened the inhibition by a factor of ~600 on an average. On the other hand, introduction of a hydrophobic group (compare Entries 11 and 12) was beneficial in this series, as well, resulting in an almost 100-fold stronger inhibitor. Enlarging the heterocyclic ring to a seven-membered one (Entry 13) gave a weaker inhibitor in comparison to the six-membered pyrimidine derivatives.
\n\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Entry
\n\t\t\t\t\t\t
Compound
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
Ki [μM]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
(Somsák et al., 2003)
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
1.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
R = H
\n\t\t\t\t\t\t
440
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
2.
\n\t\t\t\t\t\t
R = CH3
\n\t\t\t\t\t\t
160
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
(Somsák, 2011)
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
3.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
130
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
4.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
No inhibition
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
5.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
X = CH2
\n\t\t\t\t\t\t
52 % at 100 μM
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
6.
\n\t\t\t\t\t\t
X = NH
\n\t\t\t\t\t\t
3.5
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
7.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
No inhibition
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
8.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
X = S
\n\t\t\t\t\t\t
76
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
9.
\n\t\t\t\t\t\t
X = NH
\n\t\t\t\t\t\t
9
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
10.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
10 % at 625 μM
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
11.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
38
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
12.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
2.4
\n\t\t\t\t\t
\n\t\t\t\t
Table 10.
Inhibition of RMGPb by C-glucopyranosyl compounds
\n\t\t\t
Glucose derivatives with a substituent attached by a carbon-carbon bond (Table 10, Entries 1-4) showed weak or no inhibition. A comparison of the C-glucosyl compound in Entry 5 to the analogous N-glucosyl derivative in Entry 6 demonstrates that the more rigid amide type structure binds stronger to GP than its counterpart with the CH2-group lending more flexibility to the molecule. In a series of C-glucopyranosyl heterocycles (Entries 7-12) the size and nature of the heterorings proved very important showing stronger inhibition for the larger ones (compare Entries 7-9), and especially for the benzimidazole in Entry 9. Among oxadiazole derivatives of equal size (Entries 10-12) the constitution of the heterocycle proved decisive to give the low micromolar inhibitor of Entry 12.
\n\t\t\t
The anomeric spiro-hydantoin and -thiohydantoin (Table 11, Entries 1 and 2, respectively) belong to the first efficient compounds of early GP inhibitor design. Changing the sugar part from glucose to xylose (by removal of the CH2OH substituent, Entries 3 and 4) resulted in complete loss of inhibition. Reversal of the spiro-configuration (compare Entries 1 and 5) as well as spiro-annelation of a six-membered ring (Entry 6) gave compounds with significantly weaker binding (Somsák et al., 2003). Extension of the anomeric spirocycles by further ring-condensations as in Entries 7 and 8 produced practically inefficient structures (Gimisis, 2010). Substitution by aromatic groups in the spiro-isoxazolines (Entries 9 and 11) and spiro-oxathiazoles (Entries 10 and 12) gave good inhibitors and the naphthyl derivatives (Entries 11 and 12) are among the best known glucose derived compounds (Somsák, 2011).
\n\t\t\t
Contrary to α-glucosidases, iminosugar type compounds with 5-7 membered rings do not show significant inhibition against GP enzymes: e. g. nojirimicin has no effect, for 1-deoxy-nojirimicin Ki = 55000 μM (for the structures see Table 2) (\n\t\t\t\t\tCompain et al., 2007\n\t\t\t\t). There are a few exceptions to this such as DAB and isofagomine derivatives (Fig. 3) (Praly & Vidal, 2010; Somsák et al., 2008; Somsák et al., 2003). A comprehensive tabulation of glycogen phosphorylase inhibition studies with iminosugars can be found in (Compain et al., 2007).
\n\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Entry
\n\t\t\t\t\t\t
Compound
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
X
\n\t\t\t\t\t\t
Ki [μM]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
(Somsák et al., 2003)
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
1.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
O
\n\t\t\t\t\t\t
3.1
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
2.
\n\t\t\t\t\t\t
S
\n\t\t\t\t\t\t
5.1
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
3.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
O
\n\t\t\t\t\t\t
No inhibition
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
4.
\n\t\t\t\t\t\t
S
\n\t\t\t\t\t\t
No inhibition
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
5.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
320
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
6.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
59
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
(Gimisis, 2010)
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
7.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
~2100
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
8.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
~1700
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
(Somsák, 2011)
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
9.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
CH2
\n\t\t\t\t\t\t
19.6
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
10.
\n\t\t\t\t\t\t
S
\n\t\t\t\t\t\t
26
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
11.
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
CH2
\n\t\t\t\t\t\t
0.63
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
12.
\n\t\t\t\t\t\t
S
\n\t\t\t\t\t\t
0.16
\n\t\t\t\t\t
\n\t\t\t\t
Table 11.
Inhibition of RMGPb by anomeric spirocycles
\n\t\t\t
Figure 3.
Iminosugar type inhibitors of various GP enzymes
\n\t\t\t
Miscellaneous sugar derivatives including further O-, S-, and N-glucopyranosides, C-glucopyranosyl compounds, S-glucopyranosyl sulfonamide, homo- and heteromultivalent glucose derivatives, as well as other sugar type compounds with significantly lower efficiency as compared to the above listed ones were also reviewed (Praly & Vidal, 2010; Somsák, 2011; Somsák et al., 2008; Somsák et al., 2003).
\n\t\t\t
While no physiological investigations with glucose analogue inhibitors of GP can be found in the literature, very recently it has been demonstrated that glucopyranosylidene-spiro-thiohydantoin (Table 11, Entry 2) is effective in lowering blood glucose levels and restoring hepatic glycogen content in streptozotocin-induced diabetic rats (Docsa et al., 2011).
\n\t\t
\n\t\t
\n\t\t\t
5. Conclusion
\n\t\t\t
This survey provided an overview of carbohydrate derivatives and sugar like compounds (glycomimetics) which are employed in current therapies or investigated as potential future medications for type 2 diabetes mellitus. Although these applications and explorations do not exceed the symptomatic level of treatments characteristic of present curing, they promise the possibility of broadening the arsenal of the physician. Together with several other carbohydrate-based therapeutics these drugs and studied molecules pave the way for a more extensive use of saccharides in medicine.
This work was supported by the Hungarian Scientific Research Fund (OTKA CK 77712) and by the TÁMOP 4.2.1/B-09/1/KONV-2010-0007 project co-financed by the European Union and the European Social Fund.
\n\t\t
\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/22096.pdf",chapterXML:"https://mts.intechopen.com/source/xml/22096.xml",downloadPdfUrl:"/chapter/pdf-download/22096",previewPdfUrl:"/chapter/pdf-preview/22096",totalDownloads:2258,totalViews:208,totalCrossrefCites:2,totalDimensionsCites:8,totalAltmetricsMentions:0,impactScore:6,impactScorePercentile:96,impactScoreQuartile:4,hasAltmetrics:0,dateSubmitted:"November 26th 2010",dateReviewed:"July 11th 2011",datePrePublished:null,datePublished:"November 4th 2011",dateFinished:null,readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/22096",risUrl:"/chapter/ris/22096",book:{id:"1038",slug:"topics-in-the-prevention-treatment-and-complications-of-type-2-diabetes"},signatures:"László Somsák, Éva Bokor, Katalin Czifrák, László Juhász and Marietta Tóth",authors:[{id:"52137",title:"Prof.",name:"László",middleName:null,surname:"Somsák",fullName:"László Somsák",slug:"laszlo-somsak",email:"somsak@tigris.unideb.hu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"57041",title:"Dr.",name:"Éva",middleName:null,surname:"Bokor",fullName:"Éva Bokor",slug:"eva-bokor",email:"bokor.eva@science.unideb.hu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"57042",title:"Dr.",name:"Katalin",middleName:null,surname:"Czifrak",fullName:"Katalin Czifrak",slug:"katalin-czifrak",email:"czifrak.katalin@science.unideb.hu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Debrecen",institutionURL:null,country:{name:"Hungary"}}},{id:"57043",title:"Dr.",name:"László",middleName:null,surname:"Juhász",fullName:"László Juhász",slug:"laszlo-juhasz",email:"juhasz.laszlo@science.unideb.hu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"57044",title:"Dr.",name:"Marietta",middleName:null,surname:"Tóth",fullName:"Marietta Tóth",slug:"marietta-toth",email:"toth.marietta@science.unideb.hu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Inhibitors of α-glucosidase enzymes",level:"1"},{id:"sec_3",title:"3. Inhibitors of renal sodium-glucose cotransporters",level:"1"},{id:"sec_4",title:"4. Glucose analogue inhibitors of glycogen phosphorylase",level:"1"},{id:"sec_5",title:"5. Conclusion",level:"1"},{id:"sec_6",title:"6. Abbreviations",level:"1"},{id:"sec_7",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAgius\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010 Physiological control of liver glycogen metabolism: Lessons from novel glycogen phosphorylase inhibitors. 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D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCharavgi\n\t\t\t\t\t\t\tM. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKostas\n\t\t\t\t\t\t\tI. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZographos\n\t\t\t\t\t\t\tS. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOikonomakos\n\t\t\t\t\t\t\tN. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLeonidas\n\t\t\t\t\t\t\tD. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010 The binding of β-D-glucopyranosyl-thiosemicarbazone derivatives to glycogen phosphorylase: A new class of inhibitors. 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G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKurtz\n\t\t\t\t\t\t\tT. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPershadsingh\n\t\t\t\t\t\t\tH. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAvery\n\t\t\t\t\t\t\tM. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008 Type 2 diabetes and oral antihyperglycemic drugs. Current Medicinal Chemistry,\n\t\t\t\t\t15\n\t\t\t\t\t61\n\t\t\t\t\t74 .\n\t\t\t'},{id:"B51",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMohan\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPinto\n\t\t\t\t\t\t\tB. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007 Zwitterionic glycosidase inhibitors: salacinol and related analogues. Carbohydrate Research,\n\t\t\t\t\t342\n\t\t\t\t\t1551\n\t\t\t\t\t1580 .\n\t\t\t'},{id:"B52",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMoller\n\t\t\t\t\t\t\tD. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001 New drug targets for type 2 diabetes and the metabolic syndrome. Nature, 414\n\t\t\t\t\t821\n\t\t\t\t\t827 .\n\t\t\t'},{id:"B53",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMorral\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003 Novel targets and therapeutic strategies for type 2 diabetes. Trends in Endocrinology and Metabolism,\n\t\t\t\t\t14\n\t\t\t\t\t169\n\t\t\t\t\t175 .\n\t\t\t'},{id:"B54",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMuraoka\n\t\t\t\t\t\t\tO.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMorikawa\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMiyake\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAkaki\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNinomiya\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPongpiriyadacha\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYoshikawa\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011 Quantitative analysis of neosalacinol and neokotalanol, another two potent alpha-glucosidase inhibitors from Salacia species, by LC-MS with ion pair chromatography. Journal of Natural Medicines,\n\t\t\t\t\t65\n\t\t\t\t\t142\n\t\t\t\t\t148 .\n\t\t\t'},{id:"B55",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNomura\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010 Renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for new anti-diabetic agent. Current Topics in Medicinal Chemistry,\n\t\t\t\t\t10\n\t\t\t\t\t411\n\t\t\t\t\t418 .\n\t\t\t'},{id:"B56",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNomura\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSakamaki\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHongu\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKawanishi\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKoga\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSakamoto\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYamamoto\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tUeta\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKimata\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNakayama\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTsuda-Tsukimoto\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010 Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus. Journal of Medicinal Chemistry,\n\t\t\t\t\t53\n\t\t\t\t\t6355\n\t\t\t\t\t6360 .