Synthesis of thiadiazole derivatives as competitive inhibitors of α-glucosidase and tyrosinase

Abstract

A new series of thiadiazole derivatives (3a-3j) were designed and synthesized. Their structures were confirmed by spectral data and then subjected to in vitro assessment including α-glucosidase and tyrosinase inhibitory activities. The results of the inhibitory activity show that all the synthesized analogs effectively inhibit α-glucosidase and tyrosinase, with IC50 values ranging from 0.42± 0.011 to 1.83±0.076 µM for α-glucosidase and 0.97±0.025 to 3.87±0.141 µM for tyrosinase. There, compound 3e (IC50 = 0.42± 0.011 μM) exhibited the most effective anti-α-glucosidase activity, with a Ki value of 0.18 ± 0.006 μM. Furthermore, compound 3h (IC50 = 0.97±0.025 μM) showed the best tyrosinase inhibition activity with the value of Ki 0.41 ± 0.017 μM. Through the in silico molecular docking analysis, the ability of the synthesized analogs to inhibit α-glucosidase and tyrosinase was also examined. Molecular dynamics (MD) simulations and MM-GBSA calculations were performed for 3e and 3h to support our biological findings. The favorable binding affinities and interactions displayed by both compounds with the active sites of the target enzymes illuminate their potential as competitive inhibitors. The molecular dynamics results suggest insights into the system's dynamic behavior, including the ligand-receptor complex's stability and flexibility, conformational changes, and intermolecular interactions over time. As a result of this study, it was determined that the structure of the compounds is important in drug design for diabetes and dermatological disorders.