Histidine Metal Complexes in Medicinal Chemistry: Synthesis, Biological Activities and Therapeutic Applications

Abstract

Histidine is a naturally occurring amino acid which has attracted great attention in medicinal coordination chemistry due to its excellent metal binding properties through the amino, carboxylate and imidazole functional groups. Such coordination properties allow the synthesis of stable and structurally varied metal complexes with tunable physicochemical properties and potentially promising biological activities. Thus, histidine is becoming a promising ligand for the design of new metal-based drugs. This review focuses on recent developments in the synthesis, coordination chemistry, biological activities, and mechanisms of action and biomedical applications of histidine–metal complexes. Special attention is given to Schiff base-derived ligands, transition metal coordination and structure–activity relationships affecting therapeutic activity. Existing data show that histidine–metal complexes exhibit strong anticancer, antimicrobial, antioxidant and photodynamic activities through various mechanisms, including DNA interaction, apoptosis induction, modulation of ROS and enzyme inhibition. Recent advances in nanotechnology, liposomal formulations and targeted drug delivery systems have further improved the stability, bioavailability and therapeutic activity of these complexes. Despite these advances, toxicity, selectivity, pharmacokinetics and clinical translation remain important challenges. Rational ligand design, advanced delivery systems, detailed mechanism studies and extensive preclinical and clinical testing are needed. Histidine–metal complexes show great potential for developing new therapeutic agents.