Development of new thiosemicarbazones with strong ?-glucosidase and antioxidant action

Abstract

Aim: This study aimed to synthesize a new series of thiosemicarbazone derivatives (4a-r) as multifunctional antidiabetic candidates with dual alpha-glucosidase (alpha-Glu) inhibitory and antioxidant activities to address both hyperglycemia and oxidative stress in diabetes management. Materials and methods: Compounds were synthesized and characterized spectroscopically. The in vitro studies were done on compounds for alpha-Glu inhibitory and metal-chelating properties. The docking studies and MM-GBSA experimental analyses were implemented for the evaluation of binding strength, coupled with 500 ns molecular dynamics in order to validate the stability of the enzyme-ligand complex. ADME prediction tools were employed to evaluate pharmacokinetic suitability. Results: Compound 4d (p-methylbenzyl) showing the strongest alpha-Glu inhibition (IC50 = 206.91 nM, K-i = 235.86 nM), significantly surpassing acarbose. Additionally, 4d demonstrated the most effective antioxidant activity (IC50 = 26.85 & micro;g/mL). Computational findings confirmed its favorable binding free energy (-82.36 kcal/mol) and stable interactions with catalytic residues throughout the MD simulations. ADME predictions indicated good intestinal permeability and 89% oral absorption, suggesting improved pharmacokinetic behavior. Conclusion: Compound 4d emerges as a highly promising dual-function antidiabetic candidate with strong enzymatic inhibition, effective antioxidant action, and desirable drug-like features, making it a valuable lead for future optimization and further biological evaluation. [GRAPHICS] .