Abstract
Monocyclic and Bicyclic aromatic heterocycles such as imidazoles, thiazoles, thiadiazoles, oxazoles, oxadiazoles quinazolines, indoles, benzimidazoles, purines pyrido[4,3-d]pyrimidines, thiazolo[5,4-d]pyrimidines, thiazolo[4,5-d]pyrimidines, oxazolo[5,4-d]pyrimidines and thieno[2,3-d]pyrimidines are renowned pharmacophores in drug discovery. These special structures are well explained and exemplified in chemical compound libraries. In this chapter, several types of thiazole based heterocyclic scaffolds such as monocyclic or bicyclic systems synthesis and their biological activities studies are presented, which are not frequently present in books and reviews. We mention the first importance of synthetic route of various thiazole based compounds and their applications in medicinal chemistry in this chapter.
Keywords
- Thiazole
- privileged structures
- thiazolopyridine
- thiazolopyrimidines
1. Introduction
Currently, the whole pharmaceutical industry is encountered with the challenge of enhancing work rate and advancement. The key obstacles are the increasing expenses of exploration and expansion and a concurrent deteriorating amount of new chemical entities (NCEs). The source of this modernism shortfall is not the biology. Interpreting of the human genome has directed to a prosperity of drug targets. With the addition of more than 35,000 human genes, the hypothesis is that at least 2,000 are significantly tangled in the occurrence and progress of the illness. Moreover, since each of these genes is associated with the usefulness of between five and ten proteins, the deduction is that their potency be 5,000 – 10,000 aims for innovative drugs [1,2]. Even though the positive outline of protein therapeutics and the aptitude of gene therapy, key pharmaceutical establishments are even focused on research and growth of small molecular mass compounds. Therefore, the challenge is to choose the greatest drugable objectives and formulate the conforming drug-like molecules.These materials are not only relative to the mark but also have precise pharmacokinetic and toxicological properties, which was allowed to be established as a drug. Medicinal chemistry as a scientific discipline has introduced several new techniques over the last few years to the rapidity of the drug discovery process, such as combinatorial chemistry, microwave-assisted organic synthesis, and high - output refinement [3]. Despite the stable rise in R & D, the total number of NCE successes in the market has reduced fundamentally. It appears clearly that choosing the suitable molecules to synthesize is one of the most difficult queries. It has been projected that the sum of potential compounds with molecular weight of lower than 500 Da is 10200, where only 1060 may retain drug-like applications. The percentage of molecules prepared untill today has been projected as one part in 1058 or approximately the fraction of the mass of the proton to the mass of the sun. The concern is, therefore, the selection of new molecules from this vast universe that have the potential to be biologically active [4]. To build a new drug discovery mission and to discover the bioactive compounds, various possibilities are offered. Triumphs can be achieved via a virtual screening method or can be simulated from technical or manifest literature. Most often than not, drug innovation projects start with a high quantity screening operation of commercially accessible compound collections besides targeting curiosity. It became clear in recent years that combinatorial libraries are not distinct enough. As the core attention of the Laboratory of Medicinal Chemistry showed in the synthesis and biological evaluation of bicyclic aromatic heterocycles [5], it is scrutinized that the number of accessible bicyclics heterocycles is principally restricted to a well-known nitrogen enclosing compounds, such as pyrimidines, thioazoles, coumarins, thiozlopyridines and benzothiazole (Figure 1).
In vision of the significance of thiazoles and their derivatives, numerous approaches for its synthesis were developed by various groups such as Hantzsch [6], Tchernic [7], Cook-Heilborn and Gabriel [8].
A thiazole ring system originates naturally in the crucial water soluble vitamin thiamin, also known as Vitamin B1, which supports the discharge of energy from carbohydrates through the course of metabolism. The occurrence of thiazole ring in vitamin B1 and its coenzyme play a significant role in the decarboxylation of α-keto acids and as an electron sink, respectively [9]. It also assist in the regular operational of the nervous system through its character in the synthesis of acetylcholine, a neurotransmitter.
