Quinoxaline Derivatives As Anticancer Agents: Molecular Targets And SAR

Abstract

Quinoxaline is a versatile nitrogen-containing heteroaromatic scaffold with considerable potential in anticancer drug discovery because structural modifications of its fused benzene–pyrazine framework can produce compounds with diverse pharmacological activities. This review highlights recent advances in the anticancer potential of quinoxaline derivatives, emphasizing their broad molecular targets and structure–activity relationships (SAR). Quinoxaline-based compounds have demonstrated activity against topoisomerases, tubulin, DNA repair pathways, PARP, histone deacetylases, folate metabolism, reactive oxygen species, VEGFR-2, EGFR, HER2, c-Met, PI3K/Akt/mTOR, PIM kinases, BRD9, BET proteins, PFKFB3, and apoptosis- and metastasis-associated pathways. SAR studies demonstrate that substitution pattern, aromaticity, hydrogen-bonding capacity, electronic properties, linker configuration, and physicochemical characteristics strongly influence anticancer potency and selectivity. Emerging approaches include selective targeting of BRD9 and BD1, inhibition of PFKFB3, VEGFR-2 blockade in treatment-resistant tumors, and modulation of HIF-1α, VEGF, and p21. Despite these advances, most quinoxaline-based anticancer candidates remain at the preclinical stage, with limitations involving inconsistent experimental conditions, inadequate pharmacokinetic characterization, poor aqueous solubility, metabolic instability, and potential off-target toxicity. Future development should therefore emphasize target validation, structure-based optimization, advanced drug-delivery approaches, pharmacokinetic improvement, physiologically relevant disease models, and rational combination strategies. Overall, quinoxaline represents a flexible platform for developing multifunctional and target-directed anticancer agents with potential applications across diverse cancer-associated pathways.