Recent advances in multi-target pyrimidine-based derivatives as broad-spectrum antimicrobial agents

The emergence of multidrug-resistant pathogens has intensified the need for novel broad-spectrum antimicrobial agents. Pyrimidine, a privileged heterocyclic scaffold, has shown remarkable versatility in targeting multiple microbial enzymes and pathways. This review summarizes recent advances (2022–2025) in the design, synthesis, and antimicrobial evaluation of pyrimidine-based derivatives with multi-target potential. Particular emphasis is placed on synthetic strategies, structural hybridization, and structure–activity relationship (SAR) trends associated with substitutions at the C-2, C-4, C-5, and C-6 positions of the pyrimidine nucleus. Compounds containing amino, thio, aryl, and heteroaryl substituents exhibit potent activity against Gram-positive and Gram-negative bacteria, including Escherichia coli and Staphylococcus aureus , as well as fungal strains such as Candida albicans . Several hybrid derivatives incorporating chalcone, triazole, and thiazolidinone pharmacophores exhibit enhanced antimicrobial activity via multi-target mechanisms, including inhibition of DNA gyrase and dihydrofolate reductase (DHFR), cell wall disruption, and DNA interactions. The review also discusses mechanistic insights, substitution trends, and future perspectives, including AI-assisted drug design for developing next-generation pyrimidine-based antimicrobial agents to combat antimicrobial resistance.