\n\t\t\t'},{id:"B57",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNourparvar\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBulotta\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDi Mario\n\t\t\t\t\t\t\tU.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPerfetti\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004 Novel strategies for the pharmacological management of type 2 diabetes. Trends in Pharmacological Sciences,\n\t\t\t\t\t25\n\t\t\t\t\t86\n\t\t\t\t\t91 .\n\t\t\t'},{id:"B58",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOikonomakos\n\t\t\t\t\t\t\tN. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002 Glycogen phosphorylase as a molecular target for type 2 diabetes therapy. Current Protein & Peptide Science,\n\t\t\t\t\t3\n\t\t\t\t\t561\n\t\t\t\t\t586 .\n\t\t\t'},{id:"B59",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOikonomakos\n\t\t\t\t\t\t\tN. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKosmopolou\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZographos\n\t\t\t\t\t\t\tS. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLeonidas\n\t\t\t\t\t\t\tD. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSomsák\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNagy\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPraly\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDocsa\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTóth\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGergely\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002 Binding of N-acetyl-N’-β-D-glucopyranosyl urea and N-benzoyl-N’-β-D-glucopyranosyl urea to glycogen phosphorylase b: Kinetic and crystallographic studies. European Journal of Biochemistry,\n\t\t\t\t\t269\n\t\t\t\t\t1684\n\t\t\t\t\t1696 .\n\t\t\t'},{id:"B60",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOikonomakos\n\t\t\t\t\t\t\tN. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSomsák\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008 Recent advances in glycogen phosphorylase inhibitor design. Current Opinion in Investigational Drugs,\n\t\t\t\t\t9\n\t\t\t\t\t379\n\t\t\t\t\t395 .\n\t\t\t'},{id:"B61",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPadwal\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMajumdar\n\t\t\t\t\t\t\tS. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJohnson\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVarney\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Alister\n\t\t\t\t\t\t\tF. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005 A systematic delay or pre review of drug therapy to delay or prevent type 2 diabetes. Diabetes Care,\n\t\t\t\t\t28\n\t\t\t\t\t736\n\t\t\t\t\t744 .\n\t\t\t'},{id:"B62",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPanunti\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJawa\n\t\t\t\t\t\t\tA. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFonseca\n\t\t\t\t\t\t\tV. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004 Mechanisms and therapeutic targets in type 2 diabetes mellitus. Drug Discovery Today: Disease Mechanisms,\n\t\t\t\t\t1\n\t\t\t\t\t151\n\t\t\t\t\t157 .\n\t\t\t'},{id:"B63",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPraly\n\t\t\t\t\t\t\tJ. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVidal\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010 Inhibition of glycogen phosphorylase in the context of type 2 diabetes, with focus on recent inhibitors bound at the active site. Mini-Reviews in Medicinal Chemistry,\n\t\t\t\t\t10\n\t\t\t\t\t1102\n\t\t\t\t\t1126 .\n\t\t\t'},{id:"B64",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRendell\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004 The role of sulphonylureas in the management of type 2 diabetes mellitus. Drugs,\n\t\t\t\t\t64\n\t\t\t\t\t1339\n\t\t\t\t\t1358 .\n\t\t\t'},{id:"B65",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRobinson\n\t\t\t\t\t\t\tR. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMascitti\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBoustany-Kari\n\t\t\t\t\t\t\tC. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCarr\n\t\t\t\t\t\t\tC. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFoley\n\t\t\t\t\t\t\tP. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKimoto\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLeininger\n\t\t\t\t\t\t\tM. 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H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFlynn\n\t\t\t\t\t\t\tD. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKnight\n\t\t\t\t\t\t\tD. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004 Cardioprotective effects of ingliforib, a novel glycogen phosphorylase inhibitor. American Journal of Physiology-Heart and Circulatory Physiology,\n\t\t\t\t\t286\n\t\t\t\t\tH1177\n\t\t\t\t\tH1184 .\n\t\t\t'},{id:"B81",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTreadway\n\t\t\t\t\t\t\tJ. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMendys\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHoover\n\t\t\t\t\t\t\tD. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001 Glycogen phosphorylase inhibitors for treatment of type 2 diabetes mellitus. Expert Opinion on Investigational Drugs,\n\t\t\t\t\t10\n\t\t\t\t\t439\n\t\t\t\t\t454 .\n\t\t\t'},{id:"B82",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTundis\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLoizzo\n\t\t\t\t\t\t\tM. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMenichini\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010 Natural products as α-amylase and α-glycosidase inhibitors and their hypoglycaemic potential in the treatment of diabetes: An update. Mini-Reviews in Medicinal Chemistry, 2010, 10, 315,\n\t\t\t\t\t10\n\t\t\t\t\t315\n\t\t\t\t\t331 .\n\t\t\t'},{id:"B83",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tUwaifo\n\t\t\t\t\t\t\tG. I.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRatner\n\t\t\t\t\t\t\tR. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005 Novel pharmacologic agents for type 2 diabetes. Endocrinology and Metabolism Clinics of North America,\n\t\t\t\t\t34\n\t\t\t\t\t155\n\t\t\t\t\t197 .\n\t\t\t'},{id:"B84",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVaidya\n\t\t\t\t\t\t\tH. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGoyal\n\t\t\t\t\t\t\tR. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010 Exploring newer target sodium glucose transporter 2 for the treatment of diabetes mellitus. Mini-Reviews in Medicinal Chemistry,\n\t\t\t\t\t10\n\t\t\t\t\t905\n\t\t\t\t\t913 .\n\t\t\t'},{id:"B85",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWagman\n\t\t\t\t\t\t\tA. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJohnson\n\t\t\t\t\t\t\tK. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBussiere\n\t\t\t\t\t\t\tD. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004 Discovery and development of GSK3 inhibitors for the treatment of type 2 diabetes. Current Pharmaceutical Design,\n\t\t\t\t\t10\n\t\t\t\t\t1105\n\t\t\t\t\t1137 .\n\t\t\t'},{id:"B86",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWagman\n\t\t\t\t\t\t\tA. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNuss\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001 Current therapies and emerging targets for the treatment of diabetes. Current Pharmaceutical Design,\n\t\t\t\t\t7\n\t\t\t\t\t417\n\t\t\t\t\t450 .\n\t\t\t'},{id:"B87",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWashburn\n\t\t\t\t\t\t\tW. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009a\n\t\t\t\t\tDevelopment of the renal glucose reabsorption inhibitors: A new mechanism for the pharmacotherapy of diabetes mellitus type 2. Journal of Medicinal Chemistry, 52\n\t\t\t\t\t1785\n\t\t\t\t\t1794 .\n\t\t\t'},{id:"B88",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWashburn\n\t\t\t\t\t\t\tW. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009b Evolution of sodium glucose co-transporter 2 inhibitors as anti-diabetic agents. Expert Opinion on Therapeutic Patents,\n\t\t\t\t\t19\n\t\t\t\t\t1485\n\t\t\t\t\t1499 .\n\t\t\t'},{id:"B89",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWright\n\t\t\t\t\t\t\tE. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001 Renal Na+-glucose cotransporters. American Journal of Physiology-Renal Physiology,\n\t\t\t\t\t280\n\t\t\t\t\tF10\n\t\t\t\t\tF18 .\n\t\t\t'},{id:"B90",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXie\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTanabe\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAkaki\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMorikawa\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNinomiya\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMinematsu\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYoshikawa\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWu\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMuraoka\n\t\t\t\t\t\t\tO.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011 Isolation, structure identification and SAR studies on thiosugar sulfonium salts, neosalaprinol and neoponkoranol, as potent [alpha]-glucosidase inhibitors. Bioorganic & Medicinal Chemistry,\n\t\t\t\t\t19\n\t\t\t\t\t2015\n\t\t\t\t\t2022 .\n\t\t\t'},{id:"B91",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXu\n\t\t\t\t\t\t\tB. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFeng\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLv\n\t\t\t\t\t\t\tB. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXu\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tL. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDu\n\t\t\t\t\t\t\tJ. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPeng\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXub\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDong\n\t\t\t\t\t\t\tJ. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tW. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhu\n\t\t\t\t\t\t\tL. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDing\n\t\t\t\t\t\t\tH. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSheng\n\t\t\t\t\t\t\tZ. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWelihinda\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSeed\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tY. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010 ortho-Substituted C-aryl glucosides as highly potent and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors. Bioorganic & Medicinal Chemistry,\n\t\t\t\t\t18\n\t\t\t\t\t4422\n\t\t\t\t\t4432 .\n\t\t\t'},{id:"B92",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZechel\n\t\t\t\t\t\t\tD. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWithers\n\t\t\t\t\t\t\tS. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2000 Glycosidase mechanisms: Anatomy of a finely tuned catalyst. Accounts of Chemical Research,\n\t\t\t\t\t33\n\t\t\t\t\t11\n\t\t\t\t\t18 .\n\t\t\t'},{id:"B93",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhou\n\t\t\t\t\t\t\tH. Q.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDanger\n\t\t\t\t\t\t\tD. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDock\n\t\t\t\t\t\t\tS. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHawley\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRoller\n\t\t\t\t\t\t\tS. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSmith\n\t\t\t\t\t\t\tC. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHandlon\n\t\t\t\t\t\t\tA. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010 Synthesis and SAR of benzisothiazole- and indolizine-β-D-glucopyranoside inhibitors of SGLT2. ACS Medicinal Chemistry Letters,\n\t\t\t\t\t1\n\t\t\t\t\t19\n\t\t\t\t\t23 .\n\t\t\t'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"László Somsák",address:"",affiliation:'
Department of Organic Chemistry, University of Debrecen, Hungary
Department of Organic Chemistry, University of Debrecen, Hungary
'}],corrections:null},book:{id:"1038",type:"book",title:"Topics in the Prevention, Treatment and Complications of Type 2 Diabetes",subtitle:null,fullTitle:"Topics in the Prevention, Treatment and Complications of Type 2 Diabetes",slug:"topics-in-the-prevention-treatment-and-complications-of-type-2-diabetes",publishedDate:"November 4th 2011",bookSignature:"Mark B. 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1. Introduction
Environmental pollution that occurred as a consequence of industrial development, population growth, and urbanization is one of the extremely important problems of our day. Seventeen percent of water sources, 25% of forestry products, and 40% of energy sources are consumed by the construction sector [1, 2, 3]. For this reason, sustainable building design concept has emerged in the construction sector in recent years. The aim of sustainable building design is to create a built environment that does not disrupt the ecological balance, minimizes the harmful impacts of buildings on the environment, uses resources economically, and provides the necessary conditions for human comfort and health [4]. In this context, sustainable building design can be examined under environmental, economic, and social aspects. The effective use of the site, water, energy, and materials should be taken into consideration during the building design process within the scope of environmentally sustainable building design. Economic constraints in the construction sector have to be determined by using resources effectively and performing cost-effective analyses in the context of economically sustainable building design. Besides, health and well-being of users ought to be enhanced, and public awareness should be provided in the sense of socially sustainable building design.
