Dual-Action Compounds for Glycemic Control: N-Benzyl-2,5-Dioxopyrrolidin-3-yl-Methanesulfonamide and 2-Benzylsuccinimide mimic α-Amylase and α-Glucosidase activities to regulate blood glucose levels

Diabetes mellitus is one of the most alarming metabolic syndromes caused by high blood sugar levels. Herein, we report the identification of two potent antidiabetic agents: N-benzyl-2,5-dioxopyrrolidin-3-yl-methanesulfonamide (NDMS) and 2-benzylsuccinimide (2-BS). These molecules were evaluated for their antidiabetic potential using in vitro, in vivo, and in silico assays against their potential targets, α-amylase and α-glucosidase. For in vivo studies, an alloxan-induced diabetic rat model was used. Our results show that NDMS and 2-BS exhibit good in vitro enzyme inhibition compared to the standard acarbose drug. In in vivo assays, the acute toxicity profiles and IC50 values showed that NDMS at doses of 5 and 10 mg/kg/b. w. resulted in hypoglycemia with 247.9,178 mmol/L and 246.4,171 mmol/L. Similarly, 2-BS at the same dose resulted in a hypoglycemic effect by lowering blood glucose levels from 251.6 and 199 mmol/L to 244.8 and 181 mmol/L, respectively. Furthermore, their antihyperlipidemic effects revealed that these compounds also reduced total cholesterol, low-density lipoprotein (LDL), and triglyceride (TG) levels, while increasing high-density lipoprotein (HDL) levels. Moreover, these molecules significantly enhanced the number of pancreatic β-cells and restored normal liver morphology and serum creatinine level. Additionally, the in-silico results showed that both NDMS and 2-BS have remarkable interactions with α-amylase and α-glucosidase compared to those of the standard acarbose drug. Thus, our findings indicate that these molecules have good hypoglycemic and hypolipidemic effects and can be used as lead pharmacophores in the development of new antidiabetic drugs.