Thiazole ring system appears in the bacitracin and penicillin antibiotics and various synthetic drugs. Synthetic drugs belonging to the thiazole family consist of the antimicrobial agents acinitrazole
Other substantial thiazoles take account of essential dyes and fungicides or nematicide, Tricyclazole
The exhilarating outcomes of the 2,4-disubstituted thiazoles as a unique class of Src Homology 2 (SH2) inhibitors for the behavior of osteoporosis and breast cancer have also been reported [27]. Selection of the 2,4-disubstituted thiazoles as concealed pharmacophores for diacylhydrazine of SC-51089, a prospective PGE2 antagonist have also been described [28]. With these results, the thiazole ring system proves to be a well-known structural motif that originate in several pharmaceutical agents and natural products extracted from various plants and marine systems.
2. Structure of Thiazole
The structure of thiazole is reflected as the resonance amalgam of the subsequent resonating structures (Figure 1). However, some of the resonating structures are also probable with the contribution of d-orbitals of the sulfur atom.
The p-bond orders quantified by molecular orbital methods have specified thiazole molecule to be aromatic with some dienic nature. Localization energies have projected reducing order of the nucleophilic reactivities following the order: 2 > 5 > 4 and the electrophilic reactivities as: 5 > 2 > 4. Three hydrogen atoms present in the thiazole are anticipated to have the order of acidity as H2 >> H5 > H4.
3. Synthesis of Thiazole
In the assessment of the significance of thiazoles and their derivatives, numerous techniques for the synthesis of thiazole derivatives were established by various research groups such as Hantzsch [6], Tchernic [7], Cook-Heilborn and Gabriel [8]. Lately, thiazole derivatives were generated in the presence of various catalysts such as ammonium-12-molybdophosphate [29], cyclodextrins [30], iodine [31] and silica chloride [32] in organic solvents at higher temperature and solvents such as 1-methyl-2-pyrrolidinone [33], with the use of a microwave [34]. Numerous procedures for the synthesis of thiazole compounds are accessible, which can be categorized into the part structures demonstrated below. The earliest of these structures is observed to be the most significant and highly flexible of all the thiazole formation techniques. With a workable and first reactants, it approves alkyl, aryl, aralkyl or heterocycles to be taken in any one of the 2-, 3-, 4- or 5-carbons of the thiazole ring. This technique, better acknowledged by the name of the German chemist Hantzsch, who invented it in 1887, contains the condensation of a compound bearing the two heteroatoms on the same carbon with a compound attached one halogen and one carbonyl function on two adjacent carbon atoms. A boundless diversity of compounds may assist as nucleophilic reagent in this reaction, such as thiourea, thioamide, ammonium thiocarbamate or dithiocarbamate and its derivatives [35].
3.1. Synthesis from α-halocarbonyl compounds (Type Ia): Hantzsch’s synthesis.
First designated in 1887 by Hantzsch, the cyclization of α-halo carbonyl compounds by a wide diversity of reactants attached to the N-C-S portion of the ring is the most extensively popular process for formation of thiazoles.
3.1.1. Reactions with Thioamides
3.1.1.1. Chloroacetaldehyde and derivatives
Thiazole ready to obtain by condensing thioformamide and chloroacetaldehyde [36,37].
3.1.1.2. Condensation with higher thioamides (2,4-Disubstituted and 2,4,5-trisubstituted thiazoles)
The reaction between thioamide and various α-halocarbonyl compounds has been utilized broadly, and numerous thiazoles with alkyl, aryl, arylalkyl or heteroaryl of several functional groups at 2-, 4- or 5-positions have been published.
3.1.2. Reactions with N-substituted Thiourea
3.1.2.1. N -monosubstituted thioureas
The 2-monosubstituted or disubstituted aminothiazoles obtained reaction between Halo carbonyl
3.2. Thiazoles formation from reorganization of the α-thiocyanatoketones
The simple cyclic reaction of α-thiocyanatoketones in aqueous acid concentrated sulfuric acid in acetic acid, and water or alkaline solution gives to 2-hydroxy thiazoles after dilution in water. These reactions can be conceded out for various hours at room temperature or by refluxing for 1 or 2 hrs on a water bath [41-45].