In accordance with the abovementioned issues, a holistic conceptual scheme is suggested by considering aspects, strategies, criteria, and procedures in this study. According to the suggested scheme, strategies of environmentally sustainable building design aspect are classified as site efficiency, water efficiency, energy efficiency, and material efficiency; strategies of economically sustainable building design aspect are classified as resource efficiency and cost efficiency, and strategies of socially sustainable building design are classified as health and well-being and public awareness. Furthermore, related criteria for each strategy and related procedures for each criterion are determined. By this means, it is intended to create awareness among the actors of the construction sector and the researchers in terms of sustainable building design in this study. Within the scope of this intention, the aim of this study is to present a guiding scheme by considering aspects, strategies, criteria, and procedures of creating an environmental, economic, and social awareness at the local and the global level.
2. Aspects of sustainable building design
Costs of energy and natural resources used by the buildings in the construction, usage, and demolition processes are remarkably high [5]. For a more habitable and economic future, sustainable building design procedures have been developed in the world which use land efficiently, use energy effectively, experience projects to reduce water consumption, and give importance to the material efficiency and indoor air quality considering the waste problem and environmental problems [6]. Sustainable building design offers minimum operational cost for the buildings by minimizing the energy consumption, resource usage, and environmental impacts of the buildings [7]. In this context, buildings are evaluated within the framework of international building certification systems that contribute to minimizing the environmental impacts of the buildings and lead the way to the designers, and they are certificated according to sustainability classifications. The most widely accepted and commonly used building certification systems in the world can be stated as Building Research Establishment Environmental Assessment Method (BREEAM) and Leadership in Energy and Environmental Design (LEED).
BREEAM is the first sustainability assessment method for master planning projects, infrastructure, and buildings. It addresses a number of lifecycle stages such as new construction, refurbishment, and in use. BREEAM guides designers, researchers, and related actors to excel, innovate, and make effective use of resources. According to the BREEAM system developed by the Building Research Establishment (BRE), buildings become entitled to obtain pass, good, very good, excellent, and outstanding certificates. Globally in 76 countries, there are 562,455 BREEAM certified developments and almost 2,266,120 buildings registered for assessment as of November 2017, since it was first launched in 1990 [8].
LEED is a system, which identifies buildings as healthier, more environmentalist, and more economical than traditional buildings, for certifying high-performance buildings and sustainable neighborhoods [9]. LEED provides a framework to create healthy, highly efficient, and cost-saving green buildings available for all building types. LEED reveals sustainable design, construction, and operating criteria in building and urban scale. According to the LEED system developed by the US Green Building Council (USGBC), buildings become entitled to obtain platinum, gold, silver, and certificated certificates. Globally in more than 165 countries and territories, more than 2.2 million square feet built-up area is LEED certified, with more than 90,000 projects using LEED as of November 2017, since it was first launched in 1998 [10].
It is often observed that only the environmental aspect of sustainability is directly taken into account when green building certification systems are examined. However, in the design of sustainable buildings, the economic aspect that produces a long-term positive economic impact and the social aspect that improves the lives of those with whom the buildings interact need to be absolutely included in the design [9]. In this study, aspects, strategies, criteria, and procedures of sustainable building design are classified considering the conceptual frameworks of different scientific studies [4, 6, 11, 12, 13, 14, 15, 16, 17] and the LEED [10] and BREEAM [8] evaluation criteria. This classification is presented in Table 1.
Sustainable building design aspects can be achieved by certain criteria and procedures in design, construction, usage, and demolition processes of buildings by meeting the strategies of site efficiency, water efficiency, energy efficiency, and material efficiency in terms of environmentally sustainable building design; the strategies of resource efficiency and cost efficiency in terms of economically sustainable building design; and the strategies of health and well-being and public awareness in terms of socially sustainable building design.
2.1. Environmental aspect of sustainable building design
Environmental sustainability means leaving the world’s future generation something better than what has been left to, protecting environmental balance and natural systems from destruction [18]. Nowadays, as environmental problems become more and more significant, there has been an inclination for an environmentally sustainable building design to reduce these problems. In order to ensure that the buildings have environmentally sustainable characteristics, procedures are adjusted based on the strategies of site, water, energy, and material efficiency. Demand for the site, water, energy, and material increases the impact of construction sector on the environment. The local and global environments are affected by interrelated user activities and natural processes throughout the existence of buildings, and buildings impose a long lasting impact on the environment [19, 20]. In this context, the construction sector is responsible for producing sustainable environments via designing sustainable buildings. Sustainable building design includes the building materials that are sensitive to the environment; that are reusable and renewable; that minimize energy consumption; that use renewable and local sources by reducing the use of natural resources; that create healthy indoor areas; that use solar power, natural ventilation, and daylighting; and that do not require frequent maintenance and repair [21]. The emphasis for buildings should be placed on effective usage of the site, water, energy, and material within the context of environmentally sustainable building design. In this context, environmentally sustainable building design strategies can be classified as site efficiency, water efficiency, energy efficiency, and material efficiency.
2.1.1. Criteria and procedures for strategy of site efficiency
Land, which is one of the limited sources, has been decreasing due to urban expansion. For this reason, it is essential that lands must be used efficiently. The strategy of site efficiency consists of sustainable land use, habitat protection, and improvement of long-term biodiversity for the building site and surrounding land. It addresses the environment surrounding the building and emphasizes the relationships among buildings and ecosystems. In this context, the criteria for the strategy of site efficiency are classified as protection of natural habitats, protection of natural topography, protection of fertile lands, improvement of urban areas, improvement of transportation systems, and mitigation of heat island effect in this study. Additionally, related procedures for each criterion are determined and presented in Table 2.
A holistic conceptual scheme for sustainable building design.
Strategy of site efficiency
Criteria
Procedures
Protection of natural habitats
Preservation of existing natural resources Preservation of existing flora and fauna Disposal of wastes without harming the habitat
Protection of natural topography
Construction of the building in compliance with topography Preservation of water table Disposal of wastes without harming the topography
Protection of fertile lands
Prevention of misuse of agricultural lands Reduction of erosion and industrial pollutants Disuse of toxic pesticides Improvement of agricultural lands lost due to misuse Prevention of agricultural lands from being made available as settlement Carrying off fertile lands of the construction site to green areas Disposal of wastes without causing land pollution
Improvement of urban areas
Selection of location according to urban density Increase in green areas Promotion of mixed-use urban development Effective use of construction sites Redevelopment of brownfields Reclamation of abandoned mine lands Rehabilitation of existing settlements and buildings
Improvement of transportation systems
Development of pedestrian/bicycle transportation systems Extension of public transport network Integration of building design with public transportation Development of public transportation from regional parking lots to city centers Improvement of rail transport systems in urban areas Provision of human-powered public transportation More common use of clean fuels in transportation More common use of vehicles with less fuel consumption More common use of smart traffic practices and systems Rise of efficiency standards in vehicles Creation of pedestrian ways, pockets, and lanes Creation of parking systems and local parking lots
Mitigation of heat island effect
Preservation of existing tree cover Increase of forest areas Selection of right vegetation for right places around buildings Integration of green areas in building design Application of green wall systems Application of green roof systems
Table 2.
Criteria and procedures for strategy of site efficiency.
Protection of natural habitats: Soil erosion, groundwater contamination, acid rain, and other industrial pollutants are damaging the health of plant communities, thereby intensifying the challenge and necessity to restore habitats [16]. For this reason, in sustainable building design, solutions should be produced to preserve the existing natural resources, flora, and fauna, and measures must be taken to ensure that the wastes are disposed of without harming the natural habitat. It ought to be attempted to improve natural habitats through appropriate planting and water use and avoidance of chemicals as much as possible in the design of sustainable buildings. Local wildlife and vegetation should be recognized as part of the building site [19]. Furthermore, wetlands and other wildlife habitats may require protection and limit the buildable area of a site [22].
Protection of natural topography: Topography refers to the configuration of surface features of a plot of land, which influences where and how to build and develop a site. A building has to be constructed in compliance with topography, with minimum disturbance of existing land forms and natural drainage patterns while taking advantage of natural ground slopes and the microclimate of the site. In addition, the amount of cut and fill area required for construction of a foundation and site development should be equalized [22]. The existing contours of a site ought to be respected. Alteration of contours affects how wind moves through a site and how water drains [20]. The drainage of surface water and ground water must be taken into account when modifying land forms, and water table has to be preserved [22]. A building design should not need excavation below the water table and should not be constructed into the water table [19]. Moreover, it is essential that the wastes are being disposed of without harming the natural topography.
Protection of fertile lands: Fertile lands are the basis for agricultural production, and protection of fertile lands is an extremely important matter for the economy of all countries [23]. Twenty-five percent of fertile lands have been lost or degraded in the last 50 years. Fertile lands are limited because of soil, wind and water erosion, raw material extraction, groundwater contamination, water logging, acid rain, soil nutrient mining, industrial pollutants, and toxic pesticides [24]. It is a well-known fact that it takes a long time for the infertile lands to self-reclaim, and the costs of land reclamation are so high. For this reason, some solutions should be produced to prevent misuse of agricultural lands, and some precautions must be taken to improve agricultural land lost due to misuse [25]. Lands are important not only for the agricultural sector but also for the construction sector in building scale and urban scale. In urban areas, agricultural lands should be prevented from becoming available as settlements. However, if needed, fertile lands of the construction site ought to be carried to other green areas. Additionally, the wastes from the structure and infrastructure need to be removed from the land without causing pollution.
Improvement of urban areas: The spatial growth affects urban areas in terms of increased traffic, pollution, and energy consumption. Appropriate planning of urban areas can help to reduce urban sprawl, soil sealing, and biodiversity loss [26]. The scope of the planning is to locate the settlements and green areas according to urban density. These measures have to also promote mixed-use development (the mixing of residential, commercial, office, and retail spaces) that will reduce transport demand and in turn reduce pollution [27]. Moreover, appropriate planning decisions for construction sites can minimize invasion of heavy equipment and the accompanying ecosystem damage. Excavations in the construction site should not alter the flow of groundwater, and vegetation should only be removed when absolutely necessary for access [20]. It is also essential that lower environmental quality, idle or underutilized areas such as brownfields and abandoned mine lands, and empty buildings ought to be improved. Redevelopment and reclamation of these lands can provide a range of environmental, economic, and social benefits [28]. Furthermore, lands can be conserved by adopting a policy of zero expansion of existing urban areas. This could be achieved by adaptive the reuse of existing settlements and buildings, thereby eliminating the need for new construction [16].
