The P. falciparum parasites have independently developed partial resistance to artemisinin, the core compound of the best available antimalarial drugs, in several foci in the Greater Mekong subregion (GMS), Africa, Oceania and Latin America [1, 36, 37]. As a consequence, the increasing prevalence of artemisinin-resistance and the consequent emergence of resistance to the partner drugs in ACTs may well reverse the substantial recent gains in malaria control . New antimalarial drugs are urgently needed.
Recent data indicate that the average cost and time for a new drug from idea to market are about 3 billion dollars and 14 years, respectively [38, 39]. Although the malaria drug development pipeline is in a healthier state for many years at present, there is only one 8-aminoquinoline, tafenoquine, newly approved by FDA against liver stages of malaria [40, 41]. An alternative strategy is to evaluate the antimalarial activity of molecules that are already licensed for new medical indications, an approach known as drug repurposing that has been successfully applied in oncology . Since the drugs are already in routine clinical use for other purposes early phase clinical trials can be bypassed, saving time and money. Thus, this strategy offers a promising alternative to traditional drug development pipelines, and can help fast and less expensive solutions to realize malaria elimination and eradication.
Patients with P. falciparum hyperparasitemia are at increased risk for treatment failure, severe malaria and death . Parasitemia level can serve as a predictor for severe malaria . Herein, we show that CI-679 could suppress the growth of rodent malaria parasite P. yoelii BY265 at a dose-dependent manner, and even rapidly kill the parasite in mice when administrated at the peak of parasitemia. Furthermore, CI-679 has a wide therapeutic window, both effective at the rising and peak stage of parasitemia, makes it can be widely available as a partner drug in a fixed-combination. The property could make severe malaria and death much less likely.
Continued research and development to make new drugs available to replace current drugs as resistance emerges is one of the several high priority research areas identified to be addressed urgently regardless of whether the world mobilizes for a renewed effort to eliminate malaria . As the increasing threat of the emergency and spread of resistance to artemisinin, finding the optimal combination of interventions to maximize impact and mitigate the risk of resistance is a critical challenge in malaria elimination . For eradication to be effective, the concept of a drug combination Single Encounter Radical Cure and Prophylaxis (SERCaP) was developed , signify clinical candidates will necessarily require combination with mechanistically distinct drug partner(s) to alleviate the potential for drug resistance. CI-679 can kill the artemisinin-resistant P. falciparum, which is constructed by the mutation of C580Y at K13 gene. Therefore, CI-679 could be explored as an alternative antimalarial agent against artemisinin-resistant P. falciparum and a potential combination partner of ACTs against malaria parasite.
The ring stages can develop into schizonts through the trophozoites and the schizonts burst and release daughter merozoites by the end of blood stage, each of which can invade blood cells and repeat the cycle . In the blood stage, Plasmodium parasites replicate rapidly and may replicate exponentially to > 1012 parasites per patient. This rapid growth requires sustained pools of nucleotides for the synthesis of DNA and RNA . Folate is essential for the survival and growth of the malaria parasite and DNA synthesis  and the folate metabolic pathway constitutes an antimalarial target. CI-679 could efficiently inhibit the growth of P. falciparum in vitro, with more sensitivity against late phase of blood stage. This result was as expected, for CI-679 was a product of the program of the synthesis of folic acid analogs. The development of parasites in late phase of blood stage might be impeded by the insufficient DNA synthesis ascribed to the administration of CI-679.
Although CI-679 is potent against P. yoelii and P. falciparum, even artemisinin-resistant C580Y, further pharmacokinetic properties, tolerability and safety need to be characterized to support its preclinical development and to enable the compound to advance to human clinical trials. In addition, as the rising concern of resistance to antifolates, possible drug resistance mechanisms based on in vitro selection should also be included.