α-Thiocyanatoacetophenone reacts thioacid to yield 2-mercapto-4-phenyl thiazole.
α-Thiocyanatoketones highly react with alkyl amine or ammonium chloride to provide their
3.3. Thiazoles from α-aminonitriles (Cook-Heilbron’s synthesis) (Type-II)
This category of synthesis, which was examined by Cook, Heilbron [47-49] give 5-aminothiazoles differently substituted in the 2-position by reacting with an aminonitrile with salts and esters of dithioacids, carbon oxysulfide, carbon disulfide, and isothiocyanates under remarkably very mild conditions.
3.3.1. Carbon disulfide: 2-mercapto-5-aminothiazole derivatives
Carbon disulfide freely responds with α-aminonitriles giving 2-mercapto-5-amino thiazoles [50,51], which can be transformed into 5-amino thiazoles unsubstituted in the 2-position.
3.3.2. Esters and salts of dithioacids: 5-aminothiazole compounds and related condensations
By reducing the salts or the esters of both dithioformic and dithiophenacetic acids with α -aminonitriles, 5-aminothiazoles were achieved in better yields [52]. These reactions have agreed in aqueous ethereal solution at ambient temperature.
3.4. Thiazoles from acylaminocarbonyl compounds and phosphorus pentasulfide and related condensation (Gabriel’s synthesis) (Type III)
This reaction was originally designated by Gabriel [53] in 1910 phosphorus pentasulfide reacted with acylaminoketone (showed in below reaction) an equimolecular quantity to yield 2-phenyl-5-alkyl-thiazole. The reaction is analogous to the synthesis of additional five-membered oxygen and sulfur holding rings from 1,4-dicarbonyl compounds.
3.5. Thiazoles from nitriles and α-mercaptoketones: 2,4-disubstituted and 2,4,5- trisubstituted derivatives
Also, α-halocarbonyl compounds and α-mercaptoketones react with nitriles and aldehyde oximes in the presence of an acid as catalyzed reaction for the synthesis of thiazoles.
3.5.1. 2,4,5-Trisubstituted thiazoles from α-mercaptoketones and nitriles
Miyatake and Yashikawa synthesized numerous 2,4,5-trisubstituted thiazoles and gave low yield (16 to 40%) by the interaction of α-mercaptoketones on nitriles. Asinger and Thiel [54] utilized an aldehyde and ammonia as an alternative for nitrile.
3.6. Thiazoles from Vinyl Bromide
Thiazoles holding a variability of substituents such as aliphatic, aromatic, heterocyclic, or alkenyl groups can be synthesized by an intramolecular nucleophilic substitution reaction of
3.7. Synthesis of 2,4-disubstituted-5-acetoxythiazoles
From the viable existing methyl benzoate derivatives and with racemic phenyl glycine, a range of 2,4- disubstituted-5-acetoxythiazoles obtained in worthy to reasonable yields exhausting the succeeding scheme [59]. Due to the excellent thermal stability of the thiazole nucleus, the polymers integrating thiazole ring protocol have also been prepared.
4. Biological importance of thiazoles
Thiazole moiety-containing compounds invention present an extensive range of applications in medicinal chemistry such as antibiotics, bacteriostatics, CNS regulants to high selling diuretics [60-64]. Thiazole framework has established wide application in drug growth for the treatment of hypertension [65], inflammation [66] and HIV infections [67]. Aminothiazoles are famous for being ligands of estrogen receptors [68] as well as a innovative type of adenosine receptor antagonists [69]. Other equivalents are utilized as fungicides, inhibiting
Sherif. et al. [71] syntheses of two series of compounds that is thiazolylantipyrines and thiadiazolylantipyrines, in which thiazolylantipyrine series exhibits better antibacterial potencies than the thiadiazolylantipyrine series of compounds. In thiazolylantipyrine series compounds
Zablotskaya A et al. [72] prepared trimethylsilyl ethers of different hydroxyl group bearing thiazole compounds. All the compounds examined possess antihypoxic properties and extend the life of mice under conditions of hypoxia by 20-78%. The silylated and unsilylated derivatives in the preponderance of circumstances show antihypoxic activity.
