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.

Synthesis, In-vitro Antimalarial Activity and In silico Molecular Docking Study of Amino Chalcone Derivatives from 1-(2-aminophenyl)-3-(4- substituted-phenyl) prop-2-en-1-one and Dihydroquinolone Derivatives

“…Chalcones possess several physiological activities (antioxidant, antimalarial, antibacterial, antiulceral, anti-inflammatory, anti-HIV, antiviral, antifungal, antileishmanial, anticancer, antitubercular, antihyperglycemic, carboxygenase inhibitor, and insecticidal) which are generated by the presence of the reactive function α,β-unsaturated keto present in the molecule [23][24][25][26][27][28][29] . The same applies to quinolone-based compounds which have already shown several biological activities 4,30,31,32 . These two compounds are therefore very promising for the discovery of new antimalarial agents.…”

“…In general, about fifty percent of the world's community lives under the continuing threat of malaria, which is currently treated by Artemisinin, its derivatives and chloroquine in endemic countries 1,2 . This disease caused approximately 619, 000 deaths (in 2021), 90% of which were in Sub -Saharan Africa, and 78% of these deaths for children under 5 years of age 3,4 . It is the most prevalent parasitic disease and the most common cause of hospital visitation in Democratic Republic of the Congo 3 .…”

“…It is the most prevalent parasitic disease and the most common cause of hospital visitation in Democratic Republic of the Congo 3 . This is explained by the increased resistant of parasite to existing drugs such as Chloroquine and Artemisinin, which largely target the asexual blood stage of Plasmodium falciparum life cycle [3][4][5][6] . Faced to this alarming situation, much scientific research is directed towards the discovery of new antimalarial compounds with other mechanisms of action against Plasmodium falciparum and that will be active in multiple stage of life cycle of the latter.…”

“…Chalcones possess several physiological activities (antioxidant, antimalarial, antibacterial, antiulceral, anti-inflammatory, anti-HIV, antiviral, antifungal, antileishmanial, anticancer, antitubercular, antihyperglycemic, carboxygenase inhibitor, and insecticidal) which are generated by the presence of the reactive function α,β-unsaturated keto present in the molecule [23][24][25][26][27][28][29] . Quinolone, being found for the first time accidentally in the Chloroquine's synthesis in 1962, belongs to the large classes of synthetic molecules with various pharmacological and biological properties such as antimicrobial, antimalarial, antitubercular, antifungal, antileishmanial, anti-inflammatory, anticancer, antiviral, antiprotozoal, etc 4,30,31,32 . Hence, the quinolone scafold is more important for researchers.…”

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.…”