Recent Advances in Deploying d-Block Noble Metal Scaffolds for Marginalized Parasitic

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Neglected tropical diseases and malaria continue to impose a substantial health burden on
marginalized populations, while conventional antiparasitic therapies are increasingly limited by
drug resistance, toxicity, poor pharmacokinetic profiles, and inadequate accessibility. This review
highlights recent advances in the application of d-block noble-metal scaffolds, including
ruthenium, iridium, gold, platinum, silver, and palladium complexes, as promising alternatives for
the development of next-generation antiparasitic agents. Their variable oxidation states, tunable
ligand-exchange kinetics, diverse three-dimensional geometries, redox activity, and ability to
interact with parasite-specific biomolecular targets provide important advantages over
conventional organic chemotypes. Noble-metal complexes can disrupt essential parasitic processes
by inhibiting trypanothione reductase and thioredoxin reductase, inducing reactive oxygen species-
mediated oxidative stress, impairing mitochondrial function, interfering with heme detoxification,
and damaging DNA and other macromolecules. Hybrid metallodrugs incorporating nitroimidazole,
quinoline, Schiff-base, phosphine, or N-heterocyclic carbene ligands may further achieve
synergistic, multi-target activity and potentially reduce the development of resistance. The review
also discusses structural architectures such as piano-stool, polypyridyl, cyclometalated, square-
planar, and heterobimetallic complexes. Despite their considerable promise, clinical translation
remains constrained by off-target toxicity, serum-protein binding, limited tissue penetration, rapid
ligand exchange, and insufficient in vivo validation. Rational structure–activity relationship
optimization, nano-delivery systems, density functional theory, and artificial intelligence-assisted
screening may overcome these barriers.