Dae-Kee K et al. [73] produced a set of 5-(pyridin-2-yl)thiazoles enclosing a
Rajan S G et al. [74] designed and synthesized a sequence of 2-(2,4-disubstituted-thiazole-5-yl)-3-aryl-3H-quinazoline-4-one
Johan et al. [75] synthesized a unique sequence for Aurora kinase inhibitors enclosing thiazole moiety (SNS-314,
HI El-Subbagh et al. [76] synthesized a sequence of 2,4-disubstituted thiazole compounds containing
The unique model of a thiazole in the best 200 drugs citations is cefdinir
The HIV-1 protease inhibitor ritonavir [78] (Norvir
The dopamine D2-agonist pramipexole
Famotidine (
One more example of a thiazole ring enclosing drug is known in the unique xanthine oxidase inhibitor febuxostat
Takeuchi et al. described the total synthesis of the cyclic tripeptide bistratamide H
The construction of two heterocyclic rings in one synthetic step has been developed for the preparation of coumarin derivatives. In this process, the thiazole ring (
Adib et al. [88] described, in the latest work, a well-organized three component reaction that is significant to the formation of essential heterocycles titled by imidazo[1,2-
S. Zheng et. al. [89] synthesized five series of thiazole derivatives (
J. Zhu et.al. [90] reported that Human dihydroorotate dehydrogenase (HsDHODH) is a flavin-dependent mitochondrial enzyme that has been specialized as a prospective therapeutic aim for the medication of rheumatoid arthritis and other autoimmune diseases. On the basis of the main compound
S. Singh et. al. [91] P-glycoprotein (P-gp) works as a therapeutic target for the improvement of multidrug conflict reversal agents. In this study, we synthesized twenty-one novel derivatives by peptide coupling at equivalent carboxyl and amino termini of (S)-valinebased bis-thiazole and mono thiazole derivatives with different chemical scaffolds. Consuming calcein-AM efflux assay, we recognized compound 51 (IC50 = 1.0 μM) containing 3,4,5-trimethoxybenzoyl and 2-aminobenzophenone groups, respectively, at the amino and carboxyl termini of the mono thiazole zwitterion. Compound 51 inhibited the photolabeling of P-gp with [125I] - iodoarylazidoprazosin with IC50 = 0.75 μM and motivated the basal ATP hydrolysis of P-gp in a concentration-dependent manner (EC50 ATPase = 0.027 μM).
Oridonin
M. E. D. Francesco et. al. [93] reported a unique type of inhibitor, which designates the identification of a structurally various series of compounds including a 2-amino-1,3-thiazole as substitution of the carbamate in P4. Optimization studies motivated on structural variations in the P3, P2, and P1 regions of the macrocycle as well as on the linked chain caused the discovery of numerous analogs characterized by outstanding levels of enzyme and cellular activity. Among these, compound
P. J. Sanfilippo et. al. [94] reported and described the synthesis and biological activity of a different kind of thiazole containing heterocycles as inhibitors of thrombin-induced human platelet aggregation. Additional estimation of selected compounds shows they inhibit platelet aggregation as motivated by a range of agonists. The highly active compounds also were established to inhibit fibrinogen binding to platelets. To further explain the mechanism of the action of these compounds, direct binding studies with the cleaned glycoprotein (GP) IIb/IIIa receptor were conducted. Flow cytometry analyzes of
J. E. M. Koezen et. al. [95] prepared numerous
P. C. Srivastava et. al. [96] published a report in which they described the glycosylthiocarboxamides were used as the starting compounds for the synthesis of 2-D-ribofuranosylthiazole-4-carboxamide and 2-β-D-ribofuranosylthiazole-5-carboxamide (
