\r\n\tAn update on clinical manifestations, their assessment, monitoring, and imagiology, including peripheral arthritis, enthesopathy, and extra-articular findings, and, the differential diagnosis with other diseases which evolves with axial and peripheral calcifications will be provided.
\r\n
\r\n\t \r\n\tAn important component of this book must be dedicated to the more recent treatments namely with biologic therapies but focusing also on new small molecule inhibitors and experimental therapies.
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1. Introduction
Schistosomiasis is a neglected tropical disease that affects hundreds of millions of people, primarily in the developing world [1, 2]. The disease is caused by blood flukes of the genus Schistosoma; the three main infectious species are S. mansoni (in Africa and tropical South America), S. japonicum (in China and the Philippines), and S. haematobium (in Africa) [1]. Infections occur when parasites in their cercariae stage swim from their freshwater snail hosts and penetrate human skin. The cercariae then lose their tails and migrate to the intestinal or urogenital area. There they mature to adult worms, form male-female pairs, and lay eggs prolifically; the host’s disease symptoms are due to an immune response to these eggs [3]. Eggs shed into a water source by human defecation hatch and release miracidia, which infect the intermediate snail host and continue the cycle.
Chronic schistosomiasis is associated with diseases of the kidneys, spleen, liver, bladder and intestine [3]. In endemic areas, up to 75% of the incidence of bladder cancer has been attributed to infection with S. haematobium; [4, 5] the link between S. mansoni infection and cancer is still being investigated [6]. In all, the global burden due to schistosomiasis, in terms of disability-adjusted life years (DALYs, which combine premature mortality data with years lived with a disability) has been estimated at 1.7–4.5 million [7].
Current treatment of this disease relies almost exclusively on one drug: praziquantel (PZQ, Figure 1). While PZQ has so far proven effective against adult Schistosoma worms of all species, the specter of drug resistance, as well as PZQ’s ineffectiveness against immature parasites, have motivated the search for new antischistosomals. Several excellent reviews have recently been published on these efforts [8, 9, 10, 11, 12, 13]. In this chapter, I will briefly discuss current antischistosomals in use, antimalarials with anti-schistosomiasis potential, and finally, the discovery of novel scaffolds for drug development, by screening for phenotypic changes or against a specific biological target.
Figure 1.
Praziquantel (PZQ), its primary metabolite (1), and related compounds 2–5.
2. Praziquantel
In 1972, Merck and Bayer tested PZQ among 400 other drugs, in efforts to develop a commercialized treatment against schistosomiasis [14]. It was first approved and used as a veterinary treatment against the disease, but in the 1980s, it was transitioned into treatment against infections in humans [15]. It is regarded as a safe and highly effective drug against all adult Schistosoma worms [16]. PZQ’s main metabolite is its 4-trans-cyclohexanol derivative 1, which is 4 to 10 times less effective against S. mansoni than PZQ itself [17, 18].
PZQ analogs derivatized with ferrocenyl groups at various positions, including 2, were determined to have only moderate in vitro activity against S. mansoni [19]. Tricarbonylchromium PZQ derivatives such as 3, however, have demonstrated in vitro anti-schistosomiasis activity on par with that of PZQ itself [20]. Further work established that chromium derivatives of R-PZQ were more effective than derivatives of S-PZQ, but still only effected low worm burden reductions (WBRs) in vivo [21].
PZQ appears to owe its activity to its activation of a Ca2+-permeable ion channel in S. mansoni that belongs to a family of transient receptor potential (TRP) channels, which are non-selective cation channels [22, 23]. This target has been widely exploited by other antihelmintics [24, 25] as well as therapies for respiratory diseases, cancer and other conditions [26, 27, 28]. By activating this ion channel, PZQ effects a rapid calcium uptake across the ion channel, with deleterious effect to the parasite’s morphology [29].
Since PZQ has been found to target a TRP channel, TRP channels have been further studied as druggable targets for schistosomiasis. A high-throughput screen of about 16,000 compounds against a TRP channel in the melastatin family yielded 4 as a strong receptor agonist (EC50 = 1.6 ± 0.3 μM) and 32 potential receptor antagonists, including 5 [22].
3. Oxamniquine
The development of oxamniquine (OXA, Figure 2) as an anti-schistosomiasis drug began with the study of Pfizer compound UK 3883 (6) [30, 31], a conformationally restricted analog of Mirasan (7), which was itself a simplified version of the early anti-schistosomiasis drug lucanthone (8). Mirasan proved effective against S. mansoni in mice but not in primates, suggesting that it and its analogs were acting as prodrugs activated by metabolic oxidation at their benzylic positions. The hydroxymethyl metabolite of 6, OXA, has showed excellent anti-schistosomiasis activity in both mice and humans [32].
Figure 2.
Oxamniquine (OXA) and related compounds (6–11).
Although OXA can be easily absorbed orally, is active against both intestinal and liver infections, and has a lower cost than PZQ [18], it remains the second choice when compared to PZQ for a variety of reasons. OXA is only effective against S. mansoni, whereas PZQ is effective against all major forms that manifest in humans [33]. OXA also can cause a wide variety of side effects, such as nausea, dizziness, drowsiness, and headache [18]. OXA is a prodrug, converted into its reactive sulfate ester form by an S. mansoni sulfotransferase enzyme (Smp089320, or SmSULT-OR) [34, 35]. Recent work guided by the crystal structure of this enzyme has led to the development of OXA derivatives with greater efficacy not only against S. mansoni, but S. japonium and S. hematobium as well [36].
Ferrocenyl and ruthenocenyl derivatives of OXA (9–10) were also synthesized and found to be roughly as active as the parent OXA against S. mansoni, but significantly more active in in vitro testing than OXA against S. haematobium and S. japonicum [37, 38, 39]. Notably, this work also found a benzylated OXA, 11, to be effective against all three parasites in vitro [37]. However, the in vivo efficacy against the parasites was limited, in part due to their instability in acidic media [39].
4. Antischistosomal antimalarials
4.1 Artemisinins
Artemisinin (12, Figure 3) and its congeners are the active ingredients in the extracts of Artemisia annua, which have been used as traditional Chinese medicine for a variety of ailments for thousands of years [40]. The disclosure of the artemisinins’ antimalarial potential in 1979 [41] was followed closely by a 1980 report on their antischistosomal activity [42]. The schistosomicidal activity of 12 and similar antimalarials may stem from their ability to interfere with the blood-feeding parasite’s ability to detoxify heme [43].
Figure 3.
Artemisinin derivatives (12–13) and synthetic endoperoxides with antischistosomal potential (14–17).
Artemisinins such as 12 and artesunate (13) have demonstrated high in vivo efficacy against juvenile schistosomes and moderate in vivo efficacy against adult schistosomes [43], suggesting that simultaneous treatment with artemisinins and PZQ may prove complementary [40]. Although one study did find synergistic effects when artemisinins were combined with PZQ, this treatment method would have to be administered repeatedly to prevent reinfection [44].
