A review on biological and medicinal significance of thiazoles

Phosphorus, Sulfur, and Silicon and the Related Elements ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/gpss20 A review on biological and medicinal significance of thiazoles Popat M. Jadhav, Srinivas Kantevari, Atam B. Tekale, Sheshanath V. Bhosale, Rajendra P. Pawar & Sunil U. Tekale To cite this article: Popat M. Jadhav, Srinivas Kantevari, Atam B. Tekale, Sheshanath V. Bhosale, Rajendra P. Pawar & Sunil U. Tekale (2021): A review on biological and medicinal significance of thiazoles, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI: 10.1080/10426507.2021.1945601 To link to this article: https://doi.org/10.1080/10426507.2021.1945601 Published online: 02 Jul 2021. Submit your article to this journal View related articles View Crossmark data Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=gpss20 PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS https://doi.org/10.1080/10426507.2021.1945601 REVIEW A review on biological and medicinal significance of thiazoles Popat M. Jadhava, Srinivas Kantevarib, Atam B. Tekalec, Sheshanath V. Bhosaled, Rajendra P. Paware, and Sunil U. Tekalea a Department of Chemistry, Deogiri College, Aurangabad, India; bCSIR Indian Institute of Chemical Technology, Hyderabad, India; Department of Chemistry, Shri Shivaji College, Parbhani, India; dSchool of Chemical Sciences, Goa University, Goa, India; eDepartment of Chemistry, Shiv Chhatrapati College, Aurangabad, India c ABSTRACT ARTICLE HISTORY Thiazole, a five-membered heterocyclic compound constitutes the skeleton of various commercially marketed drug candidates and the heart-core in a diverse range of entities of biological and medicinal interest. It is a versatile and essential component of natural products and medicinally significant heterocyclic compounds. The chemistry of thiazoles was widely developed in terms of anti-microbial, anti-cancer, anti-tubercular, anti-oxidant, anti-inflammatory, and other therapeutically active agents after the pioneering work of Hofmann and Hantzsch, Bogert and coworkers in 1887. Besides these, thiazole heterocycles are also useful as the constituents of several dyes and photographic materials. The present review encompasses and highlights the recent progress in the development of thiazole based heterocyclic compounds for various applications focusing it a scaffold of biological and medicinal interest. Received 28 April 2021 Accepted 15 June 2021 KEYWORDS Thiazole; molecular docking; ADMET; biological activity GRAPHICAL ABSTRACT Introduction Thiazole (1), a five-membered heterocyclic compound containing sulfur and nitrogen heteroatoms, was first described by Hantzsch and Weber in 1887.[1] The thiazole nucleus has been an intensely studied area in organic and medicinal chemistry.[2] It is an essential core present in the skeleton of many naturally occurring, medicinally and biologically active compounds including commercially marketed drugs such as CONTACT Sunil U. Tekale tekale.sunil@rediffmail.com Department of Chemistry, Deogiri College, Aurangabad 431 005, MS, India; Rajendra P. Pawar rppawar@yahoo.com Department of Chemistry, Shiv Chhatrapati College, Aurangabad 431 005, MS, India. ß 2021 Taylor & Francis Group, LLC 2 P. M. JADHAV ET AL. Figure 1. Structures of some commercially marketed thiazole drugs. Table 1. Mode of action of some thiazole based drugs. Sr. No. 1 2 3 4 5 6 7 8 9 Drug Mode of action Ritonavir Tiazofurin Abafungin Sulfathiazole Pramipexole Febuxostat Vitamin-B1 Nitridazole Amiphenazole Interferes with the reproductive cycle of HIV Metabolized to an inhibitory cofactor of inosine monophosphate dehydrogenase Interferes with the formation of a vital sterol in the fungal cell membrane Inhibiting the dihydropteroate synthase enzyme Not clear Inhibiting the xanthine oxidase enzyme Reduces intracellular protein glycation Inhibits the phosphofructokinase enzyme Respiratory stimulant ritonavir, penicillin-G, tiazofurin, abafungin, sulfathiazole, sulfazole, bleomycin, pramipexole, febuxostat, vitamin-B, and so on.[3] At the initial stages of the COVID-19 pandemic outbreak, ritonavir was used to fight against the novel coronavirus COVID-19.[4] Tiazofurin is a potential anti-cancer agent,[5] abafungin is a broad-spectrum anti-fungal agent,[6] and sulfathiazole is an organosulfur compound used as a sulfa drug.[7] Pramipexole is a medication used to treat Parkinson’s disease [8] and Febuxostat is a drug used to treat gout due to high uric acid levels.