Z. Li et. al. [97] described the virtual screening data for flavivirus envelope proteins (E proteins) having been exposed to play a vital role in virus assembly, morphogenesis, and infection of host cells. Inhibition of flavivirus infection of a host cell by utilizing the small molecule envelope protein antagonist is an interesting approach to the development of antiviral agents. The virtual screening of the NCI Chemical database utilizing the dengue virus envelope protein structure showed numerous theoretical hit compounds. Bioassay consequences recognized a class of thiazole compounds with antiviral potency in cell-based analyzes. Variation of these lead compounds directed to a series of derivatives with enhanced antiviral activity and reduced cytotoxicity. The maximum activity exhibit compounds
L. J. Lombardo et.al. [98] identified thiazole-based compounds as effective as Src/Abl kinase inhibitors with outstanding antiproliferative activity against hematological and solid tumor cell lines. Compound
P. Madsen et. al. [99] explained the thiazole containing scaffold being potent human glucagon receptor antagonists with enhanced pharmacokinetic (PK) properties for expansion of pharmaceuticals for the medication of type-2 diabetes. The syntheses of compounds with cyclic moieties (5-aminothiazoles), their binding affinities for the human glucagon and GIP receptors, as well as affinities for mouse, pig, rat, dog, and monkey glucagon receptors. Normally, the compounds had less glucagon receptor affinity corresponding to compounds of the earlier series slightly, but this was rewarded for by much developed PK summaries in both rats and dogs with high oral bioavailabilities and constant high plasma coverages. The compounds exhibited species selectivity for glucagon receptor binding with very low affinities for the rat, mouse, rabbit, and pig receptors. However, dog and monkey glucagon receptor affinities seem to reflect the human situation. One of the compound sequence,
X. Cheng et.al. [100] reported a cell-based high throughput screening (HTS) operation for the search for potential candidates for octamer-binding transcription factor 4 (Oct3/4). In that process, they recognized numerous efficient small molecules for inducers of Oct3/4 expression. From HTS, optimized compounds are based on thiazole ring containing scaffold such as ethyl 2-([(4-chlorophenyl) amino])-thiazole-4-carboxylate,
C. P. Hencken et. al. [101] synthesized 23 new dehydroartemisinin (DART) trioxane analogs in which 11 thiazoles moiety-containing compounds remaining are based on two oxadiazoles, and ten carboxamides and screened them for in vitro activity in the Toxoplasma lytic cycle. Fifteen (65%) of the analogs were noncytotoxic to host cells (TD50 ≥ 320 μM). Eight thiazole compounds exhibited effective inhibition of Toxoplasma growth (IC50 = 0.25-0.42 μM), similar in potency to artemether (IC50 = 0.31 μM) and >100 times stronger inhibitory than the presently working front-line drug trimethoprim (IC50 = 46 μM). The thiazoles as a ring were more efficient than other analogs at the inhibiting progress of extracellular as well as intracellular parasites. Surprisingly, two thiazole trioxanes (
Y. Kumar et. al. [102] reported that Methyl-4-(isothiocyanatomethy1)thiazole-2-carbamate have been obtained via chemical conversion containing 2-amino-4-(chloromethy1)thiazole (
New thiazole based compounds [103] (1-(4-arylthiazol-2-yl)-2-(3-methylcyclohexylidene) -hydrazine)
A. S. Mayhoub et.al. [104] synthesized a sequence of third-generation referents of methyl 4-(dibromomethyl)-2-(4-chlorophenyl)thiazole-5-carboxylate
T. A. Dineen et.al. [105] reported the variation in structure
B. Ghosh et.al. [106] reported structure-activity relationship investigated on a unique hybrid sequence of derivatives where structural modification of aromatic hydrophobic moieties associated with the piperazine ring and bioisosteric exchange of the aromatic tetralin moieties were passed out. Binding assays were accepted with HEK-293 cells uttering either D2 or D3 receptors with tritiated spiperone to estimate inhibition constants (Ki). Functional activity of designated compounds in stimulating GTPγS binding was evaluated with CHO cells uttering human D2 receptors and AtT-20 cells uttering human D3 receptors. SAR results recognized compound 136 as one of the lead molecules with better agonist activity for D3 receptor (EC50 (GTPγS); D3= 0.52 nM; D2/D3 (EC50): 223). Compounds
