Design and synthesis of novel quinoline-piperazines fused to a phenylhydrazinecarbothioamide scaffold as promising α-glucosidase inhibitors with anti-diabetic potential.

Abstract

Aims: This study focused on the design, synthesis, and dual in vitro/in silico evaluation of novel quinoline-benzoylhydrazine derivatives as α-glucosidase inhibitor for the management of hyperglycemia and type 2 diabetes mellitus.

Materials & methods: A series of quinoline-benzoylhydrazine compounds were synthesized and evaluated as α-glucosidase inhibitors. The most active compound was subjected to the kinetic study plus molecular docking and molecular dynamics simulations to elucidate the mechanism of inhibition and stability.

Results: All synthesized compounds exhibited strong α-glucosidase inhibition. Among them, 7j was the most active, with an IC₅₀ value of 1.0 µM, approximately 750-fold more potent than acarbose. SAR confirmed that electron-donating groups increased the inhibitory potency. Molecular docking for 7j disclosed a binding energy value of -11.884 kcal/mol, with π-π stacking interactions with aromatic residues, hydrophobic contacts with Pro309, and hydrogen bonds with His239. MD simulations further indicated that the complex formed between 7j and the enzyme was stable, with limited conformational fluctuations.

Conclusion: The results confirm that quinoline-piperazine derivatives bearing phenylhydrazinecarbothioamide moieties are promising scaffolds for α-glucosidase inhibition.