4.2 Trioxolanes
The success of artemisinins as antiparasitic agents has motivated the development of fully synthetic derivatives [45]. OZ78 (14, Figure 3) is a carboxylic acid trioxolane that achieves high WBRs (greater than 80%) against juvenile S. mansoni in mice [46]. Its endoperoxide moiety appears to be necessary for its antischistosomal activity, as non-peroxidic analogs showed no activity. Another trioxolane, OZ418 (15), is orally active and targets multiple developmental stages of S. mansoni. With a single oral dose of 200 mg/kg, infections of juvenile S. mansoni were completely cured, and an 80% WBR was achieved [43]. Antimalarial hybrids of trioxolanes with quinine derivatives (e.g. the “trioxaquine” 16) have also demonstrated promising antischistosomal activity [8, 43], as have similar trioxolane-PZQ hybrids (e.g., the “trioxaquantel” 17) [47].
4.3 Other antimalarials
Other antimalarials, including mefloquine (18, Figure 4), have also shown broad antischistosomal activity [48]. Recent work has added pyronaridine (19) and methylene blue (20) to the list of antimalarial compounds that show promise against schistosomiasis; both demonstrated sub-micromolar IC50 values against schistosomula, as well as complete killing of adult worms at 30 μM [49]. Pyronaridine was found to be active against juvenile S. mansoni but not the adult parasite [48], while methylene blue showed good activity against adult worms in vivo. In a small observational trial in Gabon, three out of four children with an S. haematobium infection were cured with Pyramax, a combination of pyronaridine and artesunate (13) [49].
Figure 4.
Antimalarials/antiparasitics with anti-schistosomiasis activity (18–22).
Many natural products have demonstrated anti-schistosomiasis activity [10, 50, 51, 52]. The aurone scaffold is another source of antimalarial compounds [53, 54] that has been investigated for anti-schistosomiasis potential [55, 56]. Aurone 21 proved efficacious against S. mansoni in an in vivo mouse model (against both juvenile (21-day-old) and adult (49-day-old) parasites) and caused a marked decrease in both immature and mature eggs eliminated in feces by infected mice [55].
Cryptolepines, isolated from the roots of Cryptolepis sanguinolenta, have been used as traditional medicine in Central and West Africa, and more recently have studies as an antimalarial treatment [57]. Piperazinyl-substituted norneocryptolepines such as 22 have been shown to have high antischistosomal activity (IC50 < 5 μM against adult S. mansoni); six out of sixteen neocryptolepines showed 100% worm mortality at a concentration of 5 μg/mL after five days [58].
5. New antischistosomals found by phenotypic screening
In vitro phenotypic screening of selected compound sets has provided several new drug leads for further optimization [8, 59]. Compound sets prepared by the Medicines for Malaria Venture (MMV) have proven particularly fruitful in this regard. The first of these sets to be assessed was the Malaria Box, which contained 400 diverse, commercially available compounds, 200 of which were “drug-like” according to Lipinski’s Rule of Five, all with confirmed in vitro activity against the blood stage of P. falciparum [60]. In vitro screening of these compounds against newly transformed schistosomula (NTS) was followed by similar testing against adult parasites; the five most active of these compounds (23–27, Figure 5) were then tested in vivo for efficacy and pharmacokinetic properties [61]. While three of the five were ineffective in vivo (WBR <20%), compounds 26 and 27 were able to reduce worm burdens in infected mice by 52.5% and 40.8%, respectively, with a single 400 mg/kg dose [61].
Figure 5.
Antischistosomal hits from the MMV malaria box (23–27).
The diarylurea MMV665852 (26) above stood out for its good in vivo activity and its ease of synthesis, so it was chosen for further development. A set of MMV665852 analogs, including bissulfonamide, oxalamide, thiourea, carbamate, imidazolidinone, and pyrazine central moieties, was assessed against S. japonicum [62]. The parent MMV665852, along with six urea analogs, demonstrated IC50’s under 10 μM for both juvenile and adult parasites in in vitro testing, but none of them produced WBR values above 35% in mice harboring either a juvenile or an adult S. japonicum infection.
Commercially available analogs of 26, including ureas (25), benzamides (17), and carbamates (4), were screened for activity against S. mansoni as above [63]. While nine of these compounds had IC90’s of <10 μM against adult worms, only the salicylanilide 28 (Figure 6) demonstrated significant in vivo activity. While its worm burden reduction was greater than that of the lead compound 26, its cytotoxicity (as measured against L6 cells), and the resulting poor selectivity index (4.9), may preclude its further development as antischistosomal lead.
Figure 6.
Antischistosomal analogs of diarylurea 26 and quinoxaline 27 (28–38).
Further exploration of the diarylurea chemotype resulted in the synthesis and testing of 20 new analogs designed with aqueous solubility and chemical diversity in mind. Seven of these analogs demonstrated sub-micromolar IC50’s against adult S. mansoni with high antischistosomal selectivities [64]. Three of these (29–31), all bearing 4-fluoro-3-trifluoromethylaniline moieties, showed modest in vivo activity, with WBRs between 37% and 50%. Pharmacokinetic data suggest that 31 has significantly higher overall systemic exposure than the other two, perhaps due to the pyridine substituent. N,N′-diarylureas bearing pentafluorosulfanyl (▬SF5) groups, such as 32, have also been synthesized and assessed; like the other ureas tested, they demonstrated excellent activity in vitro (IC50’s as low as 0.6 μM against S. mansoni NTS) but marginal efficacy in vivo [65].
Another of the leads from the Malaria Box screening, the dianilinoquinoxaline MMV007204 (27), was also selected for further development. Quinoxaline compounds have previously demonstrated utility against other parasitic diseases such as malaria, Chagas disease, leishmaniasis, amebiasis, giardiasis, and filariasis [66]. Analogs of quinoxaline 27 (47, including 12 triazoloquinoxalines) were screened as above; three nitroquinoxalines (33–35) showed IC50’s of under 0.31 μM against adult S. mansoni worms. Again, the in vivo potency of these compounds was underwhelming, with highest WBR among them 46.3% for compound 35 [67]. In a separate contemporaneous study, other quinoxaline analogs of 36 bearing nitro, amine and amide functionalities were screened for both phenotypic and motility effects on schistosomula [68]. Compared to compound 27, compounds 36, 37 and 38 showed significantly greater efficacy against the adult worms; the latter two compounds also showed excellent activity against S. japonicum and S. haematobium adults [68].
The MMV Stasis Box, containing 400 compounds that whose development as drugs was stopped at an advanced stage for various reasons, was also explored as a source of new chemotypes for anti-schistosomiasis drug development [69]. Eleven of these compounds showed an in vitro effect against adults of least 75%, with four demonstrating complete lethality, but the only compound to have an in vivo effect on worm burden over 50% was MMV690534, (39, Figure 7) with a 51.4% WBR. Compound 39 is a TGF-β receptor I kinase inhibitor developed for cancer chemotherapy; [70] other kinase inhibitors with anti-schistosomiasis activity will be discussed later in this review.
