Novel oxadiazole derivatives as potent inhibitors of α-amylase and α-glucosidase enzymes: Synthesis, in vitro evaluation, and molecular docking studies

Objective(s): Alpha-amylase and alpha-glucosidase enzyme inhibition is an effective and rational approach for controlling postprandial hyperglycemia in type II diabetes mellitus (DM). Several inhibitors of this therapeutic class are in clinical use but are facing challenges of safety, efficacy, and potency. Keeping in view the importance of these therapeutic inhibitors, in this study we are reporting ۱۰ new oxadiazole analogs ۵ (a-g) & ۴a (a-c) as antidiabetic agents. Materials and Methods: The newly synthesized derivatives ۵ (a-g) & ۴a (a-c) were characterized using different spectroscopic techniques including FTIR,۱HNMR, ۱۳CNMR, and elemental analysis data. All compounds were screened for their in vitro α-amylase and α-glucosidase enzyme inhibitory potential, while two selected compounds (۵a and ۵g) were screened for cytotoxicity using MTT assay.Results: Two analogues ۵a and ۴a (a) exhibited strong inhibitory potential against α-glucosidase enzyme, i.e., IC۵۰ value=۱۲.۲۷±۰.۴۱ µg/ml and ۱۵.۴۵±۰.۲۰ µg/ml, respectively in comparison with standard drug miglitol (IC۵۰ value=۱۱.۴۷±۰.۰۲ µg/ml) whereas, one compound ۵g demonstrated outstanding inhibitory potential (IC۵۰ value=۱۳.۰۹±۰.۰۶ µg/ml) against α-amylase enzyme in comparison with standard drug acarbose (IC۵۰ value=۱۲.۲۰±۰.۷۸ µg/ml). The molecular interactions of these active compounds in the enzymes’ active sites were evaluated following molecular docking studies. Conclusion: Our results suggested that these new oxadiazole derivatives (۵a, ۵g & ۴a (a)) may act as promising drug candidates for the development of new alpha-amylase and alpha-glucosidase inhibitors. Therefore, we further recommend in vitro and in vivo pharmacological evaluations and safety assessments.

Keywords:

α-Amylase enzyme , α-Glucosidase enzyme , Molecular docking , MTT Assay , Oxadiazole