In the face of the recent pandemic and emergence of infectious diseases of viral origin, research on parasitic diseases such as malaria continues to remain critical and innovative methods are required to target the rising widespread resistance that renders conventional therapies unusable. The prolific use of auxiliary metallo-fragments has augmented the search for novel drug regimens in an attempt to combat rising resistance. The development of organometallic compounds (those containing metal-carbon bonds) as antimalarial drugs has been exemplified by the clinical development of ferroquine in the nascent field of Bioorganometallic Chemistry. With their inherent physicochemical properties, organometallic complexes can modulate the discipline of chemical biology by proffering different modes of action and targeting various enzymes. With the beneficiation of platinum group metals (PGMs) in mind, this review aims to describe recent studies on the antimalarial activity of PGM-based organometallic complexes. This review does not provide an exhaustive coverage of the literature but focusses on recent advances of bioorganometallic antimalarial drug leads, including a brief mention of recent trends comprising interactions with biomolecules such as heme and intracellular catalysis. This resource can be used in parallel with complementary reviews on metal-based complexes tested against malaria.

Quinoline-based PGM metallarectangles were evaluated against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum .

Molecular hybridization and metal incorporation are widely employed strategies for drug development aimed at enhancing pharmacological efficacy while mitigating the emergence of drug resistance. The effectiveness of these approaches is supported by numerous studies demonstrating their success against a range of diseases. Despite the deployment of malaria vaccines, effective treatment remains hindered by the persistent emergence of drug-resistant Plasmodium falciparum strains, contributing to an alarming global disease burden. Inspired by the antimalarial candidate ferroquine, this study focused on the design and synthesis of ferrocenyl-based quinoline-benzimidazole molecular hybrids. The hybrids were evaluated for their in vitro blood-stage antiplasmodial activity against drug-sensitive NF54 and multidrug-resistant K1 P. falciparum strains, exhibiting potent submicromolar activity. Notably, incorporating an N,N-dimethylaminomethyl side chain significantly enhanced activity against both strains. Further assays revealed a compound with multistage antiplasmodial activity, targeting both immature and mature gametocytes. Mechanistic studies implicated the inhibition of hemozoin formation as a key mode of action, supported by in vitro cellular heme fractionation analysis. Additionally, fluorescence assays indicated the generation of reactive oxygen species under oxidative conditions, suggesting a complementary pathway contributing to the compounds' antiplasmodial activity. These findings highlight the potential of ferrocenyl-based molecular hybrids as promising candidates in antiplasmodial drug development.

Recent advances in antimicrobial drug design have incorporated photopharmacology to control drug behavior through light activation, alongside traditional phenotypical strategies including molecular hybridization and metal incorporation. The quinoline and benzimidazole scaffolds are important chemical frameworks identified by the Medicines for Malaria Venture and are known to exert their antiplasmodial activity by inhibiting hemozoin formation, an important target in antimalarial drug design. These scaffolds form part of growing libraries in drug discovery, aimed at developing novel and potent antimalarial agents through structural modifications that improve pharmacological profiles and overcome drug resistance. Consequently, in this study, azobenzene photoswitchable chemical entities have been integrated with quinoline and benzimidazole scaffolds through rational design, aiming to investigate their interactions with hemozoin. The photoswitchable inhibitors showed excellent photo fatigue resistance and thermal relaxation rates exceeding 13 h at 37 °C. In vitro analysis against chloroquine-sensitive NF54 and multidrug-resistant K1 Plasmodium falciparum strains revealed low micromolar activity against the K1 strain. Most notably, this study culminated in two benzimidazole-containing compounds that exhibited differing levels of β-hematin inhibition upon light exposure. Density functional theory calculations and molecular docking studies provided mechanistic insights into how photoisomerization modulates molecular reactivity and hemozoin binding affinity, highlighting the potential of these compounds to be used as light-activated antiplasmodials.