Figure 7.
Antischistosomal hits from the MMV Statis, pathogen and pandemic response boxes (39–45).
The MMV also prepared a Pathogen Box containing 400 compounds with activity against various neglected diseases, including malaria, tuberculosis, toxoplasmosis, and schistosomiasis. Three institutions explored this compound set for anti-schistosomiasis activity; teams at the Swiss Tropical and Public Health (TPH) [71] and the University of California-San Diego (UCSD) conducted in vitro phenotypic assays of these compounds against S. mansoni NTS, while a team at the Fundação Oswaldo Cruz (FIOCRUZ) used a metabolic activity indicator to assess schistosomula viability [72]. The two phenotypic assays showed a strong 87% concordance, but the inclusion of the FIOCRUZ assay only lowered the overall concordance slightly, to 74%. At 72 h drug treatment, 35 compounds in the Pathogen Box, including the antimalarial mefloquine (18), registered as “active” on all three screens against schistosomula. Five of those common hits demonstrated moderate in vivo activity in mice infected with S. mansoni: MMV022478 (40, 70.7% WBR), MMV022029 (41, 67.8%), MMV688761 (42, 55.2%), MMV687273 (43, 22.4%), and MMV690102 (44, 32.8%) (Figure 7) [71].
Notably, PZQ was not one of those 35 common hits, showing only borderline activity in the Swiss TPH screen and no activity in the FIOCRUZ screen. This reminds us that overreliance on obvious phenotypic signs in screening might be keeping us from discovering anti-schistosomiasis compounds with more subtle modes of action, especially modes that rely on the host immune response. A recent essay by Zamanian and Chan recommends the further development of in vitro screens to more closely model in vivo environments [73].
The most recent MMV Box to be assessed for anti-schistosomiasis activity was the Pandemic Response Box, a set of compounds with antibacterial, antiviral and/or antifungal activity [74]. Phenotypic screening found 17 of these 400 compounds to have at least moderate activity (>66%) against adult S. mansoni in vitro. The most promising of these compounds was found to be the isoquinoline MMV1581558 (45), with an EC50 of 0.18 ± 0.01 μM against adult S. mansoni, and a WBR of 42 ± 25% in in vivo testing.
Phenotypic screening of a set of 2160 compounds purchased from Microsource Discovery Systems, containing 821 FDA-approved drugs, against S. mansoni NTS yielded about 100 hits, which were narrowed by subsequent screening against adult worms as well as consideration of known compound toxicity and side effects [75]. The ionophoric antibiotic lasalocid sodium 46 (Figure 8) effected moderate reductions in worm burden (~40%) and egg burden as well as improvements in spleen and liver pathology in the same model [75]. The anthelminthic niclosamide (47) demonstrated excellent in vitro activity but no WBR in infected mice; among related salicylanilides that were tested, rafoxanide (48) reduced WBRs by half at a 50 mg/kg dose [75].
Figure 8.
Other hits from phenotypic screening (46–50).
Recently, a set of 73 non-steroidal anti-inflammatory drugs (NSAIDs) was screened for activity against S. mansoni [76]; this was in part motivated by the reported antischistosomal activity of the NSAID diclofenac (49), which is structurally similar to PZQ [77]. The most active NSAID in the set proved to be mefenamic acid (50), with good activity in vitro (EC50 = 11.1 μM) and in vivo (at 400 mg/kg, >70% reduction in both worm and egg burden) [76].
5.2 High-throughput screening results
Development of reliable high-throughput screening (HTS) tools promises to accelerate the identification of novel anti-schistosomiasis chemotypes [78]. Using a previously developed high-throughput protocol for screening NTS [79], Mansour et al. tested over 294,000 compounds taken from MMV, Pfizer, European Screening Port, GSK (the Tres Cantos Antimalarial Set), and Enamine [80]. The compounds from this set selected for further development, compounds 51–57 (Figure 9) and the previously mentioned TRP channel ligand 4, demonstrated EC50 values under 7 μM for NTS, and under 15 μM for juvenile and adult worms.
Figure 9.
Leads resulting from a large high-throughput screening experiment (51–59).
Several of these leads bear indole or azaindole (e.g., triazolopyridine) units; indoles similar to 57 have also demonstrated activity against S. mansoni peroxiredoxin Prx2 and TGR in other high-throughput screening assays [81, 82]. Further development of the lead compound 52 led to the development of a series of pyrazolopyrimidines and imidazopyrazines, the latter typified by compounds 58 and 59 [83]. Compound 58 combined exceptional potency in in vitro testing (EC50 27 nM against juvenile worms, and 46 nM against adult worms) with decent metabolic stability and good in vivo efficacy.
Another HTS strategy uses ATP quantitation to assess test compounds’ effect on the number and viability of schistosomula in a sample [84]. Applying this screen to a 40,000-sample set, followed by clustering and retesting, led to compounds 60–62 (Figure 10) being identified as the most promising leads [85]. The latter of those, perhexiline maleate (62), is an anti-angina drug whose efficacy against schistosomiasis had been studied previously [86, 87]. Starting from those three hits, pharmacophore modeling resulted in the selection of compounds 63–67 as novel scaffolds for potential development. All eight of these compounds not only proved efficacious, in vitro and in vivo, against both juvenile and adult worms at 10 μM, but strongly impaired egg production in S. mansoni at sub-lethal doses (2.5–5 μM) [85].
Figure 10.
Leads resulting from a high throughput screen using ATP quantitation (60–67).
6. Target based approaches
6.1 Targeting thioredoxin glutathione reductase
The redox system of Schistosoma parasites depends on the enzyme thioredoxin glutathione reductase (TGR), This enzyme is critical to the redox homeostasis of schistosomes as it acts in the detoxification of reactive oxygen species present in the host. Inhibitors of this enzyme have been sought and assessed for antischistosomal potential [88, 89, 90, 91]. The silencing of S. mansoni TGR (SmTGR) expression with RNAi led to parasite death within 4 d in an in vitro study [89]. Though PZQ does not inhibit this enzyme, two previously studied antischistomals, potassium antimonyl tartrate (69, Figure 11) and oltipraz (70), were found to be effective SmTGR inhibitors.
Figure 11.
Inhibitors of S. mansoni thioredoxin glutathione reductase (SmTGR) (69–78).
Auranofin (71), a gold complex widely used to treat rheumatoid arthritis, strongly inhibited the enzyme (IC50 < 10 nM) and effected good WBRs (~60%) in infected mice [89]. Further work has established that treatment with 71 causes cysteine-gold-cysteine bridges to form in SmTGR, and that this process may be catalyzed by the selenocysteine present in the enzyme [92].
