title: Spirotetrahydro beta-carbolines (spiroindolones): a new class of potent and orally efficacious compounds for the treatment of malaria.
abstract: The antiplasmodial activity of a series of spirotetrahydro beta-carbolines is described. Racemic spiroazepineindole (1) was identified from a phenotypic screen on wild type Plasmodium falciparum with an in vitro IC(50) of 90 nM. Structure-activity relationships for the optimization of 1 to compound 20a (IC(50) = 0.2 nM) including the identification of the active 1R,3S enantiomer and elimination of metabolic liabilities is presented. Improvement of the pharmacokinetic profile of the series translated to exceptional oral efficacy in the P. berghei infected malaria mouse model where full cure was achieved in four of five mice with three daily doses of 30 mg/kg.
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, no. 05-01 Chromos, Singapore 138670. bryan.yeung@novartis.com
authors.forename: Bryan K S
authors.initials: BK
authors.lastname: Yeung
authors.forename: Bin
authors.initials: B
authors.lastname: Zou
authors.forename: Matthias
authors.initials: M
authors.lastname: Rottmann
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Lakshminarayana
authors.forename: Shi Hua
authors.initials: SH
authors.lastname: Ang
authors.forename: Seh Yong
authors.initials: SY
authors.lastname: Leong
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Tan
authors.forename: Josephine
authors.initials: J
authors.lastname: Wong
authors.forename: Sonja
authors.initials: S
authors.lastname: Keller-Maerki
authors.forename: Christoph
authors.initials: C
authors.lastname: Fischli
authors.forename: Anne
authors.initials: A
authors.lastname: Goh
authors.forename: Esther K
authors.initials: EK
authors.lastname: Schmitt
authors.forename: Philipp
authors.initials: P
authors.lastname: Krastel
authors.forename: Eric
authors.initials: E
authors.lastname: Francotte
authors.forename: Kelli
authors.initials: K
authors.lastname: Kuhen
authors.forename: David
authors.initials: D
authors.lastname: Plouffe
authors.forename: Kerstin
authors.initials: K
authors.lastname: Henson
authors.forename: Trixie
authors.initials: T
authors.lastname: Wagner
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Winzeler
authors.forename: Frank
authors.initials: F
authors.lastname: Petersen
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Veronique
authors.initials: V
authors.lastname: Dartois
authors.forename: Thierry T
authors.initials: TT
authors.lastname: Diagana
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Keller
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002243:Carbolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D010962:Plasmodium berghei; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C551616:5'-chloro-6,7-difluoro-3-methyl-2,3,4,9-tetrahydrospiro(beta-carboline-1,3'-indol)-2'(1'H)-one; D000962:Antimalarials; D002243:Carbolines; D007211:Indoles; D013141:Spiro Compounds