Pyrimidine Derivatives Containing a Thiosemicarbazide Moiety as Potential Antioxidant and α‐Glucosidase Inhibitors: Synthesis, Bioactivity Evaluation, Molecular Docking, Molecular Dynamics Simulation, ADMET, and Drug‐Likeness Studies

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Abstract
In this study, a series of pyrimidine derivatives incorporating a thiosemicarbazide functional group were synthesized, and their structures were thoroughly characterized using 1 H NMR, 13 C NMR, and HRMS. Biological assays demonstrate that compound 5a exhibits exceptional in vitro antioxidant activity, with IC 50 values of 3.96 µg/mL for DPPH radical scavenging and 2.01 µg/mL for ABTS radical scavenging, both of which are lower than those of the reference standards vitamin C (6.38 µg/mL) and trolox (8.04 µg/mL). Compound 5k shows significant in vitro α‐glucosidase inhibitory activity, achieving an IC 50 value of 38.62 µg/mL, which is markedly lower than that of acarbose (237.48 µg/mL). Meanwhile, molecular docking results reveal that compounds 5a and 5k establish strong binding affinity to intermolecular interactions with the active site of the NADPH oxidase (PDB ID: 2CDU) and human intestinal α‐glucosidase (PDB: 3TOP), respectively. Furthermore, molecular dynamics (MD) simulations indicate that compounds 5a and 5k forms stable interaction with the NADPH oxidase and human intestinal α‐glucosidase, primarily driven by van der Waals forces. In addition, ADMET and drug‐likeness analysis results show that the compound 5k is safety and possess favorable physicochemical properties suitable for potential drug candidate.

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