Early HTS efforts in this vein revealed the oxadiazole 2-oxide scaffold as a promising lead for novel SmTGR inhibitors [81]. Treatment with furoxan derivative 72 at 10 μM caused 100% parasite death in adult S. mansoni, S. japonicum and S. haematobium within 24 h in in vitro studies, and was highly effective in vivo (>88% WBR at 10 mg/kg dosage) [93]. The parasite’s phenotypic response to treatment with 72 resembled the effects of RNAi silencing of SmTGR expression [89]. The addition of a nitric oxide (NO) scavenger to the system slowed the schistosomal activity of 72 considerably, indicating that 72’s release of NO in the presence of SmTGRcontributes to its potency [93]. Further structure-activity relationship (SAR) work established the 3-cyano-1,2,5-oxadiazole-2-oxide moiety as the pharmacophore of interest [94]. Testing several aryl-substituted furoxans against S. japonicum yielded several active compounds, but no correlations between antischistosomal activity and either TGR inhibition or NO release rate [95].
HTS efforts to find other SmTGR inhibitors yielded a set of eight hits with IC50 values under 10 μM [96]. Four of these, 73–76, showed consistent antischistosomal activity against S. mansoni, S. japonicum, and S. haematobium, rapidly killing at least half the adult worms present at a 10 μM dose [96].
A secondary “doorstop pocket” binding site in SmTGR has recently been identified; binding to this site appears to preclude NADPH binding elsewhere in the enzyme [97]. Piperazine derivatives 77 and 78 were predicted to bind tightly to this pocket in binding studies, and in fact proved to be good SmTGR inhibitors with antischistosomal activity against adult worms in vitro [97].
6.2 Targeting kinases
Kinases play critical roles in regulating vital functions like cell proliferation, differentiation, apoptosis, and migration in various organisms. The use of protein-kinase-targeting drugs against S. mansoni and S. japonicum has been reviewed recently [98, 99, 100]. S. mansoni has 357 kinases; 351 of those are transcribed in adults with 268 being protein kinases (PKs) [99]. Phenotypic screening of a set of 114 approved oncology drugs against S. mansoni NTS revealed several kinase inhibitors with good activity against both NTS and adult S. mansoni (IC50 < 10 μM) in vitro [101]. Six of those compounds (Figure 12)— trametinib (79), bosutinib (80), ponatinib (81), afatinib (82), sunitinib (83), and vandetanib (84)—were then assessed for in vivo activity. In a murine model, only 79 and 84 showed in vivo efficacy, with WBR values of 63.6% and 48.1%, respectively [101].
Figure 12.
Anti-schistosomiasis kinase inhibitors (79–86).
Protein tyrosine kinases (PTKs) are involved in angiogenesis, reproduction, cell proliferation, and many other processes [102]. Many PTK inhibitors (or “tyrphostins”, for tyrosine phosphorylation inhibitors [103]) are able to inhibit multiple PTKs, including receptor tyrosine kinases (RTKs) like growth factor receptors, insulin receptors, (IR) and Venus kinase receptors (VKR). Among the RTK inhibitors that have demonstrated antischistosomal activity is BIBF1120 (85), which inhibits fibroblast growth factor receptors in S. mansoni (SmFGFR-A and -B) and which, in in vitro testing, caused unpairing of coupled worms at 5 μM and complete worm death within 48 h at 10 μM [104]. Another is tyrphostin AG1024 (86), which inhibits both insulin receptors and VKRs in S. mansoni, induces death in both schistosomula and adult worms at 10 μM [105].
Other kinases that have been studied as antischistosomal targets include mitogen-activated protein kinases (MAPKs) [106, 107], Polo-like kinases (PLKs) [108], Abl-kinase [109], and SmTAO and SmSTK25, two protein kinases discovered in a recent large-scale RNAi screen to be critical to worm survival [110].
6.3 Targeting hemozoin formation
Like other blood-feeding parasites, S. mansoni must free themselves of toxic free heme, and do so by polymerizing heme to crystalline hemozoin [111, 112]. Inhibiting the parasites’ heme polymerization, then, presents another anti-schistosomiasis strategy; this is considered to be the antischistosomal mode of action for several antimalarials [113, 114]. However, recent work showing that some hemozoin in the Schistosoma gut is actually consumed to yield free iron for egg development indicates that there is more to learn about hemozoin formation in this parasite [115].
A series of pyrido[1,2-a]benzimidazoles, some of which with demonstrated inhibition of heme polymerization in P. falciparum, were screened against S. mansoni [116]. A majority of the compounds tested (48 of 57) showed good activity against NTS, with 19 of those demonstrating IC50 values below 3 μM against adult worms. However, the correlation between hemozoin inhibition and antischistosomal activity was weak (R2 < 0.05 for both NTS and adults).
Further investigation of this scaffold led to analogs 87 and 88, with IC50’s under 0.4 μM against adult S. mansoni and moderately good WBR effects in infected mice (62.2% and 69.1%, respectively) [117], and to the chiral 1-phenylethylamine derivative 89, which combined excellent WBR activity (89.6%) at 50 mg/kg with some toxicity concerns (Figure 13) [118].
Cysteine proteases are integral to metabolism, nutrition and immune invasion in several parasites, including Trypanosoma cruzi, Trypanosoma brucei, and S. mansoni [119, 120]. In particular, S. mansoni cathepsin B1 (SmCB1) inhibitors have been assessed for anti-schistosomiasis activity. A series of thiosemicarbazone and thiazoles were assessed for SmCB1 inhibitory activity and screened for phenotypic effect on S. mansoni schistosomula and adult worms [121]. The best SmCB1 inhibitor found, thiosemicarbazole 90 (IC50 = 1.5 ± 0.4 μM), displayed no activity against the parasite in vitro, while thiazole 91, which showed no SmCB1 inhibition, was the most active compound against schistosomula, and the only one active against adult worms, in the set [121]. However, a series of peptidomimetic vinyl sulfones including K11777 (92) has demonstrated both excellent SmCB1 inhibitory efficacy (IC50 = 2.09 ± 0.08 nM for 92) and good activity against schistosomula in vitro [122, 123].
6.5 Targeting tubulin
Tubulin, and tubulin-containing cellular components like microtubules, which are essential for cell division and many other functions of the eukaryotic cell, have long been considered druggable targets in S. mansoni [124, 125]. In 1977, colchicine and vinblastine were shown to inhibit red blood cell ingestion and microtubule formation in the parasite [126]. However, the cytotoxicity of these natural products preclude their wider application as anti-schistosomiasis agents.
Phenotypic screening of a library of tubulin-binding compounds led to the further exploration of the phenylpyrimidine scaffold as a source of new leads [127]. Further development resulted in thiophene-substituted phenylpyrimidines such as 93, which reduced worm movement by over 90% at 5 μM but lacked the mammalian cell cytotoxicity of other tubulin-targeting compounds [127].
