Quinolone-3-Diarylethers: A New Class of Antimalarial Drug

Abstract

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-3-diarylethers 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.

Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action

“…Similar potencies are described for other parasitic and fungal targets, but the drug also inhibits human cyt bc 1 , although with lower submicromolar affinity 27 . The molecular basis for broad target spectrum on one hand and species-specific efficacies on the other was addressed with several molecular modelling studies 25,[28][29][30][31] and genetic approaches 29,[32][33][34][35] , but was not resolved so far.…”

Inhibition of Cytochrome bc1 as a Strategy for Single-Dose, Multi-Stage Antimalarial Therapy

“…The ozonide OZ439, 11 the aminopyridine MMV390048, 12 and the spiroindolone NITD609 13 all effectively clear asexual, blood-stage parasites in mouse models of malaria with a single oral dose and also inhibit gametocyte development, which reduces the potential for malaria transmission. In contrast, several imidazolopiperazines, 14,15 8-aminoquinolines, 16 and antirespiratory compounds 17,18 have been identified as single-dose causal prophylactics, which inhibit the sporozoite and liverstage parasites that are responsible for the earliest stages of Plasmodium infection. Although each of these antimalarials is highly potent at specific stages of the parasite life cycle, it has not yet been possible for a single agent to provide simultaneous cures for blood, liver, and transmissive stage malaria after a single oral dose.…”

“…One such target is Complex III of the mitochondrial electron transport chain, which is also known as the cytochrome bc 1 complex (cyt bc 1 ) and is essential for pyrimidine biosynthesis in Plasmodium. 19,20 Several cyt bc 1 inhibitors, including the naphthoquinone atovaquone 17 and the 4(1H)-quinolone ELQ-300, 18 are potent single-dose prophylactics, with remarkable multi-dose efficacy against blood-stage malaria parasites. 18,21 Although it has not yet been possible to formulate these compounds as singledose, blood-stage therapies, it is likely that this limitation is related to poor solubility, which restricts the plasma concentrations that can be achieved after a single oral dose.…”

Antimalarial 4(1H)-pyridones bind to the Q i site of cytochrome bc 1

“…A recent X-ray structure of cytochrome bc 1 from Saccharomyces cerevisiae has shown atovaquone bound in the catalytic Q o site, offering explanation for the cross-species resistance (20). Many different classes of compound have been investigated as potential drugs and much work has focused on inhibition of the Q o site (23,(29)(30)(31)(32). The 4(1H)-pyridones have been researched for their antimalarial properties since the 1960s, based on the compound clopidol (33,34) (Fig.…”