[9] Vitamin-B1 plays a crucial role in the release of energy from carbohydrates.[10] Nitridazole is employed to treat schistosomiasis.[11] Amiphenazole is a respiratory stimulant that acts as an antidote for barbiturate or opiate overdose.[12] The structures of some commercially marketed thiazole based drugs are depicted in Figure 1 and their modes of action are summarized in Table 1: The thiazole ring is also associated with photographic sensitizers, dyes, and pigments.[13] Thus, thiazoles occupy a prominent position in the drug discovery process. Prompted by the various biological activities,[14] in the present review we discuss the medicinal and biological significance of thiazole incorporated analogues with an emphasis on the recent developments. 2. Biological activities of thiazoles 2.1. Anti-microbial thiazoles Many bacteria and fungi behave as pathogens and parasites, affecting human health, the plant kingdom as well as the environment. Infectious diseases are the diseases caused by PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS 3 Figure 2. 2 D binding mode and residues involved in the recognition of MTX in DHFR binding pocket.[19] pathogenic microorganisms including various bacteria, fungi and viruses which are spread among the human community. These diseases are one of the leading causes of death all over the world. Despite enormous scientific progress, the treatment of infectious diseases remains a challenging health problem due to the increasing number of pathogens, genetic changes of the microbes, their mutations, and the emergence of bacterial resistance shown by the microorganisms to the existing drugs. Anti-microbial resistance threatens the effective prevention and treatment of infections caused by bacteria, fungi, viruses, and parasites.[15] Despite the availability of different anti-bacterial and anti-fungal drugs; research continues for the design and development of novel heterocyclic compounds as novel anti-microbial agents due to the genetic modifications and resistance shown by different pathogenic and nonpathogenic microbes for better tomorrow. In this section, we discuss the recent developments in the area of thiazole based anti-microbial agents. The synthesis and in vitro anti-microbial screening of triazole fused imidazo[2,1-b]thiazoles (2) is well documented in literature. Results showed good anti-microbial activity against the tested bacteria; possessing Minimum Inhibitory Concentration Values (MIC) values from 1.9 and 7.8 lg/mL. However, the MIC values in case of anti-fungal activity were comparatively higher (7.8 and 15.6 lg/mL), indicating lower anti-fungal activity than the anti-bacterial results. Molecular docking studies revealed that these compounds show good interactions with the receptor sites of dehydrosqualene synthase virulence factor present in the [16] Staphylococcus aureus. D. Bikobo et al. documented that the compounds (3) and (4) were good anti-microbial agents against two gram-positive, one gram-negative bacteria and two fungi. [17] Dihydrofolate reductase (Pf-DHFR) is an essential enzyme involved in the folate pathway of Plasmodium falciparum and hence serves as an important target for the development of anti-malarial drugs. Thiazole-1,3,5-triazine derivatives (5) were synthesized and screened for in vitro anti-malarial entities targeting Pf-DHFR against chloroquine-sensitive and resistant strains of P. falciparum. All Figure 3. Three dimensional representations showing the hydrogen bond interactions of the most active compound with keratinase enzyme pocket amino acids.[22] synthesized compounds exhibited considerable activity against chloroquine resistant strain. The results proved that thiazole-1,3,5-triazines act as lead targets for identifying a new class of Pf-DHFR inhibitors.[18] DHFR is an important cofactor involved in the biosynthesis of nucleic acids as well as of amino acids and hence plays a significant role in medicinal chemistry. It partially depletes the intracellular reduced folates and constitutes a privileged target for several anti-bacterial drugs. Thiazole clubbed chalcone derivatives viz. thiazolo[2,3-b]quinazolines (6) and pyrido[4,3-d]thiazolo[3,2-a]pyrimidines (7) were studied for anti-microbial activities against gram-positive and gram-negative bacteria including E. coli, B. subtilis, S. aureus, P. aeuroginosa and M. luteu. The observed results were compared with the standard drug ampicillin and ciprofloxacin. The study also suggested that the compounds could be orally absorbed and acted as anti-bacterial and anti-cancer agents with diminished toxicity. A few compounds in this series were found to bind with DHFR having nearly the same affinity as amino acid residues (Figure 2).