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

This study aimed to synthesize a new series of thiosemicarbazone derivatives (4a-r) as multifunctional antidiabetic candidates with dual α-glucosidase (α-Glu) inhibitory and antioxidant activities to address both hyperglycemia and oxidative stress in diabetes management.

Compounds were synthesized and characterized spectroscopically. The in vitro studies were done on compounds for α-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.

Compound 4d (p-methylbenzyl) showing the strongest α-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 µg/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.

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.