J. Das et.al. [107] explained that the 2-aminothiazole
Major medicinal chemistry researcher focused on good docking small molecules inhibits the type 2 diabetes performances to have an insufficient or deficiency in one or both of these processes. Compounds that can activate glucokinase (GK) may serve as effective treatments for type 2 diabetes. In this process R. J. Hinklin et al. [108] reported that the recognition and preliminary optimization of a series of allosteric glucokinase activators (GKAs), revealed an early thiazolylamino pyridine-based hit that was elevated using a structure-based design approach and recognized
Spinal muscular atrophy (SMA), an inherited autosomal neurodegenerative disease, is the foremost genetic disorder disturbing infant mortality. Clinically, there are four kinds of SMA (types I, II, III, and IV). In fact, SMA is the top one genetic origin of death in children below the age of two, and several children life have been spoil due to confined to wheelchairs. There is presently no medication or effective treatment for SMA. Structure-activity relationships including microsomal stability, cell permeability, and
M. D, Rose, et al. [110] discussed the inhibition and antiviral activity consequence synthesis of 14- and 15-membered macrocycles for HIV-1 protease inhibitors (PIs) as obtained by ring-closing metathesis of the respective linear PIs. The macrocycles were very highly active than the linear precursors and compound 143, with a 2-thiazolyl ring was the best potent PI of this new series (Ki 2.2 nM, EC50 = 0.2 μM).
The preparation of a sequence of quinazolines inserted at C4 by aminothiazole ring is reported [111]. Their
Approximately, the thiazole ring containing compound exhibits cathepsin K inhibitors [112]. The amalgamation of binding elements resulted at sub-250 pM, reversible, selective, and orally bioavailable cathepsin K inhibitors. In a series on of the compound exhibited single digit nanomolar inhibition
Haffner et. al. a series of thiazoloquinazolinones [113] were prepared and studied the inhibitory activity against CD38. Numerous compounds were also revealed to have good pharmacokinetic properties and established the capability to raise NAD levels in plasma, liver, and muscle tissue. Specifically, compound
Thiazolo[5,4-d]pyrimidines and thiazolo[4,5-d]pyrimidines are structurally mimic with purines, in which a 1,3-thiazole ring system exchanges the imidazole moiety. While purine chemistry is broadly discussed in the literature, the number of medicinal chemistry publications that reported the synthesis and biological studies of thiazolopyrimidines is narrow comparable with purines. Seemingly, the thiazolopyrimidine scaffold is not very often used in drug discovery platforms. However, biological activities of unequivocal thiazolo[4,5-d]pyrimidines and thiazolo[5,4-d]pyrimidines have been described. A summary of available compounds with their biological significance is presented in Figures 147,
Thiazolo[4,5-d]pyrimidine derivative
2,5-Diaminothiazolo[5,4-d]pyrimidin-7(6H)-one (Compound
5. General Synthetic Routes to Thiazolo[5,4-d]pyrimidines
In wide-ranging, pyrimidines with a nitrogen-containing substituent at position 5 (such as an amino or nitro group) can work as precursors for the formation of thiazolo[5,4-d]pyrimidines by thiazole ring condensation. 5-Amino- or 5-nitropyrimidines can be organized from diethyl amino-, nitro-, or acetylamino-malonate by reacts with coupling reagents such as thiourea [130], urea [131], guanidine [132] and amidines [133] in alkali conditions. By reaction of the 4,6-dihydroxypyrimidine analog with a thionation reagent (Lawesson’s reagent or phosphorus pentasulfide) in pyridine, alteration of oxygen into sulfur and thiazole ring closure is accomplished. Interaction of 5-amino-6- mercaptopyrimidines with reagents such as phosgene [134], formic acid [135], and acid anhydride [136] also gives thiazolo[5,4-d]pyrimidines.