6.6 Targeting histone deacetylase
Histone deacetylase (HDAC) inhibitors, developed for epigenetic cancer chemotherapy [128], have shown effectiveness against S. mansoni at all stages [129, 130, 131]. In target validation studies, reducing expression of S. mansoni HDAC8 (SmHDAC8) leads to decreased worm and egg counts in infected mice [132]. A series of hydroxamic acid SmHDAC8 inhibitors has been developed [133, 134]; the most potent of these, dibenzofuran 94, strongly inhibited SmHDAC8 (IC50 = 270 nM) and killed >98% of S. mansoni schistosomula at 10 μM, but its poor solubility foiled efforts to test its in vivo activity [134]. Triazole hydroxamic acids such as 95 were found to have similar in vitro activity [135]. Related enzyme studied as S. mansoni drug targets have included SmHDAC6 [136], histone methyltransferase EZH2 [137], and some sirtuins (particularly SmSirt1 and SmSirt2) [138, 139].
6.7 Other targets
Other S. mansoni targets being investigated for new antischistosomal drugs include phosphodiesterase-4 [140, 141, 142], dihydroorotate dehydrogenase [143], 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase [144, 145], farnesyl transferase [146], carbonic anhydrase [147], NAD+ catabolizing enzyme [148], cytochrome P450 (CYP3050A1) [149] and aldose reductase [9, 150, 151].
7. Conclusion
The drawbacks of global schistosomiasis monotherapy with PZQ have motivated considerable work to generate a pipeline of new drug leads for further development. In recent years, screening studies agnostic on candidates’ modes of action have complemented more target-focused work. The limits of both approaches are evident, as hit compounds with excellent in vitro activity often fail to ameliorate a Schistosoma infection in in vivo models. This calls for better understanding of the pharmacokinetics required of effective schistosomicides, better screening techniques to approximate in vivo conditions, and more research into host-parasite interaction. The embrace of these challenges by the drug development community is encouraging.
Acknowledgments
We thank Judith Humphries and Clayton Agler for helpful discussions.
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Many new drug leads have arisen from screening existing sets of compounds such as the Open Access Boxes developed by the Medicines for Malaria Venture (MMV) in collaboration with the Drugs for Neglected Diseases Initiative (DNDI). Other leads have been found through work focused on druggable targets such as kinases, histone deacetylases, proteases, and others. This chapter will discuss recent work concerning the discovery and development of novel anti-schistosomiasis drug leads from many sources.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/80720",risUrl:"/chapter/ris/80720",signatures:"Ezra J. Marker and Stefan L. Debbert",book:{id:"11380",type:"book",title:"Parasitic Helminths and Zoonoses - From Basic to Applied Research",subtitle:null,fullTitle:"Parasitic Helminths and Zoonoses - From Basic to Applied Research",slug:null,publishedDate:null,bookSignature:"Prof. Jorge Morales-Montor, Dr. Víctor Hugo Del Río-Araiza and Dr. Romel Hernández Bello",coverURL:"https://cdn.intechopen.com/books/images_new/11380.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-568-3",printIsbn:"978-1-80355-567-6",pdfIsbn:"978-1-80355-569-0",isAvailableForWebshopOrdering:!0,editors:[{id:"63810",title:"Prof.",name:"Jorge",middleName:null,surname:"Morales-Montor",slug:"jorge-morales-montor",fullName:"Jorge Morales-Montor"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Praziquantel",level:"1"},{id:"sec_3",title:"3. Oxamniquine",level:"1"},{id:"sec_4",title:"4. Antischistosomal antimalarials",level:"1"},{id:"sec_4_2",title:"4.1 Artemisinins",level:"2"},{id:"sec_5_2",title:"4.2 Trioxolanes",level:"2"},{id:"sec_6_2",title:"4.3 Other antimalarials",level:"2"},{id:"sec_8",title:"5. New antischistosomals found by phenotypic screening",level:"1"},{id:"sec_8_2",title:"5.1 Medium-throughput phenotypic screening results",level:"2"},{id:"sec_9_2",title:"5.2 High-throughput screening results",level:"2"},{id:"sec_11",title:"6. Target based approaches",level:"1"},{id:"sec_11_2",title:"6.1 Targeting thioredoxin glutathione reductase",level:"2"},{id:"sec_12_2",title:"6.2 Targeting kinases",level:"2"},{id:"sec_13_2",title:"6.3 Targeting hemozoin formation",level:"2"},{id:"sec_14_2",title:"6.4 Targeting cysteine proteases",level:"2"},{id:"sec_15_2",title:"6.5 Targeting tubulin",level:"2"},{id:"sec_16_2",title:"6.6 Targeting histone deacetylase",level:"2"},{id:"sec_17_2",title:"6.7 Other targets",level:"2"},{id:"sec_19",title:"7. 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PLoS Pathogens. 2013;9(9):e1003645'},{id:"B133",body:'Heimburg T, Chakrabarti A, Lancelot J, Marek M, Melesina J, Hauser AT, et al. Structure-based design and synthesis of novel inhibitors targeting HDAC8 from Schistosoma mansoni for the treatment of schistosomiasis. Journal of Medicinal Chemistry. 2016;59(6):2423-2435'},{id:"B134",body:'Ghazy E, Heimburg T, Lancelot J, Zeyen P, Schmidtkunz K, Truhn A, et al. Synthesis, structure-activity relationships, cocrystallization and cellular characterization of novel smHDAC8 inhibitors for the treatment of schistosomiasis. European Journal of Medicinal Chemistry. 2021;225:113745'},{id:"B135",body:'Kalinin DV, Jana SK, Pfafenrot M, Chakrabarti A, Melesina J, Shaik TB, et al. Structure-based design, synthesis, and biological evaluation of triazole-based smHDAC8 inhibitors. ChemMedChem. 2020;15(7):571-584'},{id:"B136",body:'Vogerl K, Ong N, Senger J, Herp D, Schmidtkunz K, Marek M, et al. Synthesis and biological investigation of phenothiazine-based benzhydroxamic acids as selective histone deacetylase 6 inhibitors. Journal of Medicinal Chemistry. 2019;62(3):1138-1166'},{id:"B137",body:'Pereira AS, Amaral MS, Vasconcelos EJ, Pires DS, Asif H, da Silva LF, et al. Inhibition of histone methyltransferase EZH2 in Schistosoma mansoni in vitro by GSK343 reduces egg laying and decreases the expression of genes implicated in DNA replication and noncoding RNA metabolism. PLoS Neglected Tropical Diseases. 2018;12(10):e0006873'},{id:"B138",body:'Lancelot J, Caby S, Dubois-Abdesselem F, Vanderstraete M, Trolet J, Oliveira G, et al. Schistosoma mansoni sirtuins: Characterization and potential as chemotherapeutic targets. PLoS Neglected Tropical Diseases. 