New phenylthiosemicarbazide‐phenoxy‐1,2,3‐triazole‐N‐phenylacetamides as dual inhibitors against α‐glucosidase and PTP‐1B for the treatment of type 2 diabetes

Abstract

AbstractThis study describes the design, synthesis, and evaluation of a novel series of phenylthiosemicarbazide‐phenoxy‐1,2,3‐triazole‐N‐phenylacetamide derivatives (7a–l) as dual inhibitors of α‐glucosidase and protein tyrosine phosphatase 1‐B (PTB‐1B). The latter enzymes are two important targets in the treatment of type 2 diabetes. The in vitro obtained data demonstrated that all title compounds 7a–l were more potent than the standard inhibitor acarbose against α‐glucosidase while only four derivatives (7a, 7g, 7h, and 7h) were more potent than the standard inhibitor suramin against PTP‐1B. Furthermore, these data showed that the most potent α‐glucosidase inhibitor was compound 7i, with sixfold higher inhibitory activity than acarbose, and the most potent PTP‐1B inhibitor was compound 7a with 3.5‐fold higher inhibitory activity than suramin. Kinetic studies of compounds 7i and 7a revealed that they inhibited their target enzymes in a competitive mode. The docking study demonstrated that compounds 7i and 7a well occupied the active site pockets of α‐glucosidase and PTP‐1B, respectively. In silico pharmacokinetic and toxicity assays of the most potent compounds were performed, and the obtained results were compared with those of the standard inhibitors.