ArticleAntimicrobial agents and chemotherapy2015
Subtle changes in endochin-like quinolone structure alter the site of inhibition within the cytochrome bc1 complex of Plasmodium falciparum.
Article in Antimicrobial agents and chemotherapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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59 citing papers in PubMed, 76 citations in OpenAlex.
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- Exploration and characterization of the antimalarial activity of cyclopropyl carboxamides that target the mitochondrial protein, cytochrome b.European journal of medicinal chemistry · 2024Article
- 3-Position Biaryl Endochin-like Quinolones with Enhanced Antimalarial Performance.ACS infectious diseases · 2024Article
- 2,8-Disubstituted-1,5-naphthyridines as Dual Inhibitors ofJournal of medicinal chemistry · 2024Article
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- Synthesis of Deuterated Endochin-Like Quinolones.Journal of labelled compounds & radiopharmaceuticals · 2024Article
- Mitochondrial CytochromeTropical medicine and infectious disease · 2024Review
- Novel Baicalein-Derived Inhibitors ofPathogens (Basel, Switzerland) · 2023Article
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
Abstract
The cytochrome bc1 complex (cyt bc1) is the third component of the mitochondrial electron transport chain and is the target of several potent antimalarial compounds, including the naphthoquinone atovaquone (ATV) and the 4(1H)-quinolone ELQ-300. Mechanistically, cyt bc1 facilitates the transfer of electrons from ubiquinol to cytochrome c and contains both oxidative (Qo) and reductive (Qi) catalytic sites that are amenable to small-molecule inhibition. Although many antimalarial compounds, including ATV, effectively target the Qo site, it has been challenging to design selective Qi site inhibitors with the ability to circumvent clinical ATV resistance, and little is known about how chemical structure contributes to site selectivity within cyt bc1. Here, we used the proposed Qi site inhibitor ELQ-300 to generate a drug-resistant Plasmodium falciparum clone containing an I22L mutation at the Qi region of cyt b. Using this D1 clone and the Y268S Qo mutant strain, P. falciparum Tm90-C2B, we created a structure-activity map of Qi versus Qo site selectivity for a series of endochin-like 4(1H)-quinolones (ELQs). We found that Qi site inhibition was associated with compounds containing 6-position halogens or aryl 3-position side chains, while Qo site inhibition was favored by 5,7-dihalogen groups or 7-position substituents. In addition to identifying ELQ-300 as a preferential Qi site inhibitor, our data suggest that the 4(1H)-quinolone scaffold is compatible with binding to either site of cyt bc1 and that minor chemical changes can influence Qo or Qi site inhibition by the ELQs.
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