2013;7(9):e2428'},{id:"B139",body:'Monaldi D, Rotili D, Lancelot J, Marek M, Wossner N, Lucidi A, et al. Structure-reactivity relationships on substrates and inhibitors of the lysine deacylase sirtuin 2 from Schistosoma mansoni (SmSirt2). Journal of Medicinal Chemistry. 2019;62(19):8733-8759'},{id:"B140",body:'Long T, Rojo-Arreola L, Shi D, El-Sakkary N, Jarnagin K, Rock F, et al. Phenotypic, chemical and functional characterization of cyclic nucleotide phosphodiesterase 4 (PDE4) as a potential anthelmintic drug target. PLoS Neglected Tropical Diseases. 2017;11(7):e0005680'},{id:"B141",body:'Botros SS, William S, Sabra AA, El-Lakkany NM, Seif El-Din SH, Garcia-Rubia A, et al. Screening of a PDE-focused library identifies imidazoles with in vitro and in vivo antischistosomal activity. International Journal for Parasitology: Drugs and Drug Resistance. 2019;9:35-43'},{id:"B142",body:'Sebastián-Pérez V, Schroeder S, Munday JC, Van Der Meer T, Zaldívar-Díez J, Siderius M, et al. Discovery of novel Schistosoma mansoni PDE4A inhibitors as potential agents against schistosomiasis. Future Medicinal Chemistry. 2019;11(14):1703-1720'},{id:"B143",body:'Calil FA, David JS, Chiappetta ER, Fumagalli F, Mello RB, Leite FH, et al. Ligand-based design, synthesis and biochemical evaluation of potent and selective inhibitors of Schistosoma mansoni dihydroorotate dehydrogenase. European Journal of Medicinal Chemistry. 2019;167:357-366'},{id:"B144",body:'Chen G, Foster L, Bennett JL. Antischistosomal action of mevinolin: Evidence that 3-hydroxy-methylglutaryl coenzyme A reductase activity in Schistosoma mansoni is vital for parasite survival. Naunyn-Schmiedeberg\'s Archives of Pharmacology. 1990;342(4):477-482'},{id:"B145",body:'Rojo-Arreola L, Long T, Asarnow D, Suzuki BM, Singh R, Caffrey CR. Chemical and genetic validation of the statin drug target to treat the helminth disease, schistosomiasis. PLoS One. 2014;9(1):e87594'},{id:"B146",body:'Probst A, Nguyen TN, El-Sakkary N, Skinner D, Suzuki BM, Buckner FS, et al. Bioactivity of farnesyltransferase inhibitors against Entamoeba histolytica and Schistosoma mansoni. Frontiers in Cellular and Infection Microbiology. 2019;9:180'},{id:"B147",body:'Da’dara AA, Angeli A, Ferraroni M, Supuran CT, Skelly PJ. Crystal structure and chemical inhibition of essential schistosome host-interactive virulence factor carbonic anhydrase SmCA. Common Biology. 2019;2(1):1-11'},{id:"B148",body:'Jacques SA, Kuhn I, Koniev O, Schuber F, Lund FE, Wagner A, et al. Discovery of potent inhibitors of Schistosoma mansoni NAD catabolizing enzyme. Journal of Medicinal Chemistry. 2015;58(8):3582-3592'},{id:"B149",body:'Ziniel PD, Karumudi B, Barnard AH, Fisher EM, Thatcher GR, Podust LM, et al. The Schistosoma mansoni Cytochrome P450 (CYP3050A1) is essential for worm survival and egg development. PLoS Neglected Tropical Diseases. 2015;9(12):e0004279'},{id:"B150",body:'Mader P, Blohm AS, Quack T, Lange-Grunweller K, Grunweller A, Hartmann RK, et al. Biarylalkyl carboxylic acid derivatives as novel antischistosomal agents. ChemMedChem. 2016;11(13):1459-1468'},{id:"B151",body:'Blohm AS, Mäder P, Quack T, Lu Z, Hahnel S, Schlitzer M, et al. Derivatives of biarylalkyl carboxylic acid induce pleiotropic phenotypes in adult Schistosoma mansoni in vitro. Parasitology Research. 2016;115(10):3831-3842'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Ezra J. Marker",address:null,affiliation:'
Department of Chemistry, Lawrence University, Appleton, Wisconsin, USA
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Department of Chemistry, Lawrence University, Appleton, Wisconsin, USA
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However, the immiscibility in the Ag and Ni constituents is diminished in the nano-sized level. The electrodeposition method has established itself as a most suitable method for synthesis of single-phase Ag-Ni alloy films due to its time efficiency, cost-effectiveness, and ability to mass production of single-phase solid solutions. In this method, the miscibility of alloying elements (i.e., Ag and Ni) and the quality of the Ag-Ni film can also be easily controlled by tuning the electrodeposition process parameters such as the magnitude of the applied current density, temperature of the electrolyte, additives in electrolytes, etc. This chapter presents a detailed overview of the process parameters affecting the miscibility, morphology, and the quality of the single solid solution of Ag-Ni film. 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Edited by Jan Oxholm Gordeladze, ISBN 978-953-51-3020-8, Print ISBN 978-953-51-3019-2, 336 pages, \nPublisher: IntechOpen \nChapters published March 22, 2017 under CC BY 3.0 license \nDOI: 10.5772/61430 \nEdited Volume
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This book serves as a comprehensive survey of the impact of vitamin K2 on cellular functions and organ systems, indicating that vitamin K2 plays an important role in the differentiation/preservation of various cell phenotypes and as a stimulator and/or mediator of interorgan cross talk. Vitamin K2 binds to the transcription factor SXR/PXR, thus acting like a hormone (very much in the same manner as vitamin A and vitamin D). Therefore, vitamin K2 affects a multitude of organ systems, and it is reckoned to be one positive factor in bringing about "longevity" to the human body, e.g., supporting the functions/health of different organ systems, as well as correcting the functioning or even "curing" ailments striking several organs in our body.
This book serves as a comprehensive survey of the impact of vitamin K2 on cellular functions and organ systems, indicating that vitamin K2 plays an important role in the differentiation/preservation of various cell phenotypes and as a stimulator and/or mediator of interorgan cross talk. Vitamin K2 binds to the transcription factor SXR/PXR, thus acting like a hormone (very much in the same manner as vitamin A and vitamin D). Therefore, vitamin K2 affects a multitude of organ systems, and it is reckoned to be one positive factor in bringing about "longevity" to the human body, e.g., supporting the functions/health of different organ systems, as well as correcting the functioning or even "curing" ailments striking several organs in our body.
