Synthesis, Biological Evaluation, and Molecular Modeling of Novel Pyrimidine Scaffolds as Prospective Anticancer and...

A series of novel pyrimidine-based acetamide derivatives (5a-5j) containing various cyclic amine substituents were designed, synthesized, and structurally characterized to identify new lead compounds with dual antiproliferative and antimicrobial activities. The synthesized compounds were evaluated for antiproliferative activity against K562 human chronic myeloid leukemia, MCF-7 human breast adenocarcinoma, and HeLa human cervical carcinoma cell lines, while selectivity toward BJ fibroblasts was assessed. Antimicrobial activity was investigated against representative Gram-positive, Gram-negative, and fungal pathogens. Among the synthesized derivatives, compound 5h exhibited the highest antiproliferative activity with IC₅₀ values of 6.39 ± 0.61, 10.34 ± 0.83, and 8.90 ± 0.71 μM against K562, MCF-7, and HeLa cells, respectively, while demonstrating comparatively lower cytotoxicity toward BJ cells. Compound 5h also displayed the most potent antibacterial activity against Escherichia coli (MBC = 25 μg/mL) and Pseudomonas aeruginosa (MBC = 50 μg/mL), together with promising antifungal activity. Structure-activity relationship analysis revealed that appropriately substituted aromatic cyclic amines significantly improved biological activity. Molecular docking against ABL1 kinase (PDB ID: 3PYY), together with DFT and ADME studies, supported the experimental findings. These results identify pyrimidine-based acetamide derivatives as promising multifunctional scaffolds for developing novel anticancer and antimicrobial agents.