| Summary: | Diabetes Mellitus (DM) is linked to various factors causing cardiovascular diseases, with uncontrolled postprandial hyperglycemia being a direct contributor. α-Glucosidase inhibitors (AGIs) aid in reducing postprandial hyperglycemia, potentially mitigating cardiovascular risks. In order to synthesize novel chemical scaffolds with possible α-glucosidase inhibition activity, a series of novel soritin sulfonamide derivatives were synthesized. The soritin hydrazide was treated with various aryl sulfonyl chlorides to obtain targeted compounds (1–16). Findings suggested that all compounds have better α-glucosidase inhibition compared to standard drugs, acarbose (2187.00 ± 1.25 μM) and 1-deoxynojirimycin (334.90 ± 1.10 μM), with IC50 values ranging from 3.81 ± 1.67 μM to 265.40 ± 1.58 μM. The most potent analog was Compound 13, a trichloro phenyl substituted compound, with IC50 value of 3.81 ± 1.67 μM. Structure–activity relationship (SAR) showed that introducing an additional chlorine group into the parent nucleus increases the potency. The docking studies validated that Compound 13 established hydrogen bonds with the active site residues Asp214, Glu276, and Asp349, while being further stabilized by hydrophobic interactions, providing an explanation for its high potency. © 2024 John Wiley & Sons Ltd.
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