[19] A new class of pyrazolecarboxamide derivatives containing thiazole (8) was evaluated for anti-fungal activity against Gibberella zeae, Phytophythora capsici, Sclerotonia sclerotiorum, Erysiphe graminis, and Puccinia sorghi. The results 4 P. M. JADHAV ET AL. Figure 4. Docked image of 4-f3-[4-methyl-2-(4-methylphenyl)-1,3-thiazol-5-yl]1-phenyl-1H-pyrazol-4-ylg-1-[(4-methylphenyl)methyl]-1H-1,2,3-triazole against sterol 14-a-demethylase.[23] showed that the compounds display good fungicidal activities, especially against E. graminis. Theoretical calculations and molecular docking supported the observed anti-microbial results.[20] Trisubstituted thiazoles (9) were synthesized and studied for anti-microbial potential against Staphylococcus aureus, Bacillus subtilis, gram-negative Proteus vulgaris, Escherichia coli bacterial strains, Aspergillus niger and Aspergillus flavus fungal strains possessing low MIC values. Among the screened compounds, trimethyl substituted thiazole exhibited a high anti-microbial activity and a low MIC value on account of highest LUMO energy.[21] The novel arylazothiazoles (10) and arylhydrazothiazoles (11) were synthesized and evaluated for anti-fungal activity. The thiazole derivatives exhibited good anti-fungal potential regarding keratinase activity and ergosterol biosynthesis against Candida albicans, Microsporum gypseum, and Trichophyton mentagrophytes. The results were compared with fluconazole as standard drug. The anti-fungal activity was observed to be more significant when both the side chains were aromatic. Two compounds among the series showed potent anti-fungal results due to inhibition of keratinase and ergosterol biosynthesis (Figure 3). The compounds are able to act as possible drugs and were studied for Absorption, Distribution, Metabolism and Excretion Toxicity (ADMET).[22] A series of 1-substituted thiazolyl-pyrazolyl-1,2,3-triazole derivatives (12) were synthesized and screened for anti-bacterial activity against two gram-negative strains - Escherichia coli, Proteus mirabilis, a gram-positive strain Staphylococcus albus, and in vitro anti-fungal activity against Candida albicans, Aspergillus niger, and Rhodotorula glutinis. The study revealed that the synthesized compounds exhibited promising anti-fungal activity against A. Niger with a MIC value of 31.5 mg/mL. Some of these compounds showed good ergosterol inhibition assay against A. niger cells sample at 31.5 mg/mL concentration. Molecular docking study performed against the sterol 14-a-demethylase (CYP51) from Candida albicans suggested that these compounds are able to act as anti-fungal drugs. The titled compounds showed favorable interactions with CYP51 having binding energy in the range of 20.20 to 24.97 kcal/mol (Figure 4). The most active compound showed good aromatic binding with TYR505, HIS373, TYR69 and hydrophobic interactions with GLU70 and GLN67.[23] Methicillin resistant Staphylococcus aureus (MRSA) infections are very significant global health challenges due to bacterial resistance to the existing drugs. 2,5-Disubstituted thiazoles (13) revealed a lead compound exhibiting antimicrobial activity against MRSA. The 2,5-disubstituted thiazole derivatives were synthesized and screened against MRSA. Structural modifications made to the linear chain at thiazole-C2 showed that potent anti-microbial activity was associated with good hydrophobic and non-polar moieties at the C2 position. Among the screened series, three compounds possessing substitutions at thiazole-C2 (an alkyne, p-acetylbenzene, and p-naphthalene) exhibited an improved toxicity profile against mammalian cells.[24] Some novel hydrazine-thiazoles (14) were shown to be effective anti-microbial in vitro agents against Candida, Cryptococcus species and Paracoccidioides brasiliensis They possess MIC values in the range of 0.45 to 31.2 lM. A few of the screened compounds were equipotent or even more active than the fluconazole and amphotericin standard drugs. Furthermore, the promising compounds were additionally evaluated for cytotoxicity against human embryonic kidney (HEK-293) cell lines. None of the compounds possessed significant cytotoxicity, reflecting their high selectivity. In vitro anti-fungal activity of these compounds proved their ability to act against clinically important Candida and Cryptococcus species, possessing MIC values in the range of low micromolar to nanomolar concentrations. The results of molecular modeling supported their use for the development of new anti-fungal agents. In addition, the active compounds showed low cytotoxicity to human embryonic kidney cells. The generated 2 D and 3 D-QSAR models satisfactorily supported the internal and external validation parameters. These results demonstrated the significant potential of this class of compounds as anti-fungal agents.