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Chem Biol DOI:10.1016/j.chembiol.2011.09.016

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

Publication TypeJournal Article
Year of Publication2011
AuthorsDong, CK, Urgaonkar, S, Cortese, JF, Gamo, F-J, Garcia-Bustos, JF, Lafuente, MJ, Patel, V, Ross, L, Coleman, BI, Derbyshire, ER, Clish, CB, Serrano, AE, Cromwell, M, Barker, RH, Dvorin, JD, Duraisingh, MT, Wirth, DF, Clardy, J, Mazitschek, R
JournalChem Biol
Date Published2011 Dec 23
KeywordsAnimals, Antimalarials, Atovaquone, Binding Sites, Electron Transport Complex III, Mice, Molecular Sequence Data, Mutation, Parasitic Sensitivity Tests, Plasmodium falciparum, Protein Structure, Tertiary, Reproducibility of Results, Structure-Activity Relationship, Thiazepines

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.


Alternate JournalChem. Biol.
PubMed ID22195562
PubMed Central IDPMC3474356
Grant ListK12-HD000850 / HD / NICHD NIH HHS / United States
K12 HD000850-17 / HD / NICHD NIH HHS / United States
K12 HD000850 / HD / NICHD NIH HHS / United States
G12 RR003051 / RR / NCRR NIH HHS / United States
G12RR03051 / RR / NCRR NIH HHS / United States
G12 MD007600 / MD / NIMHD NIH HHS / United States