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Enriching biologically relevant chemical space around 2-aminothiazole template for anticancer drug development

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Abstract

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.

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Acknowledgements

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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  1. Department of Chemistry, Indian Institute of Space Science and Technology, Valiamala Post-695 547, Thiruvananthapuram, India

    Sarah Titus & Kumaran G. Sreejalekshmi

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  1. Sarah Titus
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  2. Kumaran G. Sreejalekshmi
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Correspondence to Kumaran G. Sreejalekshmi.

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Titus, S., Sreejalekshmi, K.G. Enriching biologically relevant chemical space around 2-aminothiazole template for anticancer drug development. Med Chem Res 27, 23–36 (2018). https://doi.org/10.1007/s00044-017-2039-y

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