Synthesis, SAR and Docking Studies of Substituted Aryl phenylthiazolyl phenylcarboxamide as PTP-1B Inhibitors

AbstractInspired 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 compoundIIwhich showed lesser activity (50.5% PTP1B inhibition). To optimize the activity, further structural modifications were done on compoundIIat 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 compound38 > 30 > 29 > 37 > 22 > 19. The lowest energy conformer of compound38at PTP1B active site shows favorable binding similar to known PTP1B binders and explains its selectivity towards PTP1B. Compound38also showed promising antihyperglycemic, antidyslipidemic and insulin resistant reversal activitiesin vivoin STZ model and db/db mice model. Altogether, the compound38present an excellent candidate for future PTP1B targeted drug discovery.