Quinolone-3-Diarylethers : A new class of drugs for a new era of malaria eradication

Ideally antimalarial drugs can be developed which target multiple life cycle stages, thus impacting prevention, treatment and transmission of disease. Here we introduce 4-(1H)-quinolone-3diarylethers that are selectively potent inhibitors of the parasite’s mitochondrial cytochrome bc1 complex. These compounds are highly active against the primary human malarias (falciparum and vivax), targeting the parasite at both the liver and blood stages as well as the forms that are crucial to disease transmission: gametocytes ⇒ zygotes ⇒ ookinetes ⇒ oocysts. Chosen as the preclinical candidate, ELQ-300 has good oral bioavailability at efficacious dosages in mice, is metabolically stable, and is highly active in rodent malaria models. Given a low predicted dose in patients and a long predicted half-life, ELQ-300 offers the hope of a new molecule for the treatment, prevention and, ultimately, eradication of malaria. Malaria remains the most significant parasitic disease in the tropics where it causes ≈200 million clinical cases and is reported to claim up to 1,238,000 lives each year (1). Most of the drugs used to treat the disease target only the blood stage of infection and the efficacy of many of the historical antimalarials, such as choroquine and quinine, has been declining due to the emergence of multidrug resistant strains of Plasmodium parasites. The widespread nature of multidrug resistance has shifted the emphasis to artemisinin combination therapies (ACTs) as first-line treatments in malaria-endemic countries. While ACTs have succeeded in reducing mortality and mosquito control programs have helped to reduce the worldwide burden of disease, there are warning signs of emerging artemisinin resistance in Southeast Asia (2, 3). As a result the development of new drugs for treatment and prevention of malaria is urgently needed to circumvent resistance and to meet the challenge of malaria eradication. To support the global malaria eradication effort there is a need for new medicines that can be given by mouth as a single dose to allow direct monitoring of administration and to ensure compliance (4, 5). Ideally such drugs will be efficacious against liver and blood stage Nilsen et al. Page 2 Sci Transl Med. Author manuscript; available in PMC 2014 November 11. infections and active against resistant strains. There is also a need for next generation drugs that kill gametocytes as well as the vector stages (i.e., ookinetes and oocysts) and thus can be used to prevent disease transmission. Ideally these desirable features can be incorporated into new molecules with longer half-lives to give chemoprophylaxis and to provide longterm protection against re-infection. Several years ago the Medicines for Malaria Venture (MMV) formed a team of investigators to evaluate the potential for development of an endochin (Fig. 1) derivative for clinical use. The team used a test cascade to optimize endochin which included the design and chemical synthesis of structural analogs, in vitro tests to compare antiplasmodial activity with mammalian cytotoxicity with profiling of the life-cycle fingerprint across all parasites stages, assessment of ex vivo efficacy against P. falciparum and P. vivax clinical field isolates, the determination of metabolic stability and enzyme inhibition, assessment of in vivo efficacy against blood and liver stages of infection in murine models of malaria, pharmacokinetic and safety profiling. This paper focuses on two 4(1H)-quinolone derivatives, ELQ-300 and P4Q-391, that were identified as late lead candidates. Brief history of endochin Andersag and coworkers first described endochin over 70 years ago (6). The drug attracted interest because of its ability to prevent and treat sporozoite-induced malaria in an avian model of the disease (Plasmodium cathemerium in canaries); it failed to work in humans (7). More recent studies confirm that endochin exhibits potent antiplasmodial activity , but it is metabolically unstable in the presence of liver microsomes from all tested mammalian species, including human, and is converted to poorly active metabolites (8, 9). As a consequence we set out to design endochin derivatives with enhanced metabolic stability and potent activity against drug resistant malaria parasites. Targeting parasite cytochrome bc1 complex Endochin appears to target parasite mitochondrial processes since it is known to block respiration in Plasmodium infected red blood cells (9). The parasite mitochondrion has been validated as a target for malaria therapy by the clinical success of atovaquone (Fig. 1), which selectively inhibits the parasite cytochrome bc1 complex (10). Because atovaquone monotherapy leads to the rapid selection of drug resistant mutants, it is co-administered with proguanil in a synergistic combination (Malarone®). Although Malarone® is commonly prescribed for malaria prophylaxis in travel medicine it is not widely used in malaria control programs due to the high cost of production. As a result, there is increasing interest in the development of less expensive alternatives to atovaquone that target parasite respiration, are active against all known strains, and are not prone to rapid resistance selection.