[25] Thiazolylpyrazoline derivatives (15) were synthesized and evaluated for anti-fungal activity against pathogenic yeasts and molds by use of the broth microdilution technique. The study showed that the most promising anti-fungal derivatives were active against C. zeylanoides and had a MIC value of 250 mg/mL.[26] The 1,3,4-thiadiazole substituted thiazole derivatives (16) and (17) were synthesized and screened for in vitro antimicrobial activity against A. flavus, S. racemosum, G. candidum, and C. Albicans, gram-positive bacteria S. Pyogenes, B. subtilis, and gram-negative bacteria, P. aeruginosa and E. coli. The tested compounds possess moderate to high activity against all used fungal and bacterial strains except gramnegative bacteria as compared with the standard fungicide Amphotericin and bactericides Gentamicin and Ampicillin.[27] PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS 5 Figure 5. Molecular docking pose of E. coli DNA gyrase inhibitor II in the ATP-binding site of E. coli DNA gyrase.[28] Some 5-arylhydrazonothiazoles (22) were studied for 18 different dermatophyte fungal isolates related to Microsporum canis, Epidermophyton floccosum, and Trichophyton rubrum. The in vivo experiments revealed that one of the tested compounds was conjugated with anti-body inducing 100% healing after 45 days as revealed on T. rubrum and M. canis-infected guinea pigs.[30] The structures of some anti-microbial thiazoles are depicted in Figure 7. 2.2. Anti-cancer thiazoles Figure 6. Molecular docking pose of inhibitor (S)-7 (magenta sticks) in the E. coli DNA gyrase ATP-binding site.[28] DNA gyrase is a well validated target for the development of anti-bacterial drugs. This enzyme catalyzes changes in DNA topology during replication by introducing negative supercoils. Structural similarity of DNA gyrase and topoisomerase IV helps for dual targeting in most of the bacteria. In this regard, two series of novel E. coli DNA gyrase inhibitors possessing 2-(2-aminothiazol-4-yl)acetic acid as a central core (18) and 4,5,6,7-tetrahydrobenzo[1,2-d]thiazoles (19) and (20) were synthesized and explored to Structure Activity Relationship (SAR) to improve their anti-bacterial potential. The results showed that active compounds inhibit E. coli DNA gyrase in the sub-micromolar to low micromolar range against gram-positive E. faecalis and S. aureus and gram-negative P. aeruginosa and E. coli strains. A molecular docking study was performed to understand the binding modes of inhibitors (Figures 5 and 6). The analogues possessing a 2-(2-aminothiazol-4-yl)acetic acid skeleton showed weaker DNA gyrase inhibition (IC50: 15.9 to 169 lM).[28] Novel arylazothiazoles derived from 1-methylpiperidine4-one exhibited anti-dermatophytic potential. Some of the screened compounds were effective against the screened fungi. In particular, the substituted derivative (21) was comparable with the anti-fungal standard drug fluconazole.[29] Cancer is one of the major public health problems all over the world. It is regarded as the second major cause of death across the globe and is responsible for the death of approximately 9.6 million patients in 2018.[31] Anti-apoptotic Bcl-2 proteins significantly alter several types of tumor and constitute important targets for therapeutic intervention. Thiazole-based small molecules (23) were screened for in vitro anti-cancer activity against Bcl-2Jurkat, A-431 cancerous, and ARPE-19 cell lines. Almost all the molecules showed considerable activities as compared with the standard doxorubicin. The most potent molecule was found to be equipotent in both the cell lines, interacted with protein via hydrophobic and a few hydrogen bonding interactions (Figure 8). Molecular Dynamic simulation studies were performed to analyze conformational changes induced by the ligands in Bcl-2 (Figure 9). The molecules can be optimized to target Bcl-2 and may be developed as future anti-cancer leads.