7-N-Substituted-3-oxadiazole Quinolones with Potent Antimalarial Activity Target the Cytochrome bc₁ Complex

Abstract

The development of new antimalarials is required because of the threat of resistance to current antimalarial therapies.To discover new antimalarial chemotypes, we screened the Janssen Jumpstarter library against the P. falciparum asexual parasite and identified the 7-N-substituted-3-oxadiazole quinolone hit class. We established the structure−activity relationship and optimized the antimalarial potency. The optimized analog WJM228 (17) showed robust metabolic stability in vitro, although the aqueous solubility was limited. Forward genetic resistance studies uncovered that WJM228 targets the Q o site of cytochrome b (cyt b), an important component of the mitochondrial electron transport chain (ETC) that is essential for pyrimidine biosynthesis and an established antimalarial target. Profiling against drug-resistant parasites confirmed that WJM228 confers resistance to the Q o site but not Q i site mutations, and in a biosensor assay, it was shown to impact the ETC via inhibition of cyt b. Consistent with other cyt b targeted antimalarials, WJM228 prevented pre-erythrocytic parasite and male gamete development and reduced asexual parasitemia in a P. berghei mouse model of malaria. Correcting the limited aqueous solubility and the high susceptibility to cyt b Q o site resistant parasites found in the clinic will be major obstacles in the future development of the 3-oxadiazole quinolone antimalarial class.

Design of the Global Health chemical diversity library v2 for screening against infectious diseases

“…Fortunately, recent successes in target identification of phenotypic hit compounds are identifying good drug targets in some of these diseases [ 2 ]. In some areas, such as malaria, tuberculosis and the kinetoplastid diseases, significant numbers of compounds have been screened and hits followed up using corporate libraries and those available through academic groups and product development partnerships [ 3 – 6 ]. The need remains for new screening libraries occupying novel chemical space to find new phenotypic hits and new chemical matter for precedented protein targets.…”

Analysis of <em>Plasmodium falciparum</em> Mitochondrial Electron Transport Chain Activity Using Seahorse XFe96 Extracellular Flux Assays

“…The assay can be used to screen compound libraries to identify ETC inhibitors in P. falciparum . The assay can aid in determining the molecular target of identified inhibitors in the ETC and the effectiveness of novel inhibitors against drug-resistant parasite strains ( Hayward et al, 2023 ; Nguyen et al, 2023 ). The assay can also be used to obtain molecular insights into the functionality of the P. falciparum ETC.…”