Comprehensive Analysis of Structure Activity Relationships in Quinoxaline Derivatives Covering Antimicrobial Applications

ABSTRACT Antimicrobial resistance (AMR) has emerged as one of the most critical global health challenges, undermining the clinical efficacy of existing antibiotics and threatening modern therapeutic strategies. The ongoing misuse and overuse of antimicrobial agents have accelerated the evolution of resistant bacterial strains and parasites, underscoring the need to discover new molecules with enhanced potency and selectivity. Quinoxaline derivatives, a versatile class of nitrogen‐containing heterocycles, have attracted significant attention for their broad‐spectrum antimicrobial and antiparasitic activities owing to their tunable electronic properties and structural flexibility. This review provides a comprehensive and up‐to‐date overview of the chemistry, structure–activity relationships (SARs), and biological mechanisms of quinoxaline‐based compounds, offering novel SAR insights that extend and refine those presented in previous quinoxaline reviews. Unique to this manuscript is the explicit cross‐comparison of SAR trends across a diverse set of studies, highlighting both consensus and divergence in how key substituent classes—including halogens, N‐oxides, and cationic or hybrid frameworks—influence activity profiles against bacteria, fungi, and parasites. Mechanistic targets such as DNA gyrase, dihydrofolate reductase (DHFR), and membrane disruption are discussed with attention to how scaffold tuning enables novel modes of action. By consolidating advances in synthetic chemistry, mechanistic understanding, and rational scaffold optimization, this review demonstrates the broad therapeutic potential of quinoxaline frameworks and provides guidance for the development of next‐generation antimicrobial and antiparasitic agents to address the growing threat of AMR.