Thiosemicarbazone metal complexes as multifunctional therapeutic platforms: Advances, mechanisms, and future...

Thiosemicarbazones belong to the most versatile classes of physiologically active ligands in medicinal and bioinorganic chemistry due to their structural tunability, diverse coordination behaviour, and wide spectrum of pharmacological activity. They are rich in donor atoms and thione-thiol tautomerism and can coordinate a large number of transition and post-transition metal ions, usually leading to a marked increase in biological activity compared to the parent ligands. Thiosemicarbazone-based metal complexes have attracted a great deal of attention as potential therapeutic agents for the treatment of cancer, microbial infections, tuberculosis, parasitic diseases, and other pathological conditions. The therapeutic potentials are derived from a variety of processes, including metal chelation, disturbance of cellular metal homeostasis, production of reactive oxygen species, enzyme inhibition, and interactions with nucleic acids and proteins. Of note, the differences in ligand architecture, substituent pattern, donor atom environment, and metal center strongly affect biological activity, selectivity, and mechanism of action, emphasizing the role of structure-activity relationships in the rational design of effective metallodrugs. The present review critically summarizes recent progress in the coordination chemistry, biological properties, and therapeutic applications of metal complexes derived from thiosemicarbazones, focusing on anticancer, antimicrobial, antitubercular, antiparasitic, antioxidant, and diagnostic applications. Particular attention is devoted to ruthenium-thiosemicarbazone complexes owing to their unique coordination chemistry, favourable pharmacological properties, and significant therapeutic potential. Representative systems based on ruthenium, copper, silver, gold, gallium, zinc, nickel, palladium, platinum, and other biometals are described together with developing mechanistic insights and design techniques. Current issues in toxicity, selectivity, stability, pharmacokinetics, and clinical translation are also discussed. Collectively, the available evidence highlights the growing importance of thiosemicarbazone metal complexes as multifunctional therapeutic platforms and underscores their potential for the development of next-generation metallodrugs.