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Potent antimalarial 4-pyridones with improved physico-chemical properties

Authors
Journal
Bioorganic & Medicinal Chemistry Letters
0960-894X
Publisher
Elsevier
Publication Date
Volume
21
Issue
18
Identifiers
DOI: 10.1016/j.bmcl.2011.07.044
Keywords
  • Malaria
  • Plasmodium Falciparum
  • 4-Pyridones
  • Solubility
  • Pharmacokinetic

Abstract

Abstract Antimalarial 4-pyridones are a novel class of inhibitors of the plasmodial mitochondrial electron transport chain targeting Cytochrome bc1 (complex III). In general, the most potent 4-pyridones are lipophilic molecules with poor solubility in aqueous media and low oral bioavailability in pre-clinical species from the solid dosage form. The strategy of introducing polar hydroxymethyl groups has enabled us to maintain the high levels of antimalarial potency observed for other more lipophilic analogues whilst improving the solubility and the oral bioavailability in pre-clinical species.

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