Tiantian Zhuang, Wenmin Pan, You Zhang, Yongxiang Wu, Xiang Wang, Pei Li
ABSTRACT In this study, a novel series of 4‐chromanone derivatives bearing a thiosemicarbazone moiety was rationally designed and efficiently synthesized. The structures of all newly obtained compounds were thoroughly characterized via various spectroscopic methods. The biological evaluation focused on their in vitro antioxidant activity and inhibitory effects against α‐glucosidase. The biological evaluation revealed that several derivatives displayed notable antioxidant and enzyme inhibitory properties. In particular, compound ( E )‐2‐(chroman‐4‐ylidene)‐ N ‐methylhydrazine‐1‐carbothioamide ( 3a ) exhibited remarkable ABTS free radical scavenging ability, achieving an IC 50 of 3.76 μg/mL—outperforming the reference standard trolox, which showed an IC 50 of 8.04 μg/mL. Additionally, compound ( E )‐ N ‐(2‐(chroman‐4‐ylidene)hydrazine‐1‐carbonothioyl)benzamide ( 3j ) emerged as a highly effective inhibitor of α‐glucosidase, with an IC 50 value of 20.17 μg/mL, markedly lower than that of acarbose (237.48 μg/mL), indicating superior inhibitory potency. Molecular docking simulations demonstrated that compound 3a interacts with the active site of NADPH oxidase (PDB: 2CDU) through van der Waals forces, π–sulfur, and π–alkyl contacts. In contrast, compound 3j engaged more extensively with the catalytic pocket of human intestinal α‐glucosidase (PDB: 3TOP), forming multiple interactions such as van der Waals, electrostatic attractions, conventional hydrogen bonds, π–π T‐shaped, and π–alkyl bonds. ADMET profiling and drug‐likeness assessments indicated that these lead compounds exhibit acceptable safety profiles and favorable physicochemical characteristics, aligning well with criteria for prospective therapeutic agents. To the best of our knowledge, this study presents the first comprehensive report on the synthesis, characterization, and biological assessment of this class of 4‐chromanone derivatives bearing a thiosemicarbazone moiety.