Improvement of transportation systems: As the natural and economic resources are limited, sustainable development of the transportation systems in urban areas is extremely important in order to maintain future quality of life [29]. Transportation systems are an indispensable element of sustainable development due to the environmental, economic, and social impacts. Establishing a sustainable transportation system requires a comprehensive and integrated approach to policymaking and decision-making, with the aim of developing affordable, accessible, economically viable, low carbon, comfortable, people-oriented, and environment-friendly systems [30]. For all these elements to be achieved, it is necessary to integrate the procedures such as improving and expanding pedestrian and bicycle transportation systems, extending public transport network, integrating building design with public transportation, better connection with public transportation to city centers from regional parking lots, improving the attraction of public transportation [31], and enhancing rail transportation systems in urban areas. Besides these, human-powered public transportation systems, less fuel-consuming vehicles, clean fuels in transportation, smart traffic practices, and systems ought to be more widely used to reduce urban air pollution, to tackle climate change, and to contribute limiting the use of private cars. Efficiency standards for environmental performance of vehicles and comfort of users should be also improved [32], and technological solutions have to be developed aiming to reduce the negative impact per car and per kilometer [33]. Moreover, pedestrian zones and parking systems should be developed, and local parking lots ought to be increased in order to encourage nonmotorized modes, to limit the number of vehicles in the city centers, and to reduce the traffic congestion.
Reduction of heat island effect: Heat island is the most documented phenomenon of climate change [34]. A building’s roof, façade, and site area influence the heat gain and retention of a building’s surroundings [35] and can cause heat island effect. As a result of heat island effect, high temperatures occur in urban areas. High temperatures affect health, economy, leisure activities, and well-being of users and may also enhance air pollution, for example, by increasing surface ozone concentration with several negative impacts on human health [36]. In order to reduce heat island effect, existing tree cover should be preserved, and forest areas should be increased principally. Additionally, trees and plants help to cool the environment, making vegetation an effective way to reduce heat island effect. Planting right vegetation for right places around buildings can contribute to lower surface and air temperatures by providing shade and evapotranspiration [37]. Deciduous trees planted in the south of a building ensure solar heat gain in winter and shade in summer. Coniferous trees planted on the north protect the building from wind in winter and provide shade in summer. Integration of green areas in building design may, therefore, be essential for adaptation to and mitigation of thermal impacts of both local and global warming processes [36]. Another essential procedure for mitigation of heat island effect is greening roofs and walls combining nature and buildings. These systems can lower the surface temperatures of roofs and walls and thus can decrease the corresponding sensible heat flux to the atmosphere [34]. Greening walls with vegetation to intercept the radiation can reduce the warming up of walls, especially in dense urban areas. In the urban areas, the impact of evapotranspiration and shading of plants can significantly reduce the amount of heat that would be reradiated by walls [38].
2.1.2. Criteria and procedures for strategy of water efficiency
Water is probably the most important matter in the environment and humankind’s life cycle. Protecting clean water resources has a vital importance [39]. The strategy of water efficiency consists of indoor use, outdoor use, specialized uses, and metering in the building site and surrounding land. It addresses all sources of water related to building and surroundings, including appliances, fixtures, fittings, process water, and irrigation. In this context, the criteria for the strategy of water efficiency are classified as the reduction of water consumption, reuse of waste water, and unpolluted use of water resources in this study. Additionally, related procedures for each criterion are determined and presented in Table 3.
Strategy of water efficiency
Criteria
Procedures
Reduction of water consumption
Use of waterless toilets and urinals Use of bio composting toilets Use of small volume cisterns Use of water-saving flushes Use of low-flow fixtures Use of timers and automatic control devices Use of indigenous landscaping Use of vegetation with less water need Use of low-maintenance vegetation
Reuse of waste water
Treatment and reuse of graywater Treatment and reuse of rainwater
Unpolluted use of water resources
Renovation of sewage systems to prevent contamination of water resources Control of polluting elements in sewage and storage areas Disposal of wastes without causing pollution in water resources Reduction of toxic pesticides Management of water resources systems
Table 3.
Criteria and procedures for strategy of water efficiency.
Reduction of water consumption: Efficient water use is an environmental priority in all countries. Special attention must, therefore, be given to the reduction of water consumption in building design [40]. For this reason, losses through water installations and leakages ought to be minimized. Water-efficient devices such as waterless toilets and urinals, bio composting toilets, small volume cisterns, water-saving flushes, low-flow fixtures, timers, and automatic control devices should be utilized for indoor use. It should be noted that the use of these devices also contributes to the reduction of energy consumption, cost, and waste water. Apart from these, indigenous landscaping for outdoor building design has to be encouraged, which, once established, virtually eliminates the need for watering [41]. In the meanwhile, vegetation with less water and maintenance need to be planted for outdoor use.
Reuse of waste water: As the water resources are limited, providing water efficiency in the building and surroundings is vitally important. The efficient use of water may reduce input and output water resources. This is because the water that is supplied to a building and the water that leaves the building as waste water should be treated. Therefore, a reduction in water use produces a reduction in waste water [42]. Waste water in buildings can be classified as graywater and black water. Graywater means the low polluted wastewater from bathtubs, showers, hand-washing basins, and washing machines excluding wastewater from the kitchen and the toilet flushing system [43]. Graywater might be treated by installing graywater treatment systems in order to flush toilets and to irrigate vegetation except for edible plants. In addition, the reuse of graywater promotes a significant reduction in potable water consumption and sewage production [44]. Blackwater is any waste from toilets or urinals containing disease-causing bacteria and viruses that can result in human illness and must be discharged to the municipal sewage system. Rainwater might be seen as a resource that provides many environmental and economic benefits. Rainwater ought to be treated by installing rainwater treatment systems in order to restore natural hydrologic conditions, to reduce the possibility of flooding, and to irrigate vegetation [35].
Unpolluted use of water resources: As the world’s population grows, ensuring reliable access to clean water is becoming increasingly difficult [45]. It is therefore that water resources must not be contaminated. In order to prevent contamination of water resources, existing sewage systems should be rehabilitated, and polluting elements in sewage and storage areas ought to be monitored. In the meantime, wastes have to be disposed without causing pollution, and measures must be taken to reduce toxic pesticides in water resources. In addition to all these, proper planning and managing have to be performed to increase benefits from the existing water resources.
2.1.3. Criteria and procedures for strategy of energy efficiency
Energy requirement increases approximately 5% every year mainly due to industrialization, rapidly growing population, and improvement in the living standards [3]. Ever-increasing consumption of fossil fuel reserves providing the major portion of the energy needs, directly or indirectly, gives rise to the ozone layer depletion, air pollution, and climatic change. In this respect, efficient utilization of energy has become more crucial than ever in construction sector [39, 46]. Strategy of energy efficiency consists of utilization of renewable energy resources for natural heating, ventilating, air conditioning, and illumination. It addresses the use of the passive and active systems in the building and surroundings. In this context, the criteria for the strategy of energy efficiency are classified as the use of passive heating, ventilating, and air conditioning; the use of active heating, ventilating, and air conditioning; and utilization of daylight. Additionally, related procedures for each criterion are determined and presented in Table 4.
Strategy of energy efficiency
Criteria
Procedures
Use of passive heating, ventilating, and air conditioning
Use of Trombe walls for natural heating and air conditioning Use of metal walls for natural heating and air conditioning Use of double-skin façades for natural heating and air conditioning Use of greenhouses for natural heating and air conditioning Use of Venturi chimneys for natural ventilating Use of wind scoops for natural ventilating Use of atriums for natural heating and air conditioning Use of building shading devices for natural air conditioning Use of labyrinth systems for natural heating, ventilating, and air conditioning Use of wind energy by cross ventilation method for natural ventilating Use of effective insulation systems Selection of appropriate distance to other buildings compatible with local climatic conditions Selection of appropriate position for building compatible with local climatic conditions Selection of appropriate building form compatible with local climatic conditions Use of appropriate colors on façades compatible with local climatic conditions Determination of building envelope surface compatible with local climatic conditions Selection of appropriate location for building Selection of right vegetation for right direction around buildings Preservation of existing green areas
Use of active heating, ventilating, and air conditioning
Use of photovoltaic panels for power generation Use of solar collectors for water heating Use of wind turbines for power generation Use of water source heat pumps for power generation and water heating Use of geothermal heat pumps for power generation and water heating Use of energy efficient appliances and equipment with timing devices
Utilization of daylighting
Use of light shelves Use of solar tubes Use of heliostats Use of anidolic ceilings
Table 4.
Criteria and procedures for strategy of energy efficiency.
The use of passive heating, ventilating, and air conditioning: Parts of the major energy consumption in buildings are the heating, ventilating, and air conditioning (HVAC) systems. These systems can be accepted as indoor climate controls that regulate humidity and temperature. With the total amount of HVAC’s energy consumption in buildings, they are closely related to the local climatic condition, whether it is necessary to heat the space or cool it. Heating systems are to collect and to store the solar heat and to retain the heat within the building. On the contrary, cooling systems are to provide cold or to protect the building from direct solar radiation and to improve air ventilation. Space heating is the most important building energy user in cold countries, whereas air conditioning is a major contributor to peak electricity demand in hot climate countries or during summer [47]. In this regard, Trombe walls, metal walls, double-skin façades, greenhouses, Venturi chimneys, wind scoops, atriums, building shading devices, cross ventilation, and labyrinth systems ought to be used as passive systems. Aside from these, the use of high-performance windows and wall, ground, ceiling, and roof insulation prevents heat gain or loss and thus reduces energy consumption. In accordance with local climatic conditions, procedures of appropriate building distance, position, form, façade color, location, and building envelope surface must be taken into account in passive building design. Vegetation is also a procedure that affects the building design in terms of heat gain and loss. In this sense, deciduous trees ought to be planted on the south of a building and coniferous trees on the north (see Section 2.1.1), and existing green areas should certainly be preserved.
The use of active heating, ventilating, and air conditioning: The main goal for energy conservation is to reduce the consumption of fossil fuels as well as increasing the use of renewable energy resources such as solar, wind, water, and geothermal [16]. This could be achieved by utilizing active heating, ventilating, and air conditioning systems in buildings, which is essential in terms of energy efficiency. In order to maximize energy efficiency, active systems should be integrated with passive systems in building design. Active heating, ventilating, and air conditioning systems, which enable the efficient use of renewable energy sources in buildings, contain mechanic and electronic appliances and equipment. Photovoltaic panels, solar collectors, wind turbines, water source heat pumps, geothermal heat pumps, energy efficient appliances, and equipment with timing devices should be integrated to building design in the scope of active systems. The installation cost of active systems is considered as an additional initial cost of the building. However, these systems ensure a significant decrease in operating costs.
Utilization of daylighting: Typically, one third of the energy used in many buildings is consumed by electric lighting. Therefore, in recent years daylighting has become a major topic in energy efficient building design next to passive solar heating and cooling [48]. Good daylighting design can reduce electricity consumption for lighting; improve standards of visual comfort, health, and amenity for the users [49]; and provide a better indoor light environment than artificial lighting. Artificial lighting not only consumes a large amount of electricity but also dissipates waste heat into indoor space, which causes the increase of cooling loads. If the effective use of daylighting is integrated in building design, the cooling and lighting energy can decrease [48]. Daylighting can be achieved by bringing natural light into buildings with some systems such as light shelves, solar tubes, heliostats, and anidolic ceilings.
