Synthesis Of Chalcone-based Thiazolidnedinone Derivatives As PTP1B Inhibitors

The prevalence of type 2 diabetes mellitus (T2DM) increased dramatically as a result of the obesity epidemic and socio-economic burden presently. T2DM was characterized by defects in insulin secretion and insulin resistance of target tissues. An ideal treatment for T2DM would result in the alleviation of the insulin-resistant state combined with weight loss. A drug target offering both of these approaches is protein tyrosine phosphatase 1B (PTP1B). PTP1B has received much attention due to its role as a negative regulator of insulin signaling.Thiazolidinedione (TZD) derivatives activate peroxisome proliferator-activated receptor y (PPARy) and used as a class of antidiabetic drug in the treatment for T2DM. Recently, some compounds containing TZD moiety exhibited PTP1B inhibitory effects. Besides, chalcones have been received considerable attention because of wide variety of pharmacological activities.In an attempt to search for more potent and highly selective PTP1B inhibitors, our researching team primarily found (Z)-5-(4-hydroxybenzylidene)oxazolidine-2,4-dione as a PTP1B inhibitor with moderate half maximal inhibitory concentration (IC50= 17.70μM). Further research to optimize the compound was carried out by introducing chalcone scaffold to the phenyl ring of benzylidene-2,4-thiazolidinedione moiety, and we varied the substituents on A ring of chalcone, besides, thiazolidinedione derivatives (11a-i), with an acetic chain substituted on N-3 position were also prepared to investigate the contribution of such structural changes to the biological activity. (Z)-5-(4-hydroxybenzylidene)thiazolidine-2,4-dione R’= H 4a-u,8a-c,9a and 9b R’= CH2COOH 11a-11iAll synthesized compounds were evaluated in vitro for their inhibitory activity against PTP1B using p-nitrophenyl phosphate (pNPP) as the substrate. Comparing with our lead compound, compounds 4a-u,8a-c,9a and 9b exhibited a remarkable enhancement in activity, expecially,4t, the most potent (IC50= 3.25μM), was 5.5-fold more active than our lead compound. This clearly demonstrated that the natural chalcone employed in this study was advantageous as an aryl moiety for the enhancement of binding affinity toward PTP1B. Meanwhile, most compounds (lla-g) incorporation of an acetic chain on N-3 of thiazolidinedione ring showed significant improvement in the potency. Especially,4-chloro and 4-bromo derivatives (11c and 11d) were tested to be more potent than others, with IC50 values of 0.96 and 1.11μM, respectively. The results indicated that acetic chain on N-3 was critical for activity, and it confirmed the importance of an anionic head in the interaction with enzyme.The compounds synthesized were characterized by IR,1H-NMR, MS.