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\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
\r\n
\r\n\t
\r\n
\r\n\tThis Series focuses on covering research and applied research involving the five Ps through the following topics:
\r\n
\r\n\t
\r\n
\r\n\t1. Sustainable Economy and Fair Society that relates to SDG 1 on No Poverty, SDG 2 on Zero Hunger, SDG 8 on Decent Work and Economic Growth, SDG 10 on Reduced Inequalities, SDG 12 on Responsible Consumption and Production, and SDG 17 Partnership for the Goals
\r\n
\r\n\t
\r\n
\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
\r\n
\r\n\t
\r\n
\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
\r\n
\r\n\t
\r\n
\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
\r\n
\r\n\t
\r\n
\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
\r\n
\r\n\t
\r\n
\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
",coverUrl:"https://cdn.intechopen.com/series/covers/24.jpg",latestPublicationDate:"May 26th, 2022",hasOnlineFirst:!0,numberOfOpenTopics:4,numberOfPublishedChapters:12,numberOfPublishedBooks:0,editor:{id:"262440",title:"Prof.",name:"Usha",middleName:null,surname:"Iyer-Raniga",fullName:"Usha Iyer-Raniga",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRYSXQA4/Profile_Picture_2022-02-28T13:55:36.jpeg",biography:"Usha Iyer-Raniga is a professor in the School of Property and Construction Management at RMIT University. Usha co-leads the One Planet Network’s Sustainable Buildings and Construction Programme (SBC), a United Nations 10 Year Framework of Programmes on Sustainable Consumption and Production (UN 10FYP SCP) aligned with Sustainable Development Goal 12. The work also directly impacts SDG 11 on Sustainable Cities and Communities. She completed her undergraduate degree as an architect before obtaining her Masters degree from Canada and her Doctorate in Australia. Usha has been a keynote speaker as well as an invited speaker at national and international conferences, seminars and workshops. Her teaching experience includes teaching in Asian countries. She has advised Austrade, APEC, national, state and local governments. She serves as a reviewer and a member of the scientific committee for national and international refereed journals and refereed conferences. She is on the editorial board for refereed journals and has worked on Special Issues. Usha has served and continues to serve on the Boards of several not-for-profit organisations and she has also served as panel judge for a number of awards including the Premiers Sustainability Award in Victoria and the International Green Gown Awards. Usha has published over 100 publications, including research and consulting reports. Her publications cover a wide range of scientific and technical research publications that include edited books, book chapters, refereed journals, refereed conference papers and reports for local, state and federal government clients. She has also produced podcasts for various organisations and participated in media interviews. She has received state, national and international funding worth over USD $25 million. Usha has been awarded the Quarterly Franklin Membership by London Journals Press (UK). Her biography has been included in the Marquis Who's Who in the World® 2018, 2016 (33rd Edition), along with approximately 55,000 of the most accomplished men and women from around the world, including luminaries as U.N. Secretary-General Ban Ki-moon. In 2017, Usha was awarded the Marquis Who’s Who Lifetime Achiever Award.",institutionString:null,institution:{name:"RMIT University",institutionURL:null,country:{name:"Australia"}}},subseries:[{id:"91",title:"Sustainable Economy and Fair Society",keywords:"Sustainable, Society, Economy, Digitalization, KPIs, Decision Making, Business, Digital Footprint",scope:"
\r\n\tGlobally, the ecological footprint is growing at a faster rate than GDP. This phenomenon has been studied by scientists for many years. However, clear strategies and actions are needed now more than ever. Every day, humanity, from individuals to businesses (public and private) and governments, are called to change their mindset in order to pursue a virtuous combination for sustainable development. Reasoning in a sustainable way entails, first and foremost, managing the available resources efficiently and strategically, whether they are natural, financial, human or relational. In this way, value is generated by contributing to the growth, improvement and socio-economic development of the communities and of all the players that make up its value chain. In the coming decades, we will need to be able to transition from a society in which economic well-being and health are measured by the growth of production and material consumption, to a society in which we live better while consuming less. In this context, digitization has the potential to disrupt processes, with significant implications for the environment and sustainable development. There are numerous challenges associated with sustainability and digitization, the need to consider new business models capable of extracting value, data ownership and sharing and integration, as well as collaboration across the entire supply chain of a product. In order to generate value, effectively developing a complex system based on sustainability principles is a challenge that requires a deep commitment to both technological factors, such as data and platforms, and human dimensions, such as trust and collaboration. Regular study, research and implementation must be part of the road to sustainable solutions. Consequently, this topic will analyze growth models and techniques aimed at achieving intergenerational equity in terms of economic, social and environmental well-being. It will also cover various subjects, including risk assessment in the context of sustainable economy and a just society.
",annualVolume:11975,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/91.jpg",editor:{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",fullName:"Antonella Petrillo",profilePictureURL:"https://mts.intechopen.com/storage/users/181603/images/system/181603.jpg",institutionString:null,institution:{name:"Parthenope University of Naples",institutionURL:null,country:{name:"Italy"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"179628",title:"Prof.",name:"Dima",middleName:null,surname:"Jamali",fullName:"Dima Jamali",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSAIlQAO/Profile_Picture_2022-03-07T08:52:23.jpg",institutionString:null,institution:{name:"University of Sharjah",institutionURL:null,country:{name:"United Arab Emirates"}}},{id:"170206",title:"Prof.",name:"Dr. Orhan",middleName:null,surname:"Özçatalbaş",fullName:"Dr. Orhan Özçatalbaş",profilePictureURL:"https://mts.intechopen.com/storage/users/170206/images/system/170206.png",institutionString:null,institution:{name:"Akdeniz University",institutionURL:null,country:{name:"Turkey"}}},{id:"250347",title:"Associate Prof.",name:"Isaac",middleName:null,surname:"Oluwatayo",fullName:"Isaac Oluwatayo",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRVIVQA4/Profile_Picture_2022-03-17T13:25:32.jpg",institutionString:null,institution:{name:"University of Venda",institutionURL:null,country:{name:"South Africa"}}},{id:"141386",title:"Prof.",name:"Jesús",middleName:null,surname:"López-Rodríguez",fullName:"Jesús López-Rodríguez",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRBNIQA4/Profile_Picture_2022-03-21T08:24:16.jpg",institutionString:null,institution:{name:"University of A Coruña",institutionURL:null,country:{name:"Spain"}}},{id:"208657",title:"Dr.",name:"Mara",middleName:null,surname:"Del Baldo",fullName:"Mara Del Baldo",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRLMUQA4/Profile_Picture_2022-05-18T08:19:24.png",institutionString:"University of Urbino Carlo Bo",institution:null}]},{id:"92",title:"Health and Wellbeing",keywords:"Ecology, Ecological, Nature, Health, Wellbeing, Health production",scope:"
\r\n\tSustainable approaches to health and wellbeing in our COVID 19 recovery needs to focus on ecological approaches that prioritize our relationships with each other, and include engagement with nature, the arts and our heritage. This will ensure that we discover ways to live in our world that allows us and other beings to flourish. We can no longer rely on medicalized approaches to health that wait for people to become ill before attempting to treat them. We need to live in harmony with nature and rediscover the beauty and balance in our everyday lives and surroundings, which contribute to our well-being and that of all other creatures on the planet. This topic will provide insights and knowledge into how to achieve this change in health care that is based on ecologically sustainable practices.