2.1.4. Criteria and procedures for strategy of material efficiency
Materials are the fundamental components of a building. Construction sector consumes approximately 3 billion tons of raw materials which comes up to 40% of total usage per year globally [46]. The production and consumption of building materials has diverse impacts on the local and global environments. Extracting, processing, manufacturing, transporting, and recycling building materials cause environmental impacts to some extent [50]. The strategy of material efficiency consists of reducing these impacts through the entire life cycle of building materials from extraction to the end of life, as well as reducing the construction wastes and sizing the building properly. It focuses on procurement of materials that are sourced in a responsible way and have a low embodied impact over their life cycle [8]. In this context, the criteria for the strategy of material efficiency are classified as reduction of environmental impact, reduction of waste, and proper sizing of building and systems in this study. Additionally, related procedures for each criterion are determined and presented in Table 5.
Strategy of material efficiency
Criteria
Procedures
Reduction of environmental impacts
Use of local building materials Use of natural building materials Use of high-performance building materials Use of long-lasting building materials Use of durable building materials Use of nontoxic and noncarcinogenic building materials Use of antibacterial building materials Use of low embodied energy building materials Use of low volatile organic compound (VOC) building materials Use of building materials made from renewable sources Use of building materials with less maintenance need Use of building materials extracted without ecological damage Use of certified wood materials Use of environmental and health product declarations
Reduction of wastes
Use of reusable building materials Use of recyclable building materials Use of reclaimed building materials Use of recycled building materials Use of nonconventional products as building materials Rehabilitation and reuse of existing structures Rehabilitation and reuse of existing infrastructures Sorting, storage, and disposal of wastes by waste management
Proper sizing of building and systems
Design of sufficient-sized interior spaces Reduction of building envelope surface Use of simple geometrical forms for building design Utilization of flexible and modular building design Utilization of standard building material sizes
Table 5.
Criteria and procedures for strategy of material efficiency.
Reduction of environmental impacts: Buildings maintain their relationship with the environment throughout their life cycles on local or global scales and cause a number of environmental impacts [51]. In this context, the sustainable construction sector is responsible for designing buildings which do not disturb the balances of ecosystems, which secure human health, welfare, and comfort; which ensure economic use of materials; which encourages conservation of nonrenewable energy resources; which saves transportation energy; and thus which contributes to minimizing environmental impacts. It is essential to use local, natural, high-performance, long-lasting, durable, nontoxic, noncarcinogenic, antibacterial, low embodied energy, and low volatile organic compound (VOC) building materials. Furthermore, the use of building materials made of renewable sources, with less maintenance need, and those extracted without ecological damage are of great importance as well as the use of certified wood materials and reporting tools such as Environmental Product Declarations [52] and Health Product Declarations [53].
Reduction of wastes: The rate of construction sector-based wastes corresponds more than 30% of the total wastes. Within this scope, it is of great importance to target sustainable building design in the construction sector [54]. It should be noted that buildings that are demolished become the resources for new buildings [55]. During the process of building design, it is necessary to select reusable, recyclable, reclaimed, recycled building materials and nonconventional products in order to lower embodied energy of materials; to reduce the need for new landfills; to reduce air, water, and soil pollution; to minimize transportation requirements; to reduce the use of raw materials; and to enable the economic use of materials. On the other hand, rehabilitation and reuse of existing structures and infrastructures instead of brand-new ones are other effective procedures that reduce construction sector-based wastes. Apart from these, waste management of construction and demolition phases in terms of sorting, storage, and disposal of wastes should be implemented.
Proper sizing of building and systems: It is necessary to optimize the building size in order to reduce overall building material use, wastes, embodied energy, energy loads, and costs and to conserve resources. This can be achieved by ensuring functionality between spaces and circulation according to target utilization rates (number of square meters per person or unit), by designing individual spaces to fulfill multiple functions, and by dumping unused spaces [56]. Furthermore, reducing building envelope surface, using simple geometrical mass forms; designing flexible and modular spaces; and utilizing standard commercially available material sizes are the other procedures for proper sizing.
2.2. Economic aspect of sustainable building design
Economic sustainability is defined as the use of various strategies for employing existing resources optimally, so that a responsible and beneficial balance can be achieved over the longer term [57]. Economic sustainability is inextricably linked to both environmental and social sustainability [58]. Sustainable building design does not only improve the quality of environment and comfort of users but also has many economic benefits as well. The initial cost of the building can be higher than a conventional building owing to the innovative use of sustainable building materials, systems, and equipment through integrated sustainable building design process. However, sustainable buildings decrease annual costs in terms of energy, water, maintenance and repair, and other operating costs so that the life cycle cost is lower than the cost of conventional buildings. In addition to the mentioned cost savings, sustainable buildings also provide indirect economic benefits such as increasing comfort and productivity of users, reducing absenteeism, and increasing property value, to both the actors of the construction sector and users [59]. Reducing costs based on construction wastes, pollution, infrastructure, and transportation can also be considered as indirect economic benefits. In this context, economically sustainable building design criteria can be classified as resource efficiency and cost efficiency.
2.2.1. Criteria and procedures for strategy of resource efficiency
The construction sector is a major consumer of all resources, and therefore the actors of the construction sector have pursued to design sustainable buildings focusing on increasing the efficiency of resource use [16]. Resource efficiency refers to the conservation of raw materials and nonrenewable resources based on life cycle conception to design buildings that consume fewer resources and that leads to less environmental impacts. The strategy of resource efficiency comprises both energy and material efficiency (see Sections 2.1.3 and 2.1.4). Whereas energy efficiency considers the economical use of nonrenewable resources, encouraging the use of renewable resources, material efficiency is about the economical use of raw materials and reduction of wastes. Resource efficiency addresses human impacts on natural resources, economic requirements for land use, environmental impacts, amount of material used, and the ratio of gross domestic product (GDP) to material used [60]. In this context, the criteria for the strategy of resource efficiency are classified as conservation of raw materials and conservation of nonrenewable resources in this study. Additionally, related procedures for each criterion are determined and presented in Table 6.
Strategy of resource efficiency
Criteria
Procedures
Conservation of raw materials
Use of reusable building materials Use of recyclable building materials Use of reclaimed building materials Use of recycled building materials Use of long-lasting building materials Rehabilitation and reuse of existing structures and infrastructures Development of new eco-innovative building materials Optimization of supply chain Optimization of material production techniques
Conservation of nonrenewable resources
Increase of use of renewable energy resources Reduction of energy consumption in all life cycle stages of buildings Use of energy saving electrical installation Use of energy saving heating, ventilating, and air conditioning installation
Table 6.
Criteria and procedures for strategy of resource efficiency.
Conservation of raw materials: Conservation of resources means achieving more with less [16]. Nowadays, certain resources are becoming extremely rare; that’s why the use of remaining stocks should be treated cautiously [61]. The scarcity of raw material stocks results in a threat for the economy. The extraction of raw materials may damage lands; the production, usage, and disposal of materials can have significant environmental impacts; and these processes may be energy intensive, labor intensive, and very costly [60]. In this context, resource efficiency ought to be handled based on life cycle assessment (LCA) methodology, as depletion of abiotic resources is one of the prominent environmental impact indicators of this methodology [62]. Raw materials, which are assigned as abiotic resources, can be conserved by using secondary materials such as reusable, recyclable, reclaimed, recycled building materials. Construction wastes can be also reduced by this way. Improving durability, service life, the technical and economic performance of building materials, reusing existing structures and infrastructures, and developing new eco-innovative building materials are other procedures of conservation of raw materials. Additionally, supply chain and material production techniques should be optimized in order to convert raw materials into final building products with less environmental impacts [63].
Conservation of nonrenewable resources: Energy use in buildings from life cycle perspective is one of the significant economic issues, as buildings are intensive energy consumers. Buildings consume energy at each stage of their life cycles, from cradle to grave. The energy consumed in usage stage of buildings accounts for a considerable part of the total energy. For this reason, minimizing the use of energy in usage stage is a central task in sustainable building [64]. Energy use in usage stage of the buildings includes both operational and embodied energy [65]. Operational energy comes out as a result of heating, ventilating, air conditioning, and hot water use in buildings, while the embodied energy occurs from the choice of building materials used. Nowadays, energy used in buildings for electricity is supplied from nonrenewable resources, which are fossil fuels such as natural gas, fuel oil, and coal. The reserves of these resources are limited reserves. The entire world, therefore, looks for the means of safe and continuous access to energy [66]. In this sense, using renewable energy resources, reducing the energy consumption of in all life cycle stages of buildings, and using energy saving electrical, heating, ventilating, and air conditioning installations are important tasks to take into consideration.
2.2.2. Criteria and procedures for strategy of cost efficiency
The construction sector can be mentioned as the sector of the economy which plans, designs, constructs, alters, refurbishes, maintains, repairs, and eventually demolishes buildings. The inputs of the sector are obtained from other sectors of the economy, such as manufacturing, financial services, local government, commercial sectors, and industrial sectors supplying materials. Due to these dealings, there have been considerable procedural and structural changes in the construction sector, such as the increased use of design and construct arrangements, integrated project management processes, novation, partnering, benchmarking, re-engineering, management contracting, private finance initiatives, and public and private partnerships. Concordantly, life cycle cost management of building projects has become progressively important in terms of delivering the highest-quality projects in time with accurate budgeting and cost control, ensuring cost efficiency [67]. Through life cycle cost perspective, there are three main costs to be considered at the outset of a building project, being the initial building investment cost, the cost of the building in use, and the cost of building recovery [68]. In this respect, the strategy of cost efficiency focuses on long-term economic performance with minimized initial, operating, and recovery costs providing satisfaction of the actors of the construction sector. The criteria for the strategy of cost efficiency are classified as the reduction of initial cost, reduction of operating cost, reduction of recovery cost, and satisfaction of the construction sector actors in this study. Additionally, related procedures for each criterion are determined and presented in Table 7.
Strategy of cost efficiency
Criteria
Procedures
Reduction of initial cost
Use of local building materials to reduce transportation cost Use of recycled building materials Use of reclaimed building materials Reduction of transportation to and from the site Utilization of flexible and modular building design Use of standardized building components Use of common and available building components Safe and correct storage of building materials Reduction of time for assembly of building materials on site Selection of appropriate construction technologies for various building types Selection of appropriate suppliers for building materials Selection of right labor force for right positions
Reduction of operating cost
Selection of long lasting building materials and components Reduction of maintenance and repair cost Reduction of regular cleaning cost Selection of right location for heating, ventilating, and air conditioning systems Use of easy-to-use building automation and control systems
Reduction of recovery cost
Consideration of recycling potential of building materials in design phase Consideration of reclaiming potential of building materials in design phase Reuse of building materials or components Consideration of ease of demolition of building in the design phase Reuse of an existing building
Satisfaction of the construction sector actors
Improvement of productivity Increase of profitability Development of lower-cost projects by increasing cost estimation Shortening the completion time of the project
Table 7.
Criteria and procedures for strategy of cost efficiency.
