Mechanism and Molecular Target of Substituted Triazoles: A Therapeutic Strategy in Anticancer Drug Discovery

Cancer remains a leading cause of mortality worldwide, necessitating the continuous discovery and development of novel therapeutic agents with improved efficacy and reduced toxicity. Heterocyclic compounds are privileged scaffolds in medicinal chemistry, and among them, the triazole ring system (1,2,3-triazoles and 1,2,4-triazoles) has emerged as a highly versatile and promising pharmacophore for anti-cancer drug discovery. This review is an attempt to bridge the gap between synthetic structural biology and translational oncology by systematically connecting the structure- activity relationships of novel triazole hybrids targeting Aromatase, VEGFR-2, IDO1, and Carbonic Anhydrase. We present a comprehensive overview of the recent advancements in the design, structure-activity relationships, and biological evaluation of triazole derivatives as potent anticancer agents. Triazoles are known to play an important role in modulating key oncogenic pathways (such as apoptosis induction, cell cycle arrest, angiogenesis inhibition, and metastasis suppression) by binding to various pharmacological targets. Here, we critically present the spatial configuration, such as the "tail approach" needed for carbonic anhydrase inhibition and the very specific heme-iron distances of the IDO1 pathway that govern the therapeutic promise. Clinical progress, toxicity, bioavailability, and resistance challenges have also been addressed. This review underscores the significance of triazole derivatives as multifunctional anticancer agents and provides insights into future directions for their development as targeted and potent chemotherapeutic agents. Although triazole derivatives are widely recognized as versatile, drug-like moieties, a critical research gap persists in understanding minor structural or electronic modifications near the triazole ring system to make the molecule target-specific and prevent liabilities due to non-selectivity.