Thiazolo[5,4-d]pyrimidine-1-N-oxides, ready to obtain from 6-chloro-1,3-dimethyl-5-nitropyrimidinone by reaction with mercapto compounds, monitored by base catalyzed dehydrative cyclization, can be simply deoxygenated to produce thiazolopyrimidines. Reductive deoxygenation by treatment of the thiazolopyrimidine oxides with sodium dithionite or oxidative deoxygenation with dimethylformamide at reflux temperature can produce the anticipated thiazolopyrimidines [137].
2-Mercaptothiazolo[5,4-d]pyrimidines easily obtained from 6-chloro-5-nitropyrimidines by the reaction with carbon disulfide and sodium sulfide [138].
2-Amino-7-chlorothiazolo[5,4-d]pyrimidines are prepared from 5-amino-4,6-dichloropyrimidine and isothiocyanate in presence base [139].
Ahmed et al. [140] reported the synthesis of thiazolo[5,4-d]pyrimidines from pyrimidines without 5-amino or 5-nitro substituents. The reaction between 5-bromo-4-thioxo-pyrimidinones and dimethylcyanamide affords carbodiimide intermediates, which is a very fast intramolecular cyclization to produce a thiazole ring.
On the other hand, thiazolo[5,4-d]pyrimidines also obtained from 5-aminothiazole derivatives, are prepared from aminomalononitrile (or its derivatives) and isothiocyanates [141] or thioesters [142]. The next to 5-amino and 4-cyano (or conforming carboxamide or ester groups) on the thiazole ring are proper functionalities to concept a fused pyrimidine ring system. 7-Aminothiazolo[5,4-d]pyrimidines can be prepared from 5-amino-4-cyanothiazoles by reaction with reagents such as orthoesters and amidines [143,144]. The reaction between 5-amino-4-carboxamide (or carboxylate) thiazoles and orthoesters [145], formamide [146], and ethyl chloroformate/DMF [147] gives thiazolo[5,4-d]pyrimidin-7(6H)ones.
Additionally, Thiazolo[5,4-d]pyrimidinones readily to obtained from the corresponding oxazolopyrimidines. In fact, that 1,3-oxazole ring system is quickly converted into a 1,3-thiazole by a thermal rearrangement. The thioamide replaced oxazole derivative is prepared from the corresponding amide by reacts with Lawesson’s reagent. Heating generates the nitrile ylide by electrocyclic ring opening, followed by a 1,5-dipolar electrocyclization affording the thiazole [148].
6. General Synthetic Routes to Thiazolo[4,5-d]pyrimidines
The preparation of thiazolo[4,5-d]pyrimidines from a properly substituted pyrimidine compound yields 2-aminothiazolo[4,5-d]pyrimidines. Thiocyanation of 6- aminopyrimidines reacts with potassium thiocyanate, bromine and pyridine, proceeded by cyclization yields the 2-aminothiazolo[4,5-d]pyrimidines [149].
Condensation of 5-bromobarbituric acid with thiourea and/or its derivatives in the presence of an alkali yields thiazolo[4,5-d]pyrimidine derivatives [150].
Another significant technique for the preparation of thiazolo[4,5-d]pyrimidines from thiazoles is via the aza-Wittig reaction [151]. The iminophosphorane intermediates are found from 4-chloro-5-formylthiazoles which reacts with sodium azide and triphenylphosphine (Staudinger reaction). In Addition, reaction with isocyanates affords the corresponding carbodiimides, followed by heating, and undergo an electrocyclic ring closing, which upon a Dimroth-type rearrangement obtained thiazolo[4,5-d]pyrimidines [152].
