BIOORGANOMETALLIC FERROQUINE AND RELATED COMPOUNDS AS ANTIMALARIAL CHEMOTHERAPEUTIC AGENTS: A SHORT REVIEW

Abstract

Drug resistant Plasmodium falciparum is a major threat to global health. Eradicating the parasite in endemic regions, especially sub-Saharan Africa is daunting. Milestones and a general target of 2030 have been set for this. However, funding and disruptions due to Ebola virus disease epidemic and COVID-19 pandemic are some of the cog in the wheel of the malaria eradication program. The recent WHO approval of the first malaria vaccine is a hope raiser and is expected to merely catalyze the eradication effort. Chemoprevention is a key malaria eradication strategy. Ferroquine, an organometallic chloroquine-ferrocene conjugate with effective antimalarial properties is capable of overcoming resistant strains and restoring chloroquine antimalarial properties. It has a novel mechanism of action. Like chloroquine, it forms complex with Fe(III)PPIX, strongly inhibit ß-hematin formation and drug accumulation in the acidic digestive vacuole. ferroquine is more lipophilic at cytosolic pH and cannot be pumped out of digestive vacuole thereby evading the chloroquine resistance mechanism. Clinical trials showed the drug candidate to be safe and tolerable. The ferroquine molecule can be conveniently synthesized via a reductive amination reaction involving a condensation of 7-chloroquinolin-4-amine and amino ferrocenyl aldehyde in a single stage procedure. It is well characterized. Studies revealed that covalently bonded chloroquine-ferrocene is responsible for the molecule's efficacy against P. falciparum. The pure chloroquine or ferrocene moieties are less active. Structural adjustments in amino group side chain, changes in position of the ferrocenyl organometallic group, substituting the Fe with other bioactive metals (Ru, Rh, Os) and substituting chloroquine for other organic molecules with antimalarial properties, all resulted in analogues with potent antimalarial properties similar to or better than chloroquine but not as effective as ferroquine.