[32] RAF kinases (ARAF, BRAF and CRAF) play a significant role in the activation of MAPK signaling pathway. Among these, BRAF is the major activator of MAPK signaling pathway. The novel imidazo[2,1-b]thiazoles (24) were synthesized and evaluated for in vitro cytotoxicity potential showing excellent activity against melanoma and colon cancer cell lines. The synthesized compounds exhibited superior activity as compared with the sorafenib standard. Most of the compounds possessed promising cytotoxic activity 6 P. M. JADHAV ET AL. Figure 7. Structures of anti-microbial thiazoles. against colon cancer and melanoma cell lines. The most potent compound exhibited a potential inhibitory effect against v600e BRAF (Figure 10).[33] The new pyridone-thiazoles (25) were synthesized and evaluated for anti-proliferative potential against gastric carcinoma (MGC803), colon cancer (HCT-116), and hepatocellular cancer (Huh7) cell lines. The pyridine thiazole derivatives exhibited excellent anti-tumor activity (IC50: 8.17 lM and 3.15 lM) against HCT116 and MGC803 cells. The results were more promising than the positive PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS Figure 8. Representative structure showing the final docked structure of the most active compound with Bcl-2 (PDB ID: 4IEH).[32] Figure 9. Superposed starting and final conformations of Bcl-2-ligand 32 complex displaying the conformational change during the MD simulation.[32] 7 control 5-fluorouracil, indicating the potency and selectivity of these compounds as powerful anti-cancer agents.[34] Some novel bis-thiazole derivatives (26) were studied for cytotoxic activity against A549 human lung adenocarcinoma, NIH/3T3 mouse embryonic fibroblast and 5RP7 H-ras oncogene transformed rat embryo fibroblast cell lines. Excellent anti-cancer results were obtained for the bis-thiazoles (IC50: 37.3 ± 6.8 lg/mL and 11.3 ± 1.2 lg/mL).[35] The imidazo[2,1-b][1, 3]thiazoles (27) and imidazo[2,1b][1, 3, 4]thiadiazoles (28) were synthesized and studied for anti-tumor activity. The anti-proliferative activities of imidazo-thiazole and imidazo-thiadiazole conjugates were more pronounced against L1210 and CEM as compared with the FM3A and HeLa tumor cells. The results showed that antiproliferative activities were influenced by the substituents on the phenyl ring linked at the bicyclic systems of these hybrid entities.[36] Thiazole-nortopsentins (29) were shown to possess excellent anti-proliferative potential against 60 human tumor cell lines. The compounds showed anti-proliferative effect against the human breast cancer MCF-7 cells by proapoptotic mechanism. It was associated with DNA fragmentation, and plasma membrane phosphatidylserine, accompanied by perturbation of the cell cycle.[37] Y.H.E. Mohammed and coworkers documented synthesis and in vitro cytotoxicity of 2-amino phenyl thiazoles (30) against several cancer cell lines - A549, EAC, MCF-7 and DLA having an average IC50 of nearly 13 lM. The results of molecular gene studies supported the interlinking of HIF-1 up regulation and stabilization of p53 in the signaling.[38] T.D.S. Silva reported the synthesis of 2-pyridyl-2,3-thiazole derivatives (31) and (32) which were evaluated against leukemia including hepatocellular carcinoma, lung carcinoma, breast adenocarcinoma and non-tumor cells. Most of the compounds were highly potent in at least one cell line tested, possessing an average IC50 value greater than 3 lM. The mechanism of the synthesized compounds on the cell Figure 10. Molecular docking interactions of the active compounds (A) and (B) against BRAF kinase enzyme domain.[33] 8 P. M. JADHAV ET AL. Figure 11. (a) Structures of some anti-cancer thiazoles (b) Structures of some anti-cancer thiazoles. PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS Figure 11. Continued 9 10 P. M. JADHAV ET AL. Figure 12. Docking of the thiazole derivatives at the active site of CTP synthase PyrG. (A) The three-dimensional representation of interaction of 13p with CTP synthase PyrG, docking (XP G) score is 5.61 kcal/mol; (B) The two-dimensional interaction map of 13 P with CTP synthase PyrG.[57] Figure 13. Structures of some anti-tubercular thiazoles. arrest was explained on the basis of effects on mitochondrial depolarization, cell cycle, and DNA fragmentation.[39] A series of thiosemicarbazone and thiazole derivatives (33) were synthesized and cytotoxic screening was performed to evaluate performance of the new derivatives in five tumor cell lines. The compounds were shown to be promising in three tumor cell lines. These compounds showed an influence on cell cycle, DNA fragmentation, and mitochondrial depolarization.