",annualVolume:11976,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/92.jpg",editor:{id:"348225",title:"Prof.",name:"Ann",middleName:null,surname:"Hemingway",fullName:"Ann Hemingway",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035LZFoQAO/Profile_Picture_2022-04-11T14:55:40.jpg",institutionString:null,institution:{name:"Bournemouth University",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"169536",title:"Dr.",name:"David",middleName:null,surname:"Claborn",fullName:"David Claborn",profilePictureURL:"https://mts.intechopen.com/storage/users/169536/images/system/169536.jpeg",institutionString:null,institution:{name:"Missouri State University",institutionURL:null,country:{name:"United States of America"}}},{id:"248594",title:"Ph.D.",name:"Jasneth",middleName:null,surname:"Mullings",fullName:"Jasneth Mullings",profilePictureURL:"https://mts.intechopen.com/storage/users/248594/images/system/248594.jpeg",institutionString:"The University Of The West Indies - Mona Campus, Jamaica",institution:null},{id:"331299",title:"Prof.",name:"Pei-Shan",middleName:null,surname:"Liao",fullName:"Pei-Shan Liao",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000032Fh2FQAS/Profile_Picture_2022-03-18T09:39:41.jpg",institutionString:"Research Center for Humanities and Social Sciences, Academia Sinica, Taiwan",institution:null}]},{id:"93",title:"Inclusivity and Social Equity",keywords:"Social contract, SDG, Human rights, Inclusiveness, Equity, Democracy, Personal learning, Collaboration, Glocalization",scope:"
\r\n\tThis topic is dedicated to the efforts and promotion of UNESCO SDG4, the UNESCO initiative on the future of education, and the need for a new social contract for education. It aims to disseminate knowledge on policies, strategies, methods, and technologies that increase the resilience and sustainability of the development of the future of education and the new social contract for education. It will also consider the global challenges such as globalization, demographic change, digital transformation, climate change, environment and the social pillars of sustainable development.
\r\n
\r\n\tResponses to the pandemic and the widespread discontent that preceded it must be based on a new social contract and a New Global Deal for education that ensures equal opportunities for all and respects all people’s rights and freedoms (UNESCO; 2021). Such a new social contract, as proposed by UNESCO, must be based on the general principles underlying human rights - inclusion and equality, cooperation and solidarity, and collective responsibility and interconnectedness - and be guided by the following fundamental principle: Ensure that everyone has access to quality education throughout their lives.
\r\n
\r\n\tWe face the dual challenge of delivering on the unfulfilled promise of ensuring the right to quality education for every child, youth, and adult, as well as fully realizing the transformative potential of education as a pathway to a more sustainable collective future. To achieve this, we need a new social contract for education that eliminates inequities while transforming the future. This new social contract must be based on human rights and the principles of non-discrimination, social justice, respect for life, human dignity, and cultural diversity. It must include an ethic of care, reciprocity and solidarity. The new social contract builds on inclusiveness, equity, lifelong learning, SDG, collaboration and personal learning in a global context for democracy.
\r\n
\r\n\tAt an international level, the adoption of the Open Educational Resources recommendation and the Open Science recommendation represents an important step towards building more open and inclusive knowledge societies as well as the achievement of the UN 2030 Agenda. Indeed, implementing the recommendations will help to achieve at least five more Sustainable Development Goals (SDGs) that are intertwined with the topic of this book series, namely SDG 5 (Gender equality), SDG 9 (Industry, innovation and infrastructure), SDG 10 (Reduced inequalities within and across countries), SDG 16 (Peace, justice and strong institutions) and SDG 17 (Partnerships for the goals).
",annualVolume:11977,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/93.jpg",editor:{id:"210060",title:"Prof. Dr.",name:"Ebba",middleName:null,surname:"Ossiannilsson",fullName:"Ebba Ossiannilsson",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6LkBQAU/Profile_Picture_2022-02-28T13:31:48.png",institutionString:"Swedish Association for Distance Education, Sweden",institution:null},editorTwo:null,editorThree:null,editorialBoard:[{id:"320585",title:"Ph.D.",name:"Deborah",middleName:null,surname:"Young",fullName:"Deborah Young",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002vZLcTQAW/Profile_Picture_2022-05-10T08:30:47.jpg",institutionString:"Empowering Communities Globally",institution:null},{id:"348038",title:"Associate Prof.",name:"Feyza",middleName:null,surname:"Bhatti",fullName:"Feyza Bhatti",profilePictureURL:"https://mts.intechopen.com/storage/users/348038/images/system/348038.jpg",institutionString:"Girne American University",institution:{name:"Girne American University",institutionURL:null,country:{name:"Cyprus"}}},{id:"302382",title:"Dr.",name:"Gina",middleName:null,surname:"Alvarado",fullName:"Gina Alvarado",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002mZoL9QAK/Profile_Picture_2022-05-26T08:14:10.jpg",institutionString:"Landesa, Seattle",institution:null},{id:"128665",title:"Prof.",name:"Man-Chung",middleName:null,surname:"Chiu",fullName:"Man-Chung Chiu",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bR9OrQAK/Profile_Picture_2022-03-09T08:36:59.JPG",institutionString:null,institution:{name:"Beijing Normal University",institutionURL:null,country:{name:"China"}}}]},{id:"94",title:"Climate Change and Environmental Sustainability",keywords:null,scope:null,annualVolume:null,isOpenForSubmission:!1,coverUrl:"https://cdn.intechopen.com/series_topics/covers/94.jpg",editor:null,editorTwo:null,editorThree:null,editorialBoard:null},{id:"95",title:"Urban Planning and Environmental Management",keywords:"Circular economy, Contingency planning and response to disasters, Ecosystem services, Integrated urban water management, Nature-based solutions, Sustainable urban development, Urban green spaces",scope:"
\r\n\tIf we aim to prosper as a society and as a species, there is no alternative to sustainability-oriented development and growth. Sustainable development is no longer a choice but a necessity for us all. Ecosystems and preserving ecosystem services and inclusive urban development present promising solutions to environmental problems. Contextually, the emphasis on studying these fields will enable us to identify and define the critical factors for territorial success in the upcoming decades to be considered by the main-actors, decision and policy makers, technicians, and public in general.
\r\n
\r\n\tHolistic urban planning and environmental management are therefore crucial spheres that will define sustainable trajectories for our urbanizing planet. This urban and environmental planning topic aims to attract contributions that address sustainable urban development challenges and solutions, including integrated urban water management, planning for the urban circular economy, monitoring of risks, contingency planning and response to disasters, among several other challenges and solutions.
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