Exploring DHPM-azole hybrid molecules for antibacterial drug discovery: synthesis and biological assessment

A novel series of pyrimidine-based N-heterocyclic hybrids incorporating 1,2,4-triazole (10a-10j) and benzotriazole (11a-11j) moieties was synthesized and evaluated for antibacterial activity against a panel of Gram-positive and Gram-negative bacterial pathogens. The structures of all synthesized compounds were confirmed by FT-IR, ¹H NMR, ¹³C NMR, and HRMS analyses. Several derivatives exhibited potent antibacterial activity against Gram-positive strains, including Bacillus subtilis, Staphylococcus aureus, and methicillin-resistant S. aureus (MRSA), as well as Gram-negative bacteria such as Salmonella typhi, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Among them, compounds 10b, 10d, 11b, and 11i displayed pronounced activity against Gram-positive strains, with MIC values ranging from 0.78 to 6.25 µg mL^-1. Particularly, compounds 10d and 11b exhibited potent anti-MRSA activity, with MIC values of 0.78 and 3.12 µg mL^-1, respectively. Furthermore, compounds 10b, 10c, 10d, 10e, 10h, and 11i demonstrated promising activity against S. typhi and E. coli, with MIC values ranging from 0.39 to 12.50 µg mL^-1. Cytotoxicity studies against HaCaT, HEK293T, and FHC normal cell lines revealed low toxicity, indicating a favorable safety profile. In silico ADME predictions further suggested desirable drug-like characteristics, including high gastrointestinal absorption and limited blood-brain barrier penetration. Collectively, these findings identify pyrimidine-triazole hybrids as promising antimicrobial lead scaffolds for the development of new antibacterial agents.