1,3,4-Thiadiazole Derivatives as VEGFR-2 Inhibitors and Its Molecular Insight for Cancer Therapy.

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a pivotal role in tumor angiogenesis, progression, and metastasis by modulating cell proliferation, migration, and survival via VEGF-mediated signaling. Despite the therapeutic success of current VEGFR-2 inhibitors, their clinical utility is often constrained by acquired resistance, off-target toxicities, and suboptimal selectivity. The 1,3,4-thiadiazole (TDA) scaffold has emerged as a privileged moiety in cancer drug discovery due to its mesoionic character, structural diversity, and molecular pharmacology. Notably, the ─N─N═C─S motif and sulfur atom of TDA significantly contribute to VEGFR-2 binding through key molecular interactions. This work provides a comprehensive overview of the role of VEGFR-2 in cancer biology, the chemistry of 1,3,4-TDA, and the mechanistic basis of VEGFR-2 inhibition. A systematic analysis of different publications from the last decade led to the extraction and evaluation of 151 TDA-based VEGFR-2 inhibitors. Chemical space, structure-activity relationship (SAR), substitution patterns, selectivity, toxicity, and essential binding interactions (ATP or allosteric site) with VEGFR-2 were critically examined. The review underscores the potential of 1,3,4-TDA derivatives as promising scaffolds for selective and efficacious VEGFR-2 inhibition, offering strategic guidance for the rational design of next-generation VEGFR-2 inhibitors with improved efficiency, selectivity, and reduced toxicity for anticancer therapy.