Synthesis And PTP1B Inhibitory Evaluation Of Chalcone Derivatives Bearing Benzimidazole Or Benzotriazole Moieties

Protein tyrosine phosphatase 1B(PTP1B)acts as a key negative regulator in both insulin and leptin signaling pathways,thereby modulates both glucose and lipid metabolism.Studies have shown that PTP1B knockout mice exhibit phenotypes of increased insulin sensitivity,improved glucose tolerance,and resistance to diet-induced obesity and a PTP1B antisense oligonucleotide normalizes blood glucose and improves insulin sensitivity in diabetic mice via a mechanism of lowering PTP1B protein expression.Thus,small molecule PTP1B inhibitors have considerable therapeutic potential for the treatment of Type 2 diabetes and obesity.In recent years,following the elucidation of the protein structure of PTP1B,many synthetic inhibitors with submicromolar or nanomolar activity were discovered through high-throughput screening and structure-based design.However,the low selectivity and poor pharmacokinetic properties of these PTPIB inhibitors restricted their further development to clinical trials.Therefore,novel inhibitors with improved pharmacological properties are still sought after.As is well documented in the literature,benzimidazole derivatives and chalcone derivatives have been reported to possess moderate PTP1B inhibitory activity,respectively.In our previous work,a series of chalcone derivatives containing 3,4-dihydroquinolin-2(1H)-one moiety(13)were identified as potent PTP1B inhibitors.In order to search for more potent PTP1B inhibitors,considering the advantages of inhibition activity against PTPIB of benzimidazole and chalcones,a series of chalcone derivatives containing benzimidazole(7a-n)or benzotriazole(8a-k)ring were designed and synthesized using combination principles.In this paper,25 compounds were designed and synthesized,and the structures of all synthesized compounds were characterized by IR,1H-NMR and HRMS.Part of the compounds were characterized by 13C-NMR.The PTP 1B inhibitory activities of the synthesized compounds were evaluated.The results indicated that almost all of the compounds showed potent PTP1B inhibitory activities.Among them,8k was found to be the most potent(IC50=2.98±0.04 μM),which PTP1B inhibitory activities was equivalent to the positive drug(Oleanolic acid).The preliminary structure-activity relationships showed the PTP1B inhibitory activity of series 8 containing benzotriazole was significantly greater than that of the series 7 containing benzimidazole.