[40] Thiazole-2(3H)-thiones (34) bearing a 4-(3,4,5-trimethoxyphenyl) substituent were synthesized and screened for cytotoxicity against cancer cell lines (MCF-7, A549, and SKOV3). Most of the compounds exhibited a good cytotoxic activity on the screened cell lines, having IC50 values lesser than 10 lg/mL. The 3-(chlorobenzyl) derivatives exhibited the best inhibitory results against MCF-7 cells (IC50: 1.14 to 2.41 lg/mL). These thiazole derivatives did not reveal significant cytotoxicity against the normal cell lines.[41] S. M. Gomha et al. synthesized several thiazoles (35) containing a 1,3,4-thiadiazole moiety by reaction of 2-(4methyl-2-phenylthiazole-5-carbonyl)-N-phenylhydrazinecarbothioamide with hydrazonoyl chlorides. The products were evaluated for growth inhibitory potency against liver HepG2 cancer cell lines by using MTT assay. The promising compounds exhibited IC50 values ranging from 0.82 to 1.88 lM when the results were compared with doxorubicin (IC50 ¼ 0.72 lM).[42] Some novel 2-(thiazol-2-yl)hydrazonoethylthiazoles (36, 37) and (38) were studied for anti-cancer activity and their potential to inhibit matrix metalloproteinases, kinases and anti-apoptotic BCL2 proteins. The in vitro anti-cancer study against HCT-116, HT-29 and HepG2 cell lines using the MTT assay revealed IC50 values ranging from 3.16 to 3.8 lM. The observed results were supported on the basis of apoptosis mechanism through the Bcl-2 proteins.[43] S. Gomha et al. documented bis-pyrazolylthiazoles (39) incorporated with a thiophene ring for anti-tumor potential against the hepatocellular carcinoma (HepG2) cell lines. The in vitro growth inhibitory study on these compounds was carried out by using the MTT assay. The results were compared with doxorubicin as a standard which showed promising activity against the HepG2 cell lines.[44] 1,3-Thiazole-benzofuran derivatives (40–42) were documented for excellent anti-cancer potential against the human breast carcinoma (MCF-7) cell lines by S. M. Gomha et al. The compounds exhibited promising anti-cancer activity when compared with doxorubicin standard by MTT colorimetric assay.[45] Triazole incorporated thiazoles, thiadiazoles, and pyridopyrimidinones (43–45) and (46) were synthesized and PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS reported for anti-tumor activity against MCF-7 and HepG2 cell lines. SAR studies supported an excellent inhibitory potential against both the cell lines possessing IC50 ¼ 1.19 and 3.4 lM respectively.[46] Some novel hydrazono-1,3,4-thiadiazoles and phenyldiazenylthiazoles (47) exhibited anti-cancer activity against MCF-7 (WST-1 method). The most promising compounds inhibited the mitochondrial lactate dehydrogenase enzyme and were supported by the confocal laser scanning imaging of the treated cells stained by rhodamine and acridine orange dyes.[47] Some novel dihydrothiazol-3-amines (48, 49) and (50) were synthesized by using chitosan-grafted poly(4-vinylpyridine) basic catalyst under microwave irradiation. Their anticancer potential on colon carcinoma (HCT-116) and liver carcinoma (HEPG2-1) cell lines was documented. The compounds bearing 4-phenyl and 4-(thiophen-2-yl)-substituted 1,3-thiazoles turned out to be the most active compounds of the screened series.[48] The substituted thiazolyl-pyrazoles (51–53) and (54) were found to be potent anti-cancer agents against human liver carcinoma cell lines (HepG-2). Some of the evaluated compounds possess good binding affinities toward the active site of the epidermal growth factor receptor kinase enzyme. Five compounds exhibited anti-cancer results comparable with the doxorubicin standard drug.[49] Thiazoles and thiadiazoles containing a pyranochromene moiety (55-60) were documented for potent anti-cancer activity by S. M. Gomha et al.[50] A series of arylazothiazoles (61)-(63) were synthesized and studied for anti-tumor activity against colorectal (HCT116) and hepatocellular (HepG2) carcinoma cell lines.[51] The thiazoles and thiazine-thiazolidines (64)-67) were synthesized by using chitosan-grafted-poly(vinylpyridine) as basic catalyst and evaluated for anti-cancer potential against a colon carcinoma (HCT-116) as well as liver carcinoma (HEPG2) cell lines and revealed promising activity especially of the 1,3-thiazines.[52] The thiazoles (68) exhibited anti-cancer activity against colon carcinoma cell lines (HCT-116).