Substituted piperazine conjugated to quinoline-thiosemicarbazide as potent α-glucosidase inhibitors to target hyperglycemia.

Diabetes mellitus, particularly type 2 diabetes, is a growing global health challenge characterized by chronic hyperglycemia due to insulin resistance. One therapeutic approach to managing this condition is the inhibition of α-glucosidase, an enzyme involved in carbohydrate digestion, to reduce postprandial blood glucose levels. In this study, a series of thiosemicarbazide-linked quinoline-piperazine derivatives were synthesized and evaluated for their α-glucosidase inhibitory activity, to identify new agents for type 2 diabetes management. Structure-activity relationship (SAR) analysis revealed that the nature and position of substituents on the aryl ring significantly impacted the inhibitory potency. Among the synthesized derivatives, the 2,5-dimethoxy phenyl substitution (7j) exhibited the most potent activity with an IC ₅₀ value of 50.0 µM, demonstrating a 15-fold improvement compared to the standard drug acarbose. Kinetic studies identified compound 7j as a competitive inhibitor, with a K _i value of 32 µM. Molecular docking simulations demonstrated key interactions between compound 7j and the active site of α-glucosidase, while molecular dynamics simulations confirmed the stability of the enzyme-ligand complex, reflected in low RMSD and RMSF values.
Competing Interests: Declarations. Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)