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<p>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 <i>Escherichia coli</i> and <i>Staphylococcus aureus</i>, as well as fungal strains such as <i>Candida albicans</i>. 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月22日

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  • Minakshi Kumari,
  • Mahesh Kumar

摘要

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.