[53] Figures 11a and 11b depict the structures of some anticancer thiazoles. 2.3. Anti-tubercular thiazoles The dormant and resistant form of Mycobacterium tuberculosis (MTB) is the major challenge for the development of novel anti-tubercular drugs. S. Belverena studied the synthesis and anti-mycobacterial activity of some polyfunctionalized 2-(pyrrolidin-1-yl)thiazoles.[54] The thiazole based heterocyclic compounds (69) and (70) were shown to exhibit an excellent anti–tubercular activity against MTB. These thiazoles were nontoxic for the screened cell lines against the isolates of multidrug-resistant tuberculosis.[55] The pantothenate synthetase (PS) inhibiting potential of some imidazo[2,1-b]thiazoles (71) and benzo[d]imidazo[2,1- 11 Figure 14. Docked complexes of (A) Celecoxib and (B) the most promising compounds with the active sites of COX-2.[60] b]thiazoles (72) revealed a significant anti–mycobacterial activity (PS IC50: 0.53 ± 0.13 lM and MIC: 3.53 lM).[56] The trisubstituted thiazoles (73) were synthesized and evaluated for anti-tubercular activity. The results of SAR showed to inhibit the dormant MTB (H37Rv) and MTB (H37Ra) strains along with nontoxic nature to the CHO cells. An SAR study revealed necessity of ester functionality at C4, hydrophobic substituents at C2 and various functional groups having hydrogen bond acceptor character at the C5 position of the thiazole moieties to enhance the anti-tubercular activity. The compounds showed potent activity against multidrug-resistant tuberculosis isolates. These compounds selectively inhibited M. tuberculosis H37Rv. In addition, a molecular docking study revealed good interactions of thiazole derivatives with Lys24 and Lys46 residues of CTP synthase (Figure 12).[57] The structures of anti-tubercular thiazoles are depicted in Figure 13. 2.4. Anti-inflammatory thiazoles Inflammation is an essential immune response that enables survival and maintains tissue homeostasis under a variety of noxious conditions, such as infection and tissue injury. However, control of inflammation has become of prime 12 P. M. JADHAV ET AL. Figure 15. Structures of some anti-inflammatory thiazoles. Figure 16. Hypothetical binding of the most active compound in a ternary complex with DNA and Top1 (derived from PDB ID: 1SC7).[64] importance due to its association with numerous diseases which results in chronic inflammation.[58] Control of pain and inflammatory disorders requires a stepwise management including classical non-steroidal antiinflammatory drugs (NSAIDs), selective cyclooxygenase-2 (COX-2) enzyme inhibitors, corticosteroids, and immunesuppressive agents. Trisubstituted thiazole compounds (74) were synthesized and evaluated for anti-inflammatory activity as compared with the standard diclofenac sodium and ibuprofen. The study revealed that the compounds showed PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS 13 Figure 17. Molecular docking of the potent anti-oxidant with the active site of COX-2.[68] promising anti-inflammatory activity. The synthesized compounds were potent candidates for the treatment of chronic inflammatory diseases and bacterial infections.[59] The hybrids of benzimidazole and thiazole rings (75) (78) showed significant COX-2 inhibitory effects (IC50: 0.045-0.075 lM). Almost all compounds possessed a potent 15-LOX inhibitory potential with IC50 values in the range of 1.67-6.56 lM. The COX-2 inhibitory activity of these compounds was equipotent with Celecoxib. Molecular docking studies showed double inhibitory activity against the 15LOX enzyme (Figure 14).[60] The structures of some anti-inflammatory thiazoles are shown in Figure 15. Figure 18. The interacting mode of the most potent compound with the active site of hMAO-A.[69] 2.5. Miscellaneous applications of thiazoles Thiazole moieties are present in various molecules having a variety of biological activities.[61] The new triazinoindole bearing thiazoles (79) were synthesized as potent anti-diabetic agents in terms of a-amylase inhibitory potential under the positive control of acarbose standard. An SAR study was established for inhibitory potential of analogs, rationalized on the basis of various substituents at the phenyl rings and even through five-membered heterocycles like thiazole and oxazole. Overall, the analogs worked as potent a-amylase inhibitors.[62] A series of pyrazolo[3.4-d]thiazole hybrids (80) were synthesized and evaluated as anti-HIV-1 NNRT inhibitors.