Exploring the Antidiabetic Potential of Novel Carbothioamide Derivatives as α‐Glucosidase Inhibitors: In Vitro and in Vivo Insights

ABSTRACT Diabetes mellitus (DM) is a chronic metabolic disorder characterized by persistent hyperglycemia, primarily due to imbalance in insulin secretion or action, resulting in inadequate carbohydrate and lipid metabolism. In this study, carbothioamide derivatives (C1–C3) were synthesized and assessed for their antidiabetic potential through α‐glucosidase inhibition in vitro and in vivo studies. The in vitro assay revealed good α‐glucosidase inhibition, with IC 50 values of 560, 101, and 330 (µg/mL) for C1 , C2 , and C3 , respectively, compared to standard acarbose (IC 50 = 36 µg/mL). Molecular docking, DFT calculations, in silico ADMET analyses, and Mulliken charge distribution supported promising binding interactions of the compounds with key residues of α‐glucosidase (PDB ID: 5ZCC), besides with acceptable drug‐likeness, high projected gastrointestinal absorption, and no blood–brain barrier permeation. Following confirmation of in vitro activity, the derivatives were evaluated for acute toxicity and in vivo antidiabetic efficacy in alloxan‐induced diabetic mice. None of the compounds revealed toxicity up to 200 mg/kg. Compounds C1–C3 , administered at 2.5 and 5 mg/kg, considerably ( p < 0.001) reduced blood glucose levels without inducing hypoglycemia when matched compared with glibenclamide (0.5 mg/kg), and also improved body weight in diabetic mice. Among them, C2 exhibited the most promising antidiabetic activity across in vitro and in vivo models.