Reduction of initial cost: The initial cost, also referred to as acquisition cost or development cost, covers the entire cost of designing and constructing a building. In a broad sense, initial cost comprises land and building acquisition costs, professional consultant fees, the cost of the building materials, and the cost of construction processes. It can be said that the initial cost is the basic and sometimes the only source of concern for many actors in the construction sector [68]. Therefore, initial cost reduction procedures should be considered in sustainable building design process. Recycled, reclaimed, and locally available building materials have to be selected to reduce the cost value of materials and transportation costs. Deconstruction techniques rather than demolition have to be employed to reclaim materials for reuse in other applications on site [69]. Flexible and modular designs and standardized building components, which allow reconfiguration when required, must be preferred [70]. Common and readily available building components should be selected to minimize replacement costs and to reduce stocking of components. Building components that cannot be easily repaired or replaced ought to be selected as durable to minimize replacement and retrofitting [16]. Appropriate storage facilities should be provided on site to maintain the integrity of the materials [69]. Cost saving and proper construction technologies must be implemented for different types of buildings. Besides these, the right workers for the right works and the right supplier choice are the other issues that need to be carefully considered in order to reduce the initial costs.
Reduction of operating cost: The operating cost, also known as the cost in use or the running cost, is affected by the decisions made during the design and construction phases of the building design process in terms of the choice of materials and the impeccability of the detailing [68]. It involves the costs of heating, ventilating, air conditioning services, building automation and control systems, maintenance and repair, and cleaning fees in the usage stage of the building’s life cycle. Only the initial cost was estimated, and operating cost was neglected in the design phase before the life cycle cost methodology has underlined the relationship between design decisions and costs in use [68, 71]. In fact, the lower the life cycle cost, the more economically efficient the building [72]. Therefore, implementing operating cost reduction procedures would contribute reducing the life cycle cost of the buildings. Durable, long-lasting, low-maintenance building materials and components have to be preferred to reduce maintenance and repair costs [73]. The access points of central and major elements of heating, ventilating, and air conditioning systems ought to be located properly for easy maintenance, repair, and cleaning. Simple environmental automation and control systems should be selected, as opposed to complex systems with high maintenance costs [74]. If the required efficiency can be achieved by a simple system, then a complicated one ought to be avoided [16].
Reduction of recovery cost: The recovery cost, which consists of the cost of building demolition and materials recovery, is rarely considered by the actors of the construction sector due to looking for short-term gain with minimum outlay [68]. However, recovery cost is also of great importance from standpoint of the life cycle cost methodology. Therefore, implementing recovery cost reduction procedures would promote reduction of the life cycle cost of the buildings. Recycling and reclaiming potential of building materials have to be evaluated in the design phase in order to provide for maximum recovery of materials by reusing them. Besides, proper demolition techniques of the building should be considered and improved through the design phase. Another procedure for reducing recovery cost is reuse of an existing building to reduce the amounts of construction waste, raw materials, and the energy used for material production processes. When all of these are succeeded within the scope of end-of-life perspective, the allocation of resources at minimal costs would be provided, and the value of the building would be increased [75].
Satisfaction of the construction sector actors: The construction sector involves actors such as designers, users, contractors, stakeholders, suppliers, manufacturers, and several organizational levels that have different tasks. These actors make the construction sector a multilevel entity. Satisfaction of the construction sector actors can be stated as an essential criterion of the future economic success of the sector [76]. Long-term economic performance of buildings can be provided with the satisfaction of the actors by improving the productivity of labor force and enhancing profitability. Profitability could be increased by improving the management of the building project process. Meanwhile, accuracy of cost estimation is of great importance in terms of decreasing the costs of the projects. In addition, flows of information, money, goods, and services move between the construction sector actors during the project process [76]. The longer the project process, the greater the costs. In order to decrease the costs during this process, it is necessary to shorten the completion time of the project.
2.3. Social aspect of sustainable building design
Debates about sustainability do not consider sustainability solely as an environmental and economic concern but also incorporate social dimensions [77]. In this respect, the main goals of sustainable development are defined as environmental stewardship, economic prosperity, and social responsibility. These three goals should be interrelated and supportive of each other in order to execute sustainability strategies [78]. When the construction sector is examined, it is observed that the social aspect of sustainability is usually neglected, despite the anthropocentric focus of sustainability definitions [77]. In the mentioned definitions, sustainability focuses on well-being rather than well-having by sustainable livelihoods and addresses fundamental issues for humanity now and in the future, which constitutes the social aspect of sustainable building design [79]. In order to achieve socially sustainable building design, creating unpolluted and safe environments, protecting human health, improving user productivity, enhancing human comfort conditions, creating esthetically satisfactory indoor and outdoor environments, conserving local heritage and culture, improving communication with the public, and developing regulations are of great importance. In this context, socially sustainable building design criteria can be classified as health and well-being and public awareness.
2.3.1. Criteria and procedures for strategy of health and well-being
It is imperative to pay attention to enhance the quality of life in buildings that encourage a healthy and safe internal and external built environment for users [8] without exhausting natural resources or causing severe ecological damage. The strategy of health and well-being consists of building design procedures ensuring unpolluted, fire- and natural-hazard-resistant, disabled-friendly environments and good indoor environmental quality to protect the health and comfort of building users. It also addresses increased comfort, health, and safety of building users, visitors, and others within the vicinity. Livable and high-quality indoor environments contribute increasing property value, to improve productivity and to reduce absenteeism [80]. In this context, the criteria for the strategy of health and well-being are classified as the creation of livable environments and creation of appropriate indoor comfort conditions in this study. Additionally, related procedures for each criterion are determined and presented in Table 8.
Strategy of health and well-being
Criteria
Procedures
Creation of livable environments
Prevention of noise pollution Prevention of visual pollution Prevention of air pollution Prevention of water pollution Prevention of soil pollution Provision of fire protection Provision of resistance to natural hazards Consideration of the accessibility of disabled users Conservation of local heritage and culture
Creation of appropriate indoor comfort conditions
Provision of sufficient indoor air quality Provision of appropriate indoor humidity ratio Provision of indoor visual comfort conditions Creation of visual connection with the outer environment Provision of indoor thermal comfort conditions Provision of indoor acoustical comfort conditions Provision of operable windows Provision of clean fresh air Use of low volatile organic compound (VOC) building materials Prevention of electromagnetic pollution Use of nontoxic and noncarcinogenic building materials Use of antibacterial building materials
Table 8.
Criteria and procedures for strategy of health and well-being.
Creation of livable environments: The concept of livability is directly related to the quality of human life. Livability evolves out of a wealth of existing resources and conditions that promote healthy living like clean air, water, and soil. The provision of healthy and comfortable indoor and outdoor spaces is the key indicators of livability, which is related to the effects of building performance on the quality of living. The environmental aspects typically include the issues of noise, visual, air, water, and soil, which cause significant implications on health and well-being of users [81]. For this reason, solutions have to be produced to prevent abovementioned pollution in order to create livable environments. Additionally, fire protection is essential for livable environments, and fire safety systems have to be advanced. These systems, such as fire sprinklers, can offer environmental benefits by reducing air and water pollution levels and by lowering water usage and fire damage. The resistance to natural hazards should also be ensured. It is not possible to prevent these hazards, but mitigation measures ought to be taken to overcome. Accessibility of disabled users has to be considered, and accessibility features should be improved to make the environment more livable for them [82]. In addition to all these, preservation of cultural heritage and values is another significant procedure of the related criteria.
Creation of appropriate indoor comfort conditions: In developed countries, people spend more than 90% of their time indoors. Indoor conditions have therefore far-reaching implications for their health, general well-being, and performance [83]. Indoor environmental quality of building has a high-level impact on users’ health, comfort, and productivity [84]. Apart from these features, a sustainable building has appropriate ventilation and moisture control, maximizes daylighting to provide indoor visual comfort conditions, creates visual connection with the outer environment, provides indoor thermal comfort conditions, optimizes acoustic performance, provides operable windows and fresh air, and avoids the use of materials with high-VOC emissions [56]. Except these, electromagnetic pollution has to be prevented to improve the indoor air quality, and nontoxic, noncarcinogenic, and antibacterial building materials have to be used for maximizing the comfort of users.
2.3.2. Criteria and procedures for strategy of public awareness
Ensuring sustainability in construction sector depends not only on achieving environmental and economic aspects of sustainability but also the participation of the public and an understanding of the consequences of individual behaviors. Although sustainable building design is envisaged as a necessity in construction sector, in general it continues not to receive much attention between public [85]. As a matter of fact, there is a need to create greater public awareness of the health impacts of buildings, to increase the focus on sustainability strategies, and to encourage building codes to place increased emphasis on healthier building practices [86]. Strategy of public awareness comprises raising consciousness of public and the actors of the construction sector about the benefits of sustainable buildings, mobilization of sustainable building tools, adoption of procedures for sustainable building management, and development of innovative concepts and services [87]. It focuses on developing financial incentives, improving cooperation between organizations, and developing policies for innovative initiatives and technologies on sustainable design features [88]. In this context, the criteria for the strategy of public awareness are classified as educating the public and development of incentives and policies in this study. Additionally, related procedures for each criterion are determined and presented in Table 9.
Strategy of public awareness
Criteria
Procedures
Educating the public
Organization of congresses and conventions on sustainable building design Implementation of training programs about sustainable building design Preparation of educational videos about sustainable building design Organization of competitions on sustainable buildings Efficient use of media about sustainable building design Educating the public in pilot sustainable buildings
Development of incentives and policies
Provision of financial incentives such as tax and customs’ duty exemption Improvement of cooperation between public and private organizations Implementation of policies for the efficient use of renewable energy technologies Implementation of the decisions made in the international meetings on environment
Table 9.
Criteria and procedures for strategy of public awareness.
Educating the public: Creating public awareness about sustainable buildings could be achieved by educating the public. More symposiums, conferences, educational videos, programs, workshops, seminars, and professional talks have to be held under the theme of sustainable buildings in order to educate the public about the importance of sustainability and to raise the awareness. Competitions on sustainable buildings should be organized to improve ability and know-how of the actors of the construction sector that have been gained from their previous experiences [89]. Additionally, media ought to be used intensely and effectively in creating public awareness and improved understanding of issues [90], and public authorities ought to disseminate plans, programs, and other related relevant materials through media [91]. Apart from these, pilot sustainable buildings can be opened to the public for on-site training. Consequently, the public has to be completely environmental conscious and should be encouraged to prefer sustainable buildings.
Development of incentives and policies: It is very crucial to develop policies and approaches that enable utilization of domestic resources complying with the conditions of the countries and to monitor studies pertaining to energy in the world [66]. Sustainable building design and practices can be only achieved by political decision-making, including several incentives and policies based upon public awareness in this manner [92]. Financial incentives such as taxes, subsidies, tradable permits, and rewards do not usually require as much enforcement as regulations [93], whereas it is a considerable procedure for encouraging the actors of the construction sector to opt for sustainable building design. Furthermore, it can be stated that improving cooperation among public bodies, universities, private enterprises, and nongovernmental organizations can support the generalization of sustainable buildings. Finally, policies for efficient use of renewable energy technologies have to be implemented, wide range of innovative policy instruments ought to be developed, and the decisions made in the international meetings on environment must be complied with.
