Pyrimidine‐Based Scaffolds: Emerging Frontiers in Antimicrobial Drug Discovery

Abstract Pyrimidine analogs have emerged as key scaffolds in medicinal chemistry due to their structural versatility and broad therapeutic potential. Present in numerous bioactive and clinically approved drugs, pyrimidines are ideal cores for designing molecules with targeted biological activity. This review outlines recent advances in the design, synthesis, and antimicrobial evaluation of pyrimidine and fused pyrimidine derivatives, with a focus on structure–activity relationships (SAR), mechanisms of action, and microbial potency. Several compounds demonstrated potent antitubercular activity, with minimum inhibitory concentrations (MICs) ranging from 0.6 to 18.1 µg/mL, and some exhibited nanomolar efficacy. Notably, 6,7‐disubstituted quinazolin‐4‐amines showed MIC₉₀ values between 0.63–1.25 µM, whereas others displayed activity across 1.95–125 µg/mL, with selectivity indices above 250 Mycobacterium tuberculosis . These findings underscore the impact of targeted substitutions on antimicrobial efficacy. By consolidating SAR insights and recent developments, this review supports the rational design of pyrimidine‐based agents with enhanced selectivity and reduced toxicity, encouraging further exploration of novel derivatives to combat drug resistance and evolving therapeutic challenges.