Acyl pyrazole sulfonamides as new antidiabetic agents: synthesis, glucosidase inhibition studies, and molecular docking analysis

Abstract

Diabetes mellitus is a multi-systematic chronic metabolic disorder and life-threatening disease resulting from impaired glucose homeostasis. The inhibition of glucosidase, particularly <i>α</i>-glucosidase, could serve as an effective methodology in treating diabetes. Attributed to the catalytic function of glucosidase, the present research focuses on the synthesis of sulfonamide-based acyl pyrazoles <b>(5a-k)</b> followed by their <i>in vitro</i> and <i>in silico</i> screening against <i>α</i>-glucosidase. The envisaged structures of prepared compounds were confirmed through NMR and FTIR spectroscopy and mass spectrometry. All compounds were found to be more potent against <i>α</i>-glucosidase than the standard drug, acarbose (IC₅₀ = 35.1 ± 0.14 <i>µ</i>M), with IC₅₀ values ranging from 1.13 to 28.27 <i>µ</i>M. However, compound <b>5a</b> displayed the highest anti-diabetic activity (IC₅₀ = 1.13 ± 0.06 <i>µ</i>M). Furthermore, <i>in silico</i> studies revealed the intermolecular interactions of most potent compounds (<b>5a</b> and <b>5b</b>), with active site residues reflecting the importance of pyrazole and sulfonamide moieties. This interaction pattern clearly manifests various structure-activity relationships, while the docking results correspond to the IC₅₀ values of tested compounds. Hence, recent investigation reveals the medicinal significance of sulfonamide-clubbed pyrazole derivatives as prospective therapeutic candidates for treating type 2 diabetes mellitus (T2DM).