Alpha-glucosidase activity of novel pyrazolobenzothiazine 5,5-dioxide derivatives for the treatment of diabetes mellitus. Invitro combined with molecular docking approach

Abstract

Diabetes mellitus is a metabolic disease caused due to the improper secretion of insulin which leads to hyperglycaemia. According to the International Diabetes Federation (IDF), 371 million people are affected by diabetes worldwide, while 7 million people are suffering from this disease in Pakistan. Pyrazolobenzothiazine 5,5-dioxide derivatives have anti-bacterial, anti-inflammatory, antioxidant activity and have the potential to treat diabetes and other diseases. This study was designed to perform in-silico and in-vitro analysis of pyrazolobenzothiazine 5,5-dioxide derivatives against α- glucosidase for the treatment of diabetes mellitus. For this purpose, pyrazolobenzothiazine 5,5-dioxide derivatives were synthesized in the laboratory. Molecular docking analysis of pyrazolobenzothiazine 5,5-dioxide derivatives against α- glucosidase was achieved through Molecular Operating Environment (MOE) and ranked them based on binding affinity. Compounds with strong binding interaction were selected for invitro anti-diabetic analysis by enzyme inhibition assay against α- glucosidase using p-nitrophenyl-α--D-glucopyranoside (PNPG) as a substrate. Furthermore, the dose-response analysis was performed via Microdilution method. Compounds having strong bonding interactions with the active site and high scores were selected for in-vitro analysis. Compounds 1a, 1f, 1 g, 1 h showed strong bonding interaction with the active site of α- glucosidase and have docking score − 11.303, −10.189, −10.360, −10.160 respectively. Compound 1e, 1f, 1 g and 1 h showed IC50 at the concentration of 4.7 μM, 8.8 μM, 12.2 μM and 11.2 μM respectively in ezyme inhibition assay. The outcome of this study proved helpful to determine new antidiabetic agents to minimize diabetes complication.