Ferroquine

Antimicrobial resistance is a major global problem for public health, indicating the need for the development of new anti-infective drugs, among other actions (i.e., better stewardship, diagnostics, etc.). A common strategy in medicinal chemistry is to modify existing drugs with an organometallic moiety to enhance their efficacy or overcome resistance. One notable example is ferroquine, an organometallic derivative of chloroquine. Here, we describe the design, in-depth characterization, and in vitro evaluation of seven new derivatives of the antifungal drug itraconazole (ITZ) against parasitic and fungal pathogens. ITZ was selected as a privileged scaffold because it targets ergosterol biosynthesis, which is an essential component of cell membranes in fungi and trypanosomatid parasites. While none of the compounds were active against Trypanosoma cruzi and Leishmania infantum, the ferrocenyl derivatives proved to be 1.5- to 1.9-fold more potent than ITZ toward Trypanosoma brucei. Of particular interest, all of the compounds exhibited high antifungal activity against the azole-susceptible clinical isolates. Furthermore, the ferrocenyl-containing compound was the most active against Aspergillus. Despite showing 10-fold lower activity than ITZ, these organometallic derivatives constitute an interesting starting point for further pharmacomodulation since we confirmed that they blocked the ERG11 enzyme, the main target of azoles.

In 2022, malaria caused approximately 249 million cases and 608,000 deaths, primarily in Africa. Current treatments target asexual blood-stage parasites, gametocytes, and liver hypnozoites. Standard guidelines recommend a 3-day course of artemisinin-based combination therapies as a first-line treatment of uncomplicated malaria and parenteral artesunate for severe malaria. However, the emergence of partial resistance to artemisinin derivatives threatens the treatment efficacy, highlighting the urgent need for novel antimalarial drugs.

This review summarizes recent progress in the clinical development of antimalarials particularly non-artemisinin compounds under target product profile-1.

Data were gathered from Medicines for Malaria Venture (MMV)'s portfolio and clinical trial databases between 2020 and 2024.

Sixteen clinical trials were reviewed, including safety and efficacy studies involving healthy volunteers, experimentally infected volunteers, asymptomatic Plasmodium falciparum carriers and malaria patients. Six trials evaluated the safety and tolerability of MMV533, ZY19489, INE963, GSK701/MMV367 and intravenous KAE609 in healthy volunteers. Efficacy trials involving experimentally infected volunteers assessed ZY19489 and GSK701/MMV367, whereas studies on asymptomatic carriers tested ZY19489/ferroquine and cabamiquine/pyronaridine. Trials on malaria patients investigated combinations of ganaplacide/lumefantrine-SDF, cabamiquine/pyronaridine, both oral and intravenous cipargamin and INE963.

Although attrition remains a possibility, several promising candidate drugs with novel modes of action are advancing through clinical development. Many are expected to become available for treating uncomplicated and severe malaria within the next decade. These new antimalarials could significantly enhance malaria treatment, reduce resistance, and support global health efforts towards malaria control, elimination and, potentially, eradication.