[63] The stilbene analogs containing thiazole derivatives (81) were studied for topoisomerase I inhibitory activity. The results showed that the compounds possess promising Top1 inhibiting ability. The in vitro anti-fungal activity of (81) against F. graminearum, M. melonis, and T. cucumeris was evaluated. The compounds possessed moderate anti-fungal activity while some compounds showed more potent activity against F. graminearum and M. melonis as revealed from the molecular docking study (Figure 16).[64] A series of 4-(aryloxymethyl)thiazole derivatives (82) and (83) was synthesized and evaluated for the GPR119 agonistic effect. Several of the synthesized 4-(aryloxymethyl)thiazoles with pyrrolidine-2,5-dione moieties showed potent GPR119 agonist activities. The synthesized compounds showed high in vitro activity with improved human and rat liver microsomal stability.[59] A series of new hetero-aromatic thiazoles containing different heteroatoms (84) were synthesized and evaluated for type 2 diabetes in mice. The compounds exhibit a potent agonistic activity on FFA1 and produce a hypoglycemic effect both in normal and type 2 diabetic mice at the high dose of 60 mg/kg and twice the molar dose of TAK-875 revealed a low risk of hypoglycemia and liver toxicity as compared with TAK-875 without any side effects.[65] Chagas disease is a parasitic infection caused by protozoan Trypanosoma cruzi. The synthesis and anti–T cruzi activity of phthalimidothiazoles (85) and (86) are reported in the literature. These compounds showed potent inhibition of the trypomastigote form of the parasite at low cytotoxicity concentrations in spleen cells. The results showed that the novel series of phthalimidothiazole structure-based compounds showed potential effects against T. cruzi and possess good ability to act as lead targets against Chagas disease.[66] The 1,3-thiazoles (87) and (88) were synthesized and evaluated for anti–T. cruzi, cytotoxicity, and cruzain inhibition activities. Some of these compounds inhibit cruzain 14 P. M. JADHAV ET AL. Figure 19. Structures of some thiazoles exhibiting miscellaneous activities. and were observed to induce parasite cell death through an apoptotic process.[67] As an attempt to develop some bioactive thiazolylhydrazones (89), we reported a one-pot reaction of thiophene-2carbaldehyde or 2,4-dichlorobenzaldehyde thiosemicarbazide with various phenacyl bromides. The synthesized compounds were studied for in vitro anti-oxidant and anti-fungal activities. Pharmacokinetic data suggested that these compounds have a potential of high oral drug bioavailability. Molecular docking was performed to identify the nature of binding sites of the synthesized compounds with the active sites of COX-2 enzyme (Figure 17).[68] Many thiazolylhydrazine derivatives (90) display human monoamine oxidase (hMAO) inhibitory activity. The thiazolylhydrazine compounds were designed, synthesized, and evaluated against hMAO-A and hMAO-B inhibitory activity by an in vitro fluorometric method. The enzymatic studies showed potential of the compounds as selective, reversible, and competitive hMAO-A inhibitors. Molecular docking (Figure 18) and ADMET properties highlighted excellent hMAO inhibitory activity of these compounds.[69] New bis-1,3-thiazole (91) derivatives were synthesized and studied for in vitro anti-viral potential against 4 Hepatitis B, Hepatitis C, Influenza A, and Poliovirus. SAR PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS studies proved the anti-viral potential of the compounds with EC50 ¼ 0.56 mM.[70] Some novel thiazoles and 1,3-thiazines (92, 93) synthesized by the reaction of pyrazole-4-carboxylate with arylidenemalononitriles and hydrazonoyl halides were studied for anti-viral screening against the rabies virus by M. Abdalla et al. Moderate to high anti-viral activities were observed against the rabies virus as revealed by comparison with aphidicolin standard drug.[71] Novel 1,4-phenylene-bis-thiazolyls (94) were synthesized and reported to exhibit promising anti-hypertensive potential as a-blocking agents.[72] M. Badrey et al. documented some thiazole and thiadiazoles (95, 96) for MAO-A and MAO-B inhibitory potential on tryptamine seizure potentiation in model rats. These compounds showed good inhibitory ability. The studies showed that the compounds had better inhibitory results for MAO-A than the MAO-B. Substituents played a significant role on the MAO inhibitory potential.[73] The structures of thiazoles possessing miscellaneous activities are summarized in Figure 19. 3. 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