Design, Synthesis, Bioactivity Evaluation, Molecular Docking, ADMET, and Drug-likeness Studies of Novel Hesperetin Derivatives Incorporating a Thiosemicarbazone Moiety as Potential Antioxidants and α-Glucosidase Inhibitors

In this study, four novel hesperetin-based derivatives containing a thiosemicarbazone moiety were rationally designed and efficiently synthesized. Biological evaluation revealed that these compounds exhibit strong in vitro antioxidant effects and effectively inhibit α-glucosidase activity. In particular, (E)-2-[5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-ylidene]-N-methylhydrazine-1-carbothioamide displayed outstanding ABTS radical scavenging ability and remarkable α-glucosidase inhibition, with IC50 values of 0.04 and 4.53 μg/mL, respectively, significantly lower than those of the reference agents of hesperetin, trolox, and acarbose. Molecular docking simulations indicated that (E)-2-[5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-ylidene]-N-methylhydrazine-1-carbothioamide interacts with the active site of NADPH oxidase (PDB: 2CDU) via multiple binding forces, such as van der Waals contacts, electrostatic attractions, conventional hydrogen bonds, carbon hydrogen bonds, π-anion, π–π stacked, and π-alkyl interactions. Furthermore, when bound to the catalytic region of human intestinal α-glucosidase (PDB: 3TOP), (E)-2-[5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-ylidene]-N-methylhydrazine-1-carbothioamide established a broad network of interactions, including van der Waals forces, salt bridges, electrostatic attractions, hydrogen bonds, carbon hydrogen bonds, and π–π T-shaped stacking. Additionally, in silico ADMET and drug-likeness predictions indicated that (E)-2-[5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-ylidene]-N-methylhydrazine-1-carbothioamide possesses favorable absorption, distribution, metabolic stability, low toxicity potential, and overall characteristics suitable for a promising therapeutic agent.