Synthesis, SAR and Docking Studies of Substituted Aryl phenylthiazolyl phenylcarboxamide as potential Protein Tyrosine Phosphatase 1B Inhibitors

Varshney, K.; Gupta, A. K.; Rawat, A.; Srivastava, R.; Mishra, A.; Saxena, M.; Srivastava, A. K.; Jain, S.; Saxena, A. K.

doi:10.1101/472670

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bioRxiv · 10.1101/472670

Synthesis, SAR and Docking Studies of Substituted Aryl phenylthiazolyl phenylcarboxamide as potential Protein Tyrosine Phosphatase 1B Inhibitors

Varshney, K.·Gupta, A. K.·Rawat, A.·Srivastava, R.·Mishra, A.·Saxena, M.·Srivastava, A. K.·Jain, S.·Saxena, A. K.

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Abstract

Inspired by the potent PTP1B inhibitory activity reported in a novel series of substituted aryl thiazolyl phenylsulphonamides (I), sulfonyl moiety in the most active compound (I, R= OCH3, R1= CF3, 73.6% PTP1B inhibition) was replaced by benzoyl group (region B) to afford compound II which showed lesser activity (50.5% PTP1B inhibition). To optimize the activity, further structural modifications were done on compound II at region A, B and C to design and synthesize a series of 24 aryl phenylthiazolyl phenylcarboxamides for evaluation against PTP1B enzyme. Among these compounds six compounds showed good PTP1B inhibitory activity in the order of compound 38 > 30 > 29 > 37 > 22 > 19. The lowest energy conformer of compound 38 at PTP1B active site shows favorable binding similar to known PTP1B binders and explains its selectivity towards PTP1B. Compound 38 also showed promising antihyperglycemic, antidyslipidemic and insulin resistant reversal activities in vivo in STZ model and db/db mice model. Altogether, the compound 38 present an excellent candidate for future PTP1B targeted drug discovery.

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Varshney, K., Gupta, A. K., Rawat, A., Srivastava, R., Mishra, A., Saxena, M., Srivastava, A. K., Jain, S., Saxena, A. K.. 2018-11-20. Synthesis, SAR and Docking Studies of Substituted Aryl phenylthiazolyl phenylcarboxamide as potential Protein Tyrosine Phosphatase 1B Inhibitors. https://doi.org/10.1101/472670

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