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

AIM: 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.

MATERIALS AND

METHODS

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.

RESULTS

Compound 4d (p-methylbenzyl) showing the strongest α-Glu inhibition (IC50 = 206.91 nM, Ki = 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.

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.