Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 53, Issue 14, Pages 5155-5164Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm100410f
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Funding
- Medicines for Malaria Venture
- Wellcome Trust [WT078285]
- Genomics Institute of the Novartis Research Foundation
- Swiss Tropical and Public Health Institute
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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 1 R,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.
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