Antidiabetic Evaluation of Thiosemicarbazone Analogs Through α-Amylase Inhibition Complemented With Computational Studies.

The antidiabetic potential of a series of thiosemicarbazones was evaluated by examining their inhibitory activity α-amylase, a key enzyme responsible for the hydrolysis of polysaccharides into simpler sugars through cleavage of internal α(1→4)-glycosidic linkages. The results revealed several potent inhibitors, with the most active compound, 1-(4-(dimethylamino)benzylidene)thiosemicarbazide (6g), exhibiting approximately two-fold greater potency compared to the reference drug acarbose. Structure-activity relationship analysis indicated that thiosemicarbazones derived from benzaldehydes and ketones (6a-6k, 7a-e) contributed predominantly to the observed activity, outperforming analogues incorporating alternative pharmacophoric scaffolds such as isatin and furan (8a-b and 9a-d). In addition to enzyme inhibition, several compounds demonstrated notable antioxidant activity across multiple in vitro assays, including nitric oxide (NO), DPPH radical scavenging, and ferric reducing antioxidant power (FRAP) assays. Molecular docking studies of representative compounds within the catalytic site of α-amylase highlighted the critical role of hydrogen bonding and π-π stacking interactions in stabilizing ligand-enzyme complexes. Furthermore, in silico pharmacokinetic and drug-likeness evaluations revealed that all synthesized compounds exhibited favorable profiles, in contrast to acarbose, which showed multiple violations of standard drug-likeness criteria.