Enriching biologically relevant chemical space around 2-aminothiazole template for anticancer drug development
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Combinatorial library based on a biologically relevant core template, 2-aminothiazole, with immense scope of diversity multiplication was designed for anticancer therapeutics. The diversity elements were incorporated through azomethine linkage on C4 hydrazine terminus in 5-benzoyl-2-arylamino-1,3-thiazole using isopropyl, isobutyl, cyclohexyl, and benzyl fragments and enrichment of chemical space therein was evaluated. Molecular docking of an in-house 200-member virtual library in anticancer target proteins- estrogen receptor (3ERT), cyclin dependent kinase (3FDN), and Aurora kinase (3LAU), identified selective binding of the compounds as ATP competitive inhibitors of 3LAU. The synthetic access to the compounds was realized through a facile and economically viable [4 + 1] ring synthesis strategy employing commercially available reagents. The in vitro cytotoxicity of selected members against human cancer cell lines indicated the potential of the designed scaffold in anticancer drug discovery, where compounds 2b, 3b, and 4b were found to be active against MCF-7 and A549 cell lines in less than ten micro molar concentrations. Moreover the predicted physicochemical properties pointed to the drug appropriateness for most of these molecules, that they obey the rule of five (RO5). Thus we present 2-alkyl/arylamino-4-alkylidene/arylidenehydrazino-5-benzoyl-1,3-thiazoles as a prospective and expandable skeleton for diversity oriented synthesis and in the discovery of selective Aurora kinase inhibitors.
KeywordsChemical space 2-Aminothiazole HAT VCHATL Anticancer activity Molecular docking
ST acknowledges IIST for financial support. Thanks are due to NIIST-TVM, IISER-TVM for support in NMR recording and ACTREC Mumbai for in vitro anticancer screening.
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Conflict of interest
The authors declare that they have no competing interests.
- Cheng Y, Avula SR, Gao W-W, Addla D, Tangadanchu VKR, Zhang L, Lin J-M, Zhou C-H (2016) Multi-targeting exploration of new 2-aminothiazolyl quinolones: synthesis, antimicrobial evaluation, interaction with DNA, combination with topoisomerase IV and penetrability into cells. Eur J Med Chem 124:935–945CrossRefPubMedGoogle Scholar
- Dandawate P, Ahmad A, Deshpande J, Swamy KV, Khan EM, Khetmalas M, Padhye S, Sarkar F (2014) Anticancer phytochemical analogs 37: synthesis, characterization, molecular docking and cytotoxicity of novel plumbagin hydrazones against breast cancer cells. Bioorg Med Chem Lett 24:2900–2904CrossRefPubMedGoogle Scholar
- Dua R, Shrivastava S, Sonwane S, Srivastava S (2011) Pharmacological significance of synthetic heterocycles scaffold: a review. Adv Biol Res 5:120–144Google Scholar
- Fancelli D, Moll J, Varasi M, Bravo R, Artico R, Berta D, Bindi S, Cameron A, Candiani I, Cappella P (2006) 1, 4, 5, 6-tetrahydropyrrolo [3, 4-c] pyrazoles: identification of a potent Aurora kinase inhibitor with a favorable antitumor kinase inhibition profile. J Med Chem 49:7247–7251CrossRefPubMedGoogle Scholar
- Jorgensen WL, Maxwell DS, Tirado-Rives J (1996) Development and testing of the OPLS All-Atom force field on conformational energetics and properties of organic liquids. J Am Chem Soc 118:11225–11236Google Scholar
- Paula SSP, Yardilyb A, Rajasekharanc K, Reji TAF (2013) Synthesis of anticancer compounds 2-(4-amino-2-arylaminothiazol-5-oyl)-N-methylbenzimidazoles. Indian J Chem 52:560–564Google Scholar
- Romagnoli R, Baraldi PG, Carrion MD, Cruz-Lopez O, Lopez Cara C, Basso G, Viola G, Khedr M, Balzarini J, Mahboobi S (2009) 2-Arylamino-4-amino-5-aroylthiazoles.“One-pot” synthesis and biological evaluation of a new class of inhibitors of tubulin polymerization. J Med Chem 52:5551–5555CrossRefPubMedPubMedCentralGoogle Scholar
- Schneider G, Schneider P (2016) Coping with complexity in ligand-based de novo design. Frontiers in molecular design and chemical information Science-Herman Skolnik Award Symposium 2015: Jürgen Bajorath. ACS PublicationsGoogle Scholar
- Schrödinger (2014) Maestro, version 9.6. LLC, New York, NYGoogle Scholar
- Sengupta S, Smitha SL, Thomas NE, Santhoshkumar TR, Devi SK, Sreejalekshmi KG, Rajasekharan KN (2005) 4‐Amino‐5‐benzoyl‐2‐(4‐methoxyphenylamino) thiazole (DAT1): a cytotoxic agent towards cancer cells and a probe for tubulin‐microtubule system. Br J Pharmacol 145:1076–1083CrossRefPubMedPubMedCentralGoogle Scholar
- Tian F-F, Jiang F-L, Han X-L, Xiang C, Ge Y-S, Li J-H, Zhang Y, Li R, Ding X-L, Liu Y (2010) Synthesis of a novel hydrazone derivative and biophysical studies of its interactions with bovine serum albumin by spectroscopic, electrochemical, and molecular docking methods. J Phys Chem B114:14842–14853CrossRefGoogle Scholar