Cancer Drug Candidates Show Dual Power Against Malaria Parasite

Malaria continues to exact a devastating toll on global health, and the parasite responsible for the deadliest form of the disease is steadily outmaneuvering the drugs designed to destroy it. Now, a team of researchers at the University of São Paulo’s School of Pharmaceutical Sciences (FCF-USP) in Brazil has reported that a family of molecules originally developed for their anti-cancer activity can eliminate Plasmodium falciparum, the parasite that causes the most lethal form of malaria, at two critical points in its life cycle. The findings, published in July 2026 in the journal ACS Omega, suggest that repurposing compounds from oncology research could open a faster and cheaper route to urgently needed antimalarial therapies.

The scale of the problem the researchers are targeting is enormous. According to estimates by the World Health Organization, malaria was responsible for approximately 600,000 deaths in 2024, and Célia Regina da Silva Garcia, a professor in the Department of Clinical and Toxicological Analysis at FCF-USP, notes that an estimated 90 percent of those deaths are caused by P. falciparum. Effective treatments for malaria do exist, but the parasite has progressively developed resistance to frontline drugs such as chloroquine and artemisinin, the backbone of current therapy in most endemic regions. That erosion of drug efficacy has made the search for new chemical classes of antimalarials a global priority, and it is precisely the gap that the São Paulo team’s work is designed to fill.

The strategy the researchers pursued is known as drug repurposing, an approach that has gained traction across infectious disease research because it exploits compounds whose pharmacology, safety profiles, and synthetic routes are already partly understood. Rather than screening millions of novel chemicals, repurposing starts with molecules validated for another indication and asks whether they also act against a new target organism. In this case, the team synthesized and tested fourteen derivatives of an antineoplastic, or cancer-treating, drug against P. falciparum parasites cultured in the laboratory. The in vitro experiments were funded by the São Paulo Research Foundation (FAPESP) through a series of research grants and fellowships supporting the laboratory’s long-running program on parasite cell biology and chemotherapy.

The results were striking in two respects. First, the molecules proved effective at killing the parasite during its asexual stage, the phase in which Plasmodium invades and reproduces inside human red blood cells and produces the cyclical fevers that define clinical malaria. A drug that clears asexual parasites is, by definition, a treatment: it addresses the disease in the symptomatic patient. Second, and arguably more important from a public health perspective, the compounds also acted against gametocytes, the specialized sexual-stage parasites that are taken up by Anopheles mosquitoes during a blood meal and that make onward transmission possible. A therapy that eliminates gametocytes would not only cure the individual patient but could also block the passage of the parasite from humans back into the mosquito vector, interrupting transmission chains at the community level.

This dual-stage activity is rare among antimalarial candidates. Most existing drugs are optimized for the blood-stage parasites and have little or no effect on mature gametocytes, which is one reason malaria transmission can persist even in treated populations. A single molecule class capable of both curing the patient and reducing infectivity to mosquitoes would be a valuable addition to the therapeutic arsenal, particularly in regions pursuing malaria elimination rather than mere control. The São Paulo findings, while still confined to laboratory cultures, indicate that the 6-anilinopurine scaffold underlying these compounds deserves serious attention as a platform for exactly that kind of transmission-blocking chemotherapy.

Underlying the antiparasitic effect, the researchers believe, is a specific molecular target inside the parasite’s cell: histone deacetylase enzymes, and in particular an enzyme known as PfHDAC1. Histone deacetylases regulate gene expression by modifying the proteins around which DNA is wound, and they have long been recognized as important drug targets in cancer chemotherapy, which helps explain why compounds designed as anticancer agents would show activity against a parasite. By inhibiting the parasite’s version of the enzyme, the derivatives appear to disrupt essential developmental programs in Plasmodium. Garcia explains that the team’s experiments have strengthened the hypothesis that histone deacetylase enzymes are an important therapeutic target for malaria, and that this understanding has allowed the group to design new molecules that are increasingly potent and selective against the parasite.

That structure-activity analysis is the second major contribution of the study. The fourteen tested derivatives varied in their chemical structure, and by comparing how those structural differences changed antiparasitic potency, selectivity, and target engagement, the team gathered the information needed for rational drug design. As Garcia describes it, rational design allows chemists to refine a molecule’s structure in a targeted manner rather than relying on trial and error. In practical terms, the researchers can now adjust side chains and functional groups to maximize inhibition of the parasite enzyme while minimizing interaction with human cells, a balancing act that determines whether a laboratory hit can ever become a safe medicine.

Safety, in fact, remains the central caveat. Because the work so far has been conducted entirely in vitro, the potential side effects of the compounds in patients have not yet been assessed. Some of the tested derivatives showed reduced efficacy against human cells while retaining their effect on the parasites, an encouraging sign of selectivity that suggests a lower risk of serious adverse effects. Nevertheless, Garcia is candid about the concerns: molecules in that class can cause fatigue, nausea, vomiting, and hematological changes such as a decrease in platelets, and she acknowledges that it is natural for such concerns to exist. Only in vivo tests, in animal models and eventually in clinical trials, can confirm whether the therapeutic window observed in culture dishes holds up in a living body.

There is also a pharmacological hurdle specific to this chemical class that the team must overcome. Drugs of this type tend to degrade rapidly inside the body, which can undermine their effectiveness regardless of how potent they are in a test tube. In vivo studies will therefore serve a second purpose beyond safety: verifying whether the candidate molecules remain chemically stable long enough in a patient’s circulation to reach and clear the parasite. Stability, selectivity, and potency together form the triad of criteria that any successor compound emerging from the group’s rational design program will need to satisfy before it can advance toward preclinical and clinical development.

Looking further ahead, Garcia’s team intends to extend its testing to other malaria-causing parasite species, most notably Plasmodium vivax, which is the predominant malaria parasite in Brazil and across much of the equatorial world. P. vivax poses distinct challenges: it can cause relapses even after treatment because it produces latent liver-stage forms called hypnozoites that can reactivate months later, and it is more widespread in equatorial countries than P. falciparum. Garcia emphasizes that evaluating antimalarial drug candidates against different parasite species is essential to ensure they are effective in the various regions of the world where malaria burden is concentrated. If the 6-anilinopurine derivatives, or the optimized molecules designed from them, prove active against multiple Plasmodium species and safe enough for human use, the cancer research toolbox may yet deliver one of the most sought-after prizes in tropical medicine: a single therapy that treats the sick and stops the spread.

Subject of Research: Repurposing anticancer 6-anilinopurine derivatives as dual-stage antimalarial compounds targeting Plasmodium falciparum histone deacetylase

Article Title: Anti-cancer molecules show promise in the fight against malaria

Article References: Anti-cancer molecules show promise in the fight against malaria. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: malaria, Plasmodium falciparum, drug repurposing, anticancer compounds, histone deacetylase, gametocytes, University of São Paulo, FAPESP, ACS Omega, drug resistance, Plasmodium vivax, rational drug design