It is needed to expand the hit ratio in HTS campaigns; fortunate molecular scaffold systems offer a perfect basis of main compounds. A particular library created on preferable bioisosteres groups are inserted into the main scaffold and can generate the bioactive compounds in a broad range of biological tests. Numerous researchers have developed these structures in such a fashion. For example, Ghorpade and co-workers built a library based on the thiazolopyridines privileged scaffold [153] whereas Bebernitz and co-workers made use of the chlorosulfonic acid combined with thiazolopyridines scaffold [154] (compounds
Bicyclic nitrogen, sulfur - containing heterocycles, such as Thiazolo[5,4-b]quinoline, thiazolopyridines, and thiazolopyrimidines are well-known pharmacophores in drug discovery [155-157]. Examples of promoted drugs with a bicyclic core structure include AMG-369 analogs performing as Lysophospholipid edg1 (S1P1) and Receptor Agonists Lysophospholipid edg8 (S1P5) Receptor Agonists [158]. Thiazole sulfonamides based scaffold, used as antidepressants and for the treatment of Vasopressin (AVP) V1b Antagonists [159]. Kirsch and co-workers described a solution-phase synthesis of 7-amino-thiazolo[4,5-b]pyridine derivatives [160] as well as fused-pyridine analogs such as the thiopheno[2,3-b]pyridines [161] using the Friedlander reaction.
Thiazolo[4,5-b]pyridine derivatives reveal a broad range of biological properties. For example, thiazolo[4,5-b]pyridines have confirmed actions as serine protease factor Xa (fXa) inhibitors for thrombosis [162], as metabotropic glutamate receptor 5 (mGluR5) antagonists for several CNS syndromes [163], as histamine H3-receptor antagonists for epilepsy and Alzheimer’s disease [164], as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors [165], and as cAMP phosphodiesterase (PDE) III inhibitors for congestive heart catastrophe [166].
T. Lee et. al. [167] reported a series of 2,5,6,7-tetrasubstituted thiazolo[4,5-b]pyridine derivatives (
Y. Takahashi et. al [168] described the synthesis and structure−activity relationships of a unique series of 7-dialkylamino-3-phenyl-6-methoxy pyrazolo[5,1-b]thiazole derivatives to utilize as selective antagonists of the corticotropin-releasing factor 1 (CRF1) receptor. The best favorable compound, N-butyl-3-[4-(ethoxymethyl)-2,6-dimethoxyphenyl]-6-methoxy-N-(tetrahydro-2H-pyran-4-yl)pyrazolo-[5,1-b, 1,3]thiazole-7-amine (
7. Summary
This chapter discusses the high synthetic perspective of several methods for synthesis of thiazoles and its derivatives that have been published in the last three decades. Many pharmaceutically active heterocycles have been obtained based on the reaction of acid hydrazides particularly concerning Hantzsch reaction, Dimroth type rearrangement, Tchernich reaction, CooK–Heilbron reaction, Gabriel reaction, Erlenmeyer reaction, Hartke–Seib reaction and Dubs reaction. Fundamentally α-halo carbonyl compounds and substituted thiourea or thiosemicarbazide are potential precursors for the creation of wide range of thiazole analogous as main synthon constituents for generation of several diverse heterocycles. The aza-Wittig product such as iminophosphorane intermediates obtained from 4-chloro-5-formylthiazoles by treatment with sodium azide and triphenylphosphine (Staudinger reaction) with most other various reagents like isocyanate, isothiocyanate and carbondisulfide for bicyclic generation system containing thiazole moiety under basic, acidic or neutral reaction conditions. Most of these reagents are available from simply or commercially accessible, inexpensive precursors. This chapter has also verified the noticeable feature to the advancement of an eco-friendly experimental technique for the synthesis of heterocyclic compounds. The synthetic approaches showed in this chapter can be comprehensive to the synthesis of natural macrocyclic thiazole ring containing heterocycles and also suggest that α-halo carbonyl compounds can be a favorable building block in combinatorial synthesis of functionalized heterocyclic derivatives used for the design of unique very active pharmaceutical drugs with a broad spectrum of bioresponses. In certain cases, reports on the less yield of bioactive heterocycles in this chapter could be overwhelmed by forthcoming synthetic chemists with this sustained research and new methods for extensive approach and explained experimental procedures could be explored for its development for generation of a library of such multi-functional heterocycles to afford a useful encouragement to medicinal chemistry.
Acknowledgments
I acknowledge the Department of Chemistry, Nizam College, Osmania University. Moreover, grateful to Dr. Ravi Varala, Head, IIIT, Basara, India, for the valuable support to write this chapter.
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