Identification and validation of tetracyclic benzothiazepines as Plasmodium falciparum cytochrome bc1 inhibitors

Chemistry & Biology
Carolyn K DongRalph Mazitschek

Abstract

Here we report the discovery of tetracyclic benzothiazepines (BTZs) as highly potent and selective antimalarials along with the identification of the Plasmodium falciparum cytochrome bc(1) complex as the primary functional target of this novel compound class. Investigation of the structure activity relationship within this previously unexplored chemical scaffold has yielded inhibitors with low nanomolar activity. A combined approach employing genetically modified parasites, biochemical profiling, and resistance selection validated inhibition of cytochrome bc(1) activity, an essential component of the parasite respiratory chain and target of the widely used antimalarial drug atovaquone, as the mode of action of this novel compound class. Resistance to atovaquone is eroding the efficacy of this widely used antimalarial drug. Intriguingly, BTZ-based inhibitors retain activity against atovaquone resistant parasites, suggesting this chemical class may provide an alternative to atovaquone in combination therapy.

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Related Concepts

Antimalarials
Plasmodium falciparum
Structure-Activity Relationship
Thiazepines
Core II Protein, Ubiquinol-Cytochrome c Reductase
Tertiary Protein Structure
Helminth Drug Sensitivity Tests
Mepron
Combination Drug Therapy
Immunoglobulin Isotypes

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