Spirotetrahydro β-carbolines (spiroindolones): a new class of potent and orally efficacious compounds for the treatment of malaria

…, J Tan, J Wong, S Keller-Maerki, C Fischli…

Index: Yeung, Bryan K. S.; Zou, Bin; Rottmann, Matthias; Lakshminarayana, Suresh B.; Ang, Shi Hua; Leong, Seh Yong; Tan, Jocelyn; Wong, Josephine; Keller-Maerki, Sonja; Fischli, Christoph; Goh, Anne; Schmitt, Esther K.; Krastel, Philipp; Francotte, Eric; Kuhen, Kelli; Plouffe, David; Henson, Kerstin; Wagner, Trixie; Winzeler, Elizabeth A.; Petersen, Frank; Brun, Reto; Dartois, Veronique; Diagana, Thierry T.; Keller, Thomas H. Journal of Medicinal Chemistry, 2010 , vol. 53, # 14 p. 5155 - 5164

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Citation Number: 199

Abstract

The antiplasmodial activity of a series of spirotetrahydro β-carbolines is described. Racemic spiroazepineindole (1) was identified from a phenotypic screen on wild type Plasmodium falciparum with an in vitro IC50 of 90 nM. Structure− activity relationships for the optimization of 1 to compound 20a (IC50= 0.2 nM) including the identification of the active 1 R, 3 S enantiomer and elimination of metabolic liabilities is presented. Improvement of the ...