3. Conclusion
Today’s world is facing environmental, economic, and social problems. Many studies and researches in various sectors are being carried out to reduce these problems. Sustainable building design can be considered as a path of minimizing environmental, economic, and social problems in the construction sector. In this context, sustainable building design has to be contextualized properly. When reviewing the most recent interpretations of sustainable building design in the literature, many uncertainties and constraints have been observed because of the inability to integrate the environmental, economic, and social aspects of sustainability. These uncertainties and constraints are tried to be solved in this study by developing a holistic conceptual scheme, which comprehensively contextualizes all the strategies, criteria, and procedures associated with the aspects of environmentally, economically, and socially sustainable building design. By this way, it is envisaged that this study can contribute to the improving literature on sustainable building design in terms of site efficiency, water efficiency, energy efficiency, material efficiency, resource efficiency, cost efficiency, health and well-being, and public awareness. Consequently, this scheme may be adopted as a guideline for the actors of the construction sector and the researchers and can help in promoting sustainable building practices in the construction sector. Furthermore, it is of vital significance to develop new laws and regulations, to improve government incentives, to study on new standards, to carry out scientific researches, and to conduct effective training programs.
\n',keywords:"construction sector, sustainable building design, environmentally sustainable design, economically sustainable design, socially sustainable design",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/59267.pdf",chapterXML:"https://mts.intechopen.com/source/xml/59267.xml",downloadPdfUrl:"/chapter/pdf-download/59267",previewPdfUrl:"/chapter/pdf-preview/59267",totalDownloads:1102,totalViews:209,totalCrossrefCites:0,dateSubmitted:"July 3rd 2017",dateReviewed:"January 15th 2018",datePrePublished:"February 15th 2018",datePublished:"July 18th 2018",dateFinished:"February 9th 2018",readingETA:"0",abstract:"Sustainable building design concept, which has emerged in the construction sector in recent years, has appeared as a response to environmental pollution caused by the construction sector. In the context of sustainable building design, it is intended to create built environment sensitive to environmental, economic, and social problems. Within the scope of this study, sustainable building design is contextualized by a holistic conceptual scheme considering aspects, strategies, criteria, and procedures of creating an environmental, economic, and social awareness by taking into account how to design sustainable buildings. According to the suggested scheme, strategies of environmentally sustainable building design aspect are classified as site efficiency, water efficiency, energy efficiency, and material efficiency; strategies of economically sustainable building design aspect are classified as resource efficiency and cost efficiency; and strategies of socially sustainable building design are classified as health and well-being and public awareness. Furthermore, related criteria for each strategy and related procedures for each criterion are determined. This scheme is intended to indicate the responsibilities of the construction sector in the context of environmental, economic, and social sustainability and to guide the actors of the construction sector and the researchers in this sense.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/59267",risUrl:"/chapter/ris/59267",signatures:"Arzuhan Burcu Gültekin, Handan Yücel Yıldırım and Harun\nTanrıvermiş",book:{id:"6378",type:"book",title:"Sustainable Buildings",subtitle:"Interaction Between a Holistic Conceptual Act and Materials Properties",fullTitle:"Sustainable Buildings - Interaction Between a Holistic Conceptual Act and Materials Properties",slug:"sustainable-buildings-interaction-between-a-holistic-conceptual-act-and-materials-properties",publishedDate:"July 18th 2018",bookSignature:"Amjad Almusaed and Asaad Almssad",coverURL:"https://cdn.intechopen.com/books/images_new/6378.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-78923-403-9",printIsbn:"978-1-78923-402-2",pdfIsbn:"978-1-83881-441-0",isAvailableForWebshopOrdering:!0,editors:[{id:"110471",title:"Prof.",name:"Amjad",middleName:"Zaki",surname:"Almusaed",slug:"amjad-almusaed",fullName:"Amjad Almusaed"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"143644",title:"Dr.",name:"Arzuhan",middleName:"Burcu",surname:"Gültekin",fullName:"Arzuhan Gültekin",slug:"arzuhan-gultekin",email:"arzuhanburcu@yahoo.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Aspects of sustainable building design",level:"1"},{id:"sec_2_2",title:"2.1. Environmental aspect of sustainable building design",level:"2"},{id:"sec_2_3",title:"Table 1.",level:"3"},{id:"sec_3_3",title:"Table 3.",level:"3"},{id:"sec_4_3",title:"Table 4.",level:"3"},{id:"sec_5_3",title:"Table 5.",level:"3"},{id:"sec_7_2",title:"2.2. Economic aspect of sustainable building design",level:"2"},{id:"sec_7_3",title:"Table 6.",level:"3"},{id:"sec_8_3",title:"Table 7.",level:"3"},{id:"sec_10_2",title:"2.3. Social aspect of sustainable building design",level:"2"},{id:"sec_10_3",title:"Table 8.",level:"3"},{id:"sec_11_3",title:"Table 9.",level:"3"},{id:"sec_14",title:"3. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Say C, Wood A. Sustainability rating systems around the world. CTBUH Review. 2008;2:18-29'},{id:"B2",body:'Smith PF. Architecture in a Climate of Change: A Guidance to Sustainable Design. 2nd ed. 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Department of Real Estate Development and Management, Ankara University, Ankara, Turkey
Department of Real Estate Development and Management, Ankara University, Ankara, Turkey
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ALPSP
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The Association of Learned and Professional Society Publishers (ALPSP) is the largest association of scholarly and professional publishers in the world. Its mission is to connect, inform, develop and represent the international scholarly and professional publishing community. IntechOpen has been a member of ALPSP since 2016 and has consequently stayed informed about industry trends through connecting with peers and developing jointly.
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OASPA
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The Open Access Scholarly Publishers Association (OASPA) was established in 2008 to represent the interests of Open Access (OA) publishers globally in all scientific, technical and scholarly disciplines. Its mission is carried out through exchange of information, the setting of standards, advancing models, advocacy, education, and the promotion of innovation.
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STM
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COPE
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The Committee on Publication Ethics (COPE) provides advice to editors and publishers on all aspects of publication ethics and, in particular, how to handle cases of misconduct in research and publication. IntechOpen has been a member of COPE since 2013 and adheres to the COPE Code of Conduct and Best Practice Guidelines, ensuring that we maintain the highest ethical standards.
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Creative Commons
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Creative Commons (CC) is a nonprofit organization that enables the sharing and use of creativity and knowledge through free legal tools. IntechOpen uses the CC BY 3.0 license for chapters, meaning Authors retain copyright and their work can be reused and adapted as long as the source is properly cited and Authors are acknowledged.
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Crossref
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Crossref is the official Digital Object Identifier (DOI) Registration Agency for scholarly and professional publications with a goal of making scholarly communications more effective. IntechOpen deposits metadata and registers DOIs for all content using the Crossref System. IntechOpen also deposits its references and uses the Crossref Cited-by service that enables researchers to track citation statistics.
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Altmetric and Dimensions from Digital Science
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Digital Science is a technology company serving the needs of scientific and research communities at key points along the full cycle of research. They support innovative businesses and technologies that make all parts of the research process more open, efficient and effective. IntechOpen integrates tools such as Altmetric to enable our researchers to track and measure the activity around their academic research and Dimensions, to ease access to the most relevant information and better understand and analyze the global research landscape.
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CLOCKSS
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CLOCKSS preserves scholarly publications in original formats, ensuring that they always remain available and openly accessible to everyone.
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DORA
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iThenticate
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Enago
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IntechOpen collaborates with Enago, through its sister brand, Ulatus, one of the world’s leading providers of book translation services. Their services are designed to convey the essence of your work to readers from across the globe in the language they understand.
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Straive
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Amazon
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The Compact is designed to inspire action among publishers. Launched in collaboration with the International Publishers Association, the Compact aims to accelerate progress to achieve the Sustainable Development Goals (SDGs) by 2030. Signatories aspire to develop sustainable practices and act as champions of the SDGs during the Decade of Action (2020-2030), publishing books and journals that will help inform, develop, and inspire action in that direction. Learn more here
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River Valley Technology
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Figshare
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Figshare is an online open access repository where researchers can preserve and share their research outputs, including figures, datasets, images, and videos. It is free to upload content and free to access, in adherence to the principle of open data.
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OASPA
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The Open Access Scholarly Publishers Association (OASPA) was established in 2008 to represent the interests of Open Access (OA) publishers globally in all scientific, technical and scholarly disciplines. Its mission is carried out through exchange of information, the setting of standards, advancing models, advocacy, education, and the promotion of innovation.
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STM
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The International Association of Scientific, Technical and Medical Publishers (STM) is the leading global trade association for academic and professional publishers. As a member, IntechOpen has not only made a commitment to STM's Ethical Principles.
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COPE
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The Committee on Publication Ethics (COPE) provides advice to editors and publishers on all aspects of publication ethics and, in particular, how to handle cases of misconduct in research and publication. IntechOpen has been a member of COPE since 2013 and adheres to the COPE Code of Conduct and Best Practice Guidelines, ensuring that we maintain the highest ethical standards.
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Creative Commons
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Creative Commons (CC) is a nonprofit organization that enables the sharing and use of creativity and knowledge through free legal tools. IntechOpen uses the CC BY 3.0 license for chapters, meaning Authors retain copyright and their work can be reused and adapted as long as the source is properly cited and Authors are acknowledged.
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Crossref
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Crossref is the official Digital Object Identifier (DOI) Registration Agency for scholarly and professional publications with a goal of making scholarly communications more effective. IntechOpen deposits metadata and registers DOIs for all content using the Crossref System. IntechOpen also deposits its references and uses the Crossref Cited-by service that enables researchers to track citation statistics.
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Altmetric and Dimensions from Digital Science
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Digital Science is a technology company serving the needs of scientific and research communities at key points along the full cycle of research. They support innovative businesses and technologies that make all parts of the research process more open, efficient and effective. IntechOpen integrates tools such as Altmetric to enable our researchers to track and measure the activity around their academic research and Dimensions, to ease access to the most relevant information and better understand and analyze the global research landscape.
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CLOCKSS
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CLOCKSS preserves scholarly publications in original formats, ensuring that they always remain available and openly accessible to everyone.
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Counter
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COUNTER provides the Code of Practice that enables publishers and vendors to report usage of their electronic resources in a consistent way. This enables libraries to compare data received from different publishers and vendors.
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DORA
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DORA is a worldwide initiative covering all scholarly disciplines which recognizes the need to improve the ways in which the outputs of scholarly research are evaluated and seeks to develop and promote best practice. To date it has been signed by over 1500 organizations and around 14,700 individuals.
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iThenticate
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iThenticate is the leading provider of professional plagiarism detection and prevention technology and is used worldwide by scholarly publishers and research institutions to ensure the originality of written work before publication. IntechOpen uses the iThenticate plagiarism software to ensure content originality and the research integrity of our published work.
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Enago
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IntechOpen collaborates with Enago, through its sister brand, Ulatus, one of the world’s leading providers of book translation services. Their services are designed to convey the essence of your work to readers from across the globe in the language they understand.
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IntechOpen Authors that wish to use this service will receive a 20% discount on all translation services. To find out more information or obtain a quote, please visit https://www.enago.com/intech
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Straive
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Straive is the market leader in technology-driven solutions for the extraction, enrichment and transformation of content assets. IntechOpen publishing services are designed to meet the unique needs of Authors. As part of our commitment to that objective, we have an ongoing partnership agreement for production solutions.
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Amazon
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Amazon is the world’s largest online retailer and cloud services provider. IntechOpen books have been available on Amazon since 2017, guaranteeing more visibility for our Authors and Academic Editors.
