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

ABSTRACT 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.