Thiazole-based Anticancer Agents: Synthetic Strategies, Molecular Mechanisms, Comparative Structure-activity Relationships, and Rational Design Perspectives.

Cancer continues to represent a major global health challenge, prompting the search for new therapeutic agents with improved efficacy and reduced toxicity. Among heterocyclic scaffolds, thiazole has attracted considerable attention in medicinal chemistry because of its structural versatility, synthetic accessibility, and ability to interact with multiple cancer-associated molecular targets. In recent years, extensive efforts have focused on developing thiazole-based derivatives with enhanced anticancer activity through structural modification and hybrid molecular design. This review critically examines recent progress in the synthesis and biological evaluation of thiazolecontaining anticancer agents, highlighting advances in synthetic methodologies, structure-activity relationships, molecular mechanisms, and future research opportunities. Different synthetic approaches, including conventional, microwave-assisted, multicomponent, and hybridization strategies, are discussed together with representative classes such as thiazolidine-2,4-dione, pyrazole, coumarin, quinoline, benzimidazole, thiosemicarbazide, pyrano-thiazole, natural product hybrids, and kinase-targeted derivatives. Analysis of the reported structure-activity relationships demonstrates that judicious modification of the thiazole scaffold, particularly through the incorporation of electron-donating or electron-withdrawing substituents, heteroaromatic moieties, halogens, and extended π-conjugated systems, can substantially improve cytotoxic potency, selectivity, and target affinity. Several derivatives have exhibited submicromolar or nanomolar antiproliferative activity against a broad spectrum of cancer cell lines by inducing apoptosis, promoting reactive oxygen species generation, disrupting mitochondrial function, arresting cellcycle progression, damaging DNA, and suppressing key oncogenic signalling pathways, including EGFR, VEGFR, PI3K/AKT, and MAPK. Finally, the major challenges associated with optimizing pharmacokinetic properties, overcoming drug resistance, and facilitating clinical translation are discussed, together with emerging directions for the rational design of next-generation thiazolebased anticancer therapeutics.