Ferrocene Derivatives as New Generation of Antimalarial Agents: Opportunity or Illusion?

Despite significant scientific progress over the last two decades, malaria remains a global burden that causes thousands of deaths every year. In the absence of effective and practical preventive measures, the only current option for reducing the mortality and morbidity of malaria is chemotherapy. However, due to the minimal stock of active antiparasitic analogs, issues of toxicity, and the repeated appearance of drug resistance, scientists must broaden the arsenal of existing therapies beyond conventional medicinal chemistry. To curb this menace, a series of potential metal-based hybrids have been synthesized and screened. Ferrocene is one of the potent organometallic candidates and the hybridization of ferrocene with other pharmacophores results in compounds with enhanced biological activities. Many researchers have reported the ferrocene compounds as potent pharmacophores and useful as anticancer and antimalarial agents when hybridized with other pharmaceutical hybrids. Drug, such as Ferroquine (FQ, SSR97193), is currently the most advanced organometallic compound developed from the hybridization of ferrocene and chloroquine and has demonstrated great potency in clinical trials against both drug-sensitive and drug-resistant malaria. Not only ferroquine but its derivatives have shown significant activity as antimalarial agents. The present review focuses on the discovery of FQ, the hypothesis of its mode of action, and recent clinical trials of ferrocene compounds as a new class of antimalarial agents. The structure-activity relationship (SAR) of ferrocene derivatives is also discussed to provide insight into the rational design of more effective antimalarial candidates. Finally, efforts have been made to discuss the future expectations for ferrocene-based antimalarial drugs.