Hetero-substituted sulfonamido-benzamide hybrids as glucokinase activators: Design, synthesis, molecular docking and in-silico ADME evaluation

•Design and synthesis of a novel hetero-substitutued sulfonamido-benzamides.•In vivo and in vitro GK activation study by OGTT and protein 1V4S assay.•Molecular docking study performed on glucokinase 1V4S enzyme.•In-silico ADME evaluation: No violation of Lipinski's rule.•Compounds 12 and 15 appeared as most promising GK activators. A series of hetero-substituted sulphonamido-benzamide derivatives which can activate glucokinase (GK) were synthesized and screened in-vitro using Human GK activation assay and in-vivo following oral glucose tolerance test (OGTT) assays. All the molecules were docked into the active site of 1V4S receptor grid by XP docking method utilizing Schrodinger software to assess the binding interactions. Compounds 12 (EC50 = 495 nM) and 15 (EC50 = 522 nM), revealed maximum in-vitro GK activation. Selected compounds were subjected for in-vivo OGTT assay. The data revealed that same compounds 12 (135 mg/dL) showed maximum reduction in blood glucose level followed by compound 15 (142 mg/dL) at 120 min. The docking results as glide score, binding energy and interactions were reported and compounds with maximum pharmacological activity were studied precisely. In-silico ADME parameters, pharmacokinetic properties and toxicity studies were carried out and all compounds were found to have good bioavailability and nontoxic. Overall, the series of hetero-substituted sulphonamido-benzamide hybrids are safe and could be explored further for better therapeutic efficacy as GK activators. [Display omitted]