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DHL
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IntechOpen has partnered with DHL since 2011 to ensure the fastest delivery of Print on Demand books.
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United Nations Sustainable Development Goals Publishers Compact
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The Compact is designed to inspire action among publishers. Launched in collaboration with the International Publishers Association, the Compact aims to accelerate progress to achieve the Sustainable Development Goals (SDGs) by 2030. Signatories aspire to develop sustainable practices and act as champions of the SDGs during the Decade of Action (2020-2030), publishing books and journals that will help inform, develop, and inspire action in that direction. Learn more here
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River Valley Technology
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River Valley Technology is the world’s first XML-based publishing solution from submission to peer review to production and to final hosting, giving full control to publishers, with full transparency of data.
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Figshare
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Figshare is an online open access repository where researchers can preserve and share their research outputs, including figures, datasets, images, and videos. It is free to upload content and free to access, in adherence to the principle of open data.
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Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Bacterial Infectious Diseases",value:3,count:2},{group:"subseries",caption:"Parasitic Infectious Diseases",value:5,count:4},{group:"subseries",caption:"Viral Infectious Diseases",value:6,count:7}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:2},{group:"publicationYear",caption:"2021",value:2021,count:4},{group:"publicationYear",caption:"2020",value:2020,count:3},{group:"publicationYear",caption:"2019",value:2019,count:3},{group:"publicationYear",caption:"2018",value:2018,count:1}],authors:{paginationCount:229,paginationItems:[{id:"318170",title:"Dr.",name:"Aneesa",middleName:null,surname:"Moolla",slug:"aneesa-moolla",fullName:"Aneesa Moolla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/318170/images/system/318170.png",biography:"Dr. Aneesa Moolla has extensive experience in the diverse fields of health care having previously worked in dental private practice, at the Red Cross Flying Doctors association, and in healthcare corporate settings. She is now a lecturer at the University of Witwatersrand, South Africa, and a principal researcher at the Health Economics and Epidemiology Research Office (HE2RO), South Africa. Dr. Moolla holds a Ph.D. in Psychology with her research being focused on mental health and resilience. In her professional work capacity, her research has further expanded into the fields of early childhood development, mental health, the HIV and TB care cascades, as well as COVID. She is also a UNESCO-trained International Bioethics Facilitator.",institutionString:"University of the Witwatersrand",institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419588",title:"Ph.D.",name:"Sergio",middleName:"Alexandre",surname:"Gehrke",slug:"sergio-gehrke",fullName:"Sergio Gehrke",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038WgMKQA0/Profile_Picture_2022-06-02T11:44:20.jpg",biography:"Dr. Sergio Alexandre Gehrke is a doctorate holder in two fields. The first is a Ph.D. in Cellular and Molecular Biology from the Pontificia Catholic University, Porto Alegre, Brazil, in 2010 and the other is an International Ph.D. in Bioengineering from the Universidad Miguel Hernandez, Elche/Alicante, Spain, obtained in 2020. In 2018, he completed a postdoctoral fellowship in Materials Engineering in the NUCLEMAT of the Pontificia Catholic University, Porto Alegre, Brazil. He is currently the Director of the Postgraduate Program in Implantology of the Bioface/UCAM/PgO (Montevideo, Uruguay), Director of the Cathedra of Biotechnology of the Catholic University of Murcia (Murcia, Spain), an Extraordinary Full Professor of the Catholic University of Murcia (Murcia, Spain) as well as the Director of the private center of research Biotecnos – Technology and Science (Montevideo, Uruguay). Applied biomaterials, cellular and molecular biology, and dental implants are among his research interests. He has published several original papers in renowned journals. In addition, he is also a Collaborating Professor in several Postgraduate programs at different universities all over the world.",institutionString:null,institution:{name:"Universidad Católica San Antonio de Murcia",country:{name:"Spain"}}},{id:"342152",title:"Dr.",name:"Santo",middleName:null,surname:"Grace Umesh",slug:"santo-grace-umesh",fullName:"Santo Grace Umesh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/342152/images/16311_n.jpg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"333647",title:"Dr.",name:"Shreya",middleName:null,surname:"Kishore",slug:"shreya-kishore",fullName:"Shreya Kishore",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333647/images/14701_n.jpg",biography:"Dr. Shreya Kishore completed her Bachelor in Dental Surgery in Chettinad Dental College and Research Institute, Chennai, and her Master of Dental Surgery (Orthodontics) in Saveetha Dental College, Chennai. She is also Invisalign certified. She’s working as a Senior Lecturer in the Department of Orthodontics, SRM Dental College since November 2019. She is actively involved in teaching orthodontics to the undergraduates and the postgraduates. Her clinical research topics include new orthodontic brackets, fixed appliances and TADs. She’s published 4 articles in well renowned indexed journals and has a published patency of her own. Her private practice is currently limited to orthodontics and works as a consultant in various clinics.",institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"323731",title:"Prof.",name:"Deepak M.",middleName:"Macchindra",surname:"Vikhe",slug:"deepak-m.-vikhe",fullName:"Deepak M. Vikhe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/323731/images/13613_n.jpg",biography:"Dr Deepak M.Vikhe .\n\n\t\n\tDr Deepak M.Vikhe , completed his Masters & PhD in Prosthodontics from Rural Dental College, Loni securing third rank in the Pravara Institute of Medical Sciences Deemed University. He was awarded Dr.G.C.DAS Memorial Award for Research on Implants at 39th IPS conference Dubai (U A E).He has two patents under his name. He has received Dr.Saraswati medal award for best research for implant study in 2017.He has received Fully funded scholarship to Spain ,university of Santiago de Compostela. He has completed fellowship in Implantlogy from Noble Biocare. \nHe has attended various conferences and CDE programmes and has national publications to his credit. His field of interest is in Implant supported prosthesis. Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Univeristy of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:null},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:null},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"423519",title:"Dr.",name:"Sizakele",middleName:null,surname:"Ngwenya",slug:"sizakele-ngwenya",fullName:"Sizakele Ngwenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419270",title:"Dr.",name:"Ann",middleName:null,surname:"Chianchitlert",slug:"ann-chianchitlert",fullName:"Ann Chianchitlert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419271",title:"Dr.",name:"Diane",middleName:null,surname:"Selvido",slug:"diane-selvido",fullName:"Diane Selvido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419272",title:"Dr.",name:"Irin",middleName:null,surname:"Sirisoontorn",slug:"irin-sirisoontorn",fullName:"Irin Sirisoontorn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"355660",title:"Dr.",name:"Anitha",middleName:null,surname:"Mani",slug:"anitha-mani",fullName:"Anitha Mani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"355612",title:"Dr.",name:"Janani",middleName:null,surname:"Karthikeyan",slug:"janani-karthikeyan",fullName:"Janani Karthikeyan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"334400",title:"Dr.",name:"Suvetha",middleName:null,surname:"Siva",slug:"suvetha-siva",fullName:"Suvetha Siva",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}}]}},subseries:{item:{id:"22",type:"subseries",title:"Applied Intelligence",keywords:"Machine Learning, Intelligence Algorithms, Data Science, Artificial Intelligence, Applications on Applied Intelligence",scope:"This field is the key in the current industrial revolution (Industry 4.0), where the new models and developments are based on the knowledge generation on applied intelligence. The motor of the society is the industry and the research of this topic has to be empowered in order to increase and improve the quality of our lives.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/22.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11418,editor:{id:"27170",title:"Prof.",name:"Carlos",middleName:"M.",surname:"Travieso-Gonzalez",slug:"carlos-travieso-gonzalez",fullName:"Carlos Travieso-Gonzalez",profilePictureURL:"https://mts.intechopen.com/storage/users/27170/images/system/27170.jpeg",biography:"Carlos M. Travieso-González received his MSc degree in Telecommunication Engineering at Polytechnic University of Catalonia (UPC), Spain in 1997, and his Ph.D. degree in 2002 at the University of Las Palmas de Gran Canaria (ULPGC-Spain). He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. He won the “Catedra Telefonica” Awards in Modality of Knowledge Transfer, 2017, 2018, and 2019 editions, and awards in Modality of COVID Research in 2020.\n\nPublic References:\nResearcher ID http://www.researcherid.com/rid/N-5967-2014\nORCID https://orcid.org/0000-0002-4621-2768 \nScopus Author ID https://www.scopus.com/authid/detail.uri?authorId=6602376272\nScholar Google https://scholar.google.es/citations?user=G1ks9nIAAAAJ&hl=en \nResearchGate https://www.researchgate.net/profile/Carlos_Travieso",institutionString:null,institution:{name:"University of Las Palmas de Gran Canaria",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,series:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403"},editorialBoard:[{id:"13633",title:"Prof.",name:"Abdelhamid",middleName:null,surname:"Mellouk",slug:"abdelhamid-mellouk",fullName:"Abdelhamid Mellouk",profilePictureURL:"https://mts.intechopen.com/storage/users/13633/images/1567_n.jpg",institutionString:null,institution:{name:"Paris 12 Val de Marne University",institutionURL:null,country:{name:"France"}}},{id:"109268",title:"Dr.",name:"Ali",middleName:null,surname:"Al-Ataby",slug:"ali-al-ataby",fullName:"Ali Al-Ataby",profilePictureURL:"https://mts.intechopen.com/storage/users/109268/images/7410_n.jpg",institutionString:null,institution:{name:"University of Liverpool",institutionURL:null,country:{name:"United Kingdom"}}},{id:"3807",title:"Dr.",name:"Carmelo",middleName:"Jose Albanez",surname:"Bastos-Filho",slug:"carmelo-bastos-filho",fullName:"Carmelo Bastos-Filho",profilePictureURL:"https://mts.intechopen.com/storage/users/3807/images/624_n.jpg",institutionString:null,institution:{name:"Universidade de Pernambuco",institutionURL:null,country:{name:"Brazil"}}},{id:"38850",title:"Dr.",name:"Efren",middleName:null,surname:"Gorrostieta Hurtado",slug:"efren-gorrostieta-hurtado",fullName:"Efren Gorrostieta Hurtado",profilePictureURL:"https://mts.intechopen.com/storage/users/38850/images/system/38850.jpg",institutionString:null,institution:{name:"Autonomous University of Queretaro",institutionURL:null,country:{name:"Mexico"}}},{id:"239041",title:"Prof.",name:"Yang",middleName:null,surname:"Yi",slug:"yang-yi",fullName:"Yang Yi",profilePictureURL:"https://mts.intechopen.com/storage/users/239041/images/system/239041.jpeg",institutionString:"Virginia Tech",institution:{name:"Virginia Tech",institutionURL:null,country:{name:"United States of America"}}}]},onlineFirstChapters:{paginationCount:1,paginationItems:[{id:"81321",title:"Velocity Planning via Model-Based Reinforcement Learning: Demonstrating Results on PILCO for One-Dimensional Linear Motion with Bounded Acceleration",doi:"10.5772/intechopen.103690",signatures:"Hsuan-Cheng Liao, Han-Jung Chou and Jing-Sin Liu",slug:"velocity-planning-via-model-based-reinforcement-learning-demonstrating-results-on-pilco-for-one-dime",totalDownloads:3,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Applied Intelligence - 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