Molecular basis of extreme resistance in Plasmodium falciparum to atovaquone and other mitochondrial inhibitors

Siegel, Sasha V.; Rivero, Andrea; Kyle, Dennis E.

doi:10.1186/1475-2875-13-s1-p81

Cited by 3 publications

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“…Evaluation against Cyt b-Resistant Parasites. To further explore whether the oxadiazole quinolone series specifically targeted the Q o site of cyt b, we evaluated representative analogs against the ATQ (3) clinically resistant TM90-C2B strain with a Y268S mutation in the Q o site of cyt b 40,41 or the ELQ-300 (5) resistant Dd2 strain with an I22L mutation in the Q i site of cyt b 16 (mutations mapped to a model of cyt b in Figure 4). The 3-oxadiazole analogs 17 and 41 showed an approximately 150-and 50-fold respective decrease in activity against the TM90-C2B strain (Table 4) compared to the Dd2 parental strain.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…General method C was followed using 76 (125 mg, 0.30 mmol) and N′hydroxyacetamidine (44 mg, 0.60 mmol) to afford 39 as a solid (44 mg, 33%). 1 (40). General method C was followed using 78 (62 mg, 0.14 mmol) and N′hydroxyacetamidine (10 mg, 0.14 mmol) to afford 40 as a solid (36 mg, 60%).…”

Section: -Ethyl-6-fluoro-3-(3-methyl-124-oxadiazol-5-yl)-7-pyrrolidin...mentioning

confidence: 99%

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

et al. 2023

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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.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: -Ethyl-6-fluoro-3-(3-methyl-124-oxadiazol-5-yl)-7-pyrrolidin...mentioning

confidence: 99%

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

et al. 2023

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Kinetic and structural studies of Mycobacterium tuberculosis dihydroorotate dehydrogenase reveal new insights into class 2 DHODH inhibition

Teixeira¹,

Martins²,

Froes³

et al. 2023

Biochimica et Biophysica Acta (BBA) - General Subjects

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Exploration and characterization of the antimalarial activity of cyclopropyl carboxamides that target the mitochondrial protein, cytochrome b

Awalt,

Su,

Nguyen

et al. 2024

European Journal of Medicinal Chemistry

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Molecular basis of extreme resistance in Plasmodium falciparum to atovaquone and other mitochondrial inhibitors

Cited by 3 publications

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

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

Kinetic and structural studies of Mycobacterium tuberculosis dihydroorotate dehydrogenase reveal new insights into class 2 DHODH inhibition

Exploration and characterization of the antimalarial activity of cyclopropyl carboxamides that target the mitochondrial protein, cytochrome b

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Molecular basis of extreme resistance in Plasmodium falciparum to atovaquone and other mitochondrial inhibitors

Cited by 3 publications

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

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

Kinetic and structural studies of Mycobacterium tuberculosis dihydroorotate dehydrogenase reveal new insights into class 2 DHODH inhibition

Exploration and characterization of the antimalarial activity of cyclopropyl carboxamides that target the mitochondrial protein, cytochrome b

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

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