Abstract
Starting from a hit series from a GNF compound library collection and based on a cell-based proliferation assay of Plasmodium falciparum, a novel imidazolopiperazine scaffold was optimized. SAR for this series of compounds is discussed, focusing on optimization of cellular potency against wild-type and drug resistant parasites and improvement of physiochemical and pharmacokinetic properties. The lead compounds in this series showed good potencies in vitro and decent oral exposure levels in vivo. In a Plasmodium berghei mouse infection model, one lead compound lowered the parasitemia level by 99.4% after administration of 100 mg/kg single oral dose and prolonged mice survival by an average of 17.0 days. The lead compounds were also well-tolerated in the preliminary in vitro toxicity studies and represents an interesting lead for drug development.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acids / chemical synthesis
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Amino Acids / chemistry
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Amino Acids / pharmacology
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Aniline Compounds / chemical synthesis
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Aniline Compounds / chemistry
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Aniline Compounds / pharmacology
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Animals
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Antimalarials / chemical synthesis*
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Antimalarials / chemistry
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Antimalarials / pharmacology
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Benzene Derivatives / chemical synthesis
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Benzene Derivatives / chemistry
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Benzene Derivatives / pharmacology
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Cell Line
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Drug Resistance
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Female
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Humans
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Imidazoles / chemical synthesis*
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Imidazoles / chemistry
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Imidazoles / pharmacology
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Inhibitory Concentration 50
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Malaria / drug therapy
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Mice
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Mice, Inbred BALB C
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Piperazines / chemical synthesis*
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Piperazines / chemistry
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Piperazines / pharmacology
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Plasmodium berghei
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Plasmodium falciparum / drug effects
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Rats
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Structure-Activity Relationship
Substances
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Amino Acids
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Aniline Compounds
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Antimalarials
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Benzene Derivatives
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Imidazoles
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Piperazines