Design, synthesis, pharmacological evaluation and computational modeling of 4-formyl-2-nitrophenyl...

A novel series of thiosemicarbazone derivatives 6(a-i), synthesized from 4-formyl-2-nitrophenyl quinoline-8-sulfonate, was evaluated for its antidiabetic potential. Among them, compound 6i (IC₅₀ = 54.51 ± 0.84 µM) displayed the most potent α-glucosidase inhibition, whereas 6e (IC₅₀ = 9.66 ± 0.14 µM) exhibited superior α-amylase inhibition, indicating their dual therapeutic potential against key carbohydrate-hydrolyzing enzymes implicated in postprandial hyperglycemia. These derivatives showed structural diversity with potent and selective inhibition profiles. Structure-activity relationship analysis revealed that electron-withdrawing substituents enhanced enzyme affinity and biological activity. However, molecular docking studies demonstrated strong binding affinities for compounds 6f and 6b with docking scores of - 9.1 to - 10.4 kcal/mol against target proteins, via hydrogen bonding and π-π interactions with catalytic residues. Furthermore, in-silico ADMET evaluation predicted good oral bioavailability, low toxicity, and favorable pharmacokinetic properties. The Density Functional Theory (DFT) calculations supported experimental results, where studied compounds showed lower HOMO-LUMO energy gaps (2.41-3.42 eV), suggesting their significant chemical reactivity and molecular stability of these compounds. Overall, in-vitro and in-silico studies revealed that compounds 6b, 6f, 6e, and 6i emerged as promising lead molecules for developing dual-action therapeutic agents targeting hyperglycemia and oxidative damage in diabetes management.