title: Identification and validation of tetracyclic benzothiazepines as Plasmodium falciparum cytochrome bc1 inhibitors.
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.
authors.affiliation: Department of Immunology and Infectious Disease, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Carolyn K
authors.initials: CK
authors.lastname: Dong
authors.forename: Sameer
authors.initials: S
authors.lastname: Urgaonkar
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Cortese
authors.forename: Francisco-Javier
authors.initials: FJ
authors.lastname: Gamo
authors.forename: Jose F
authors.initials: JF
authors.lastname: Garcia-Bustos
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Lafuente
authors.forename: Vishal
authors.initials: V
authors.lastname: Patel
authors.forename: Leila
authors.initials: L
authors.lastname: Ross
authors.forename: Bradley I
authors.initials: BI
authors.lastname: Coleman
authors.forename: Emily R
authors.initials: ER
authors.lastname: Derbyshire
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.forename: Adelfa E
authors.initials: AE
authors.lastname: Serrano
authors.forename: Mandy
authors.initials: M
authors.lastname: Cromwell
authors.forename: Robert H
authors.initials: RH
authors.lastname: Barker
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Dvorin
authors.forename: Manoj T
authors.initials: MT
authors.lastname: Duraisingh
authors.forename: Dyann F
authors.initials: DF
authors.lastname: Wirth
authors.forename: Jon
authors.initials: J
authors.lastname: Clardy
authors.forename: Ralph
authors.initials: R
authors.lastname: Mazitschek
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D053626:Atovaquone / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D017434:Protein Structure, Tertiary; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship; D013841:Thiazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D013841:Thiazepines; D014450:Electron Transport Complex III; D053626:Atovaquone