Triazole- and Imidazole-Containing Compounds: Versatile VEGFR-2 Inhibitors for Cancer Therapy

Vascular endothelial growth factor receptor 2 (VEGFR-2) is a major mediator of pathological angiogenesis, which is critical to tumor progression and metastasis; therefore, inhibition of VEGFR-2 remains a key therapeutic strategy for cancer. Despite the established clinical efficacy of several approved VEGFR-2-targeted agents, many first-generation inhibitors are limited by dose-limiting toxicities and the emergence of resistance, highlighting an ongoing need for next-generation compounds with improved selectivity and more favorable safety profiles. Among nitrogen-containing heterocyclic frameworks, triazoles and imidazoles are widely employed in medicinal chemistry owing to their favorable structural features, including appropriate stability, synthetic accessibility, and the ability to engage in key molecular interactions. This review summarizes recent advances in the design of triazole- and imidazole-based VEGFR-2 inhibitors, containing Schiff bases, bicyclic, tricyclic, and glycoside derivatives. We comparatively describe their VEGFR-2 inhibitory activities and anticancer cytotoxicity data, and discuss key structure-activity relationships and mechanistic insights, with particular emphasis on molecular features that appear to favor potent and selective VEGFR-2 inhibition. This review compiles in vitro, in vivo, and in silico data on triazole- and imidazole-based VEGFR-2 inhibitors, providing a basis for understanding trends relevant to the design and development of optimized anti-angiogenic agents.