Abstract
Malaria is a protozoal parasitic disease that is widespread in tropical and subtropical regions of Africa, Asia, and the Americas and causes more than 800,000 deaths per year. The continuing emergence of multidrug-resistant Plasmodium falciparum drives the ongoing need for the development of new and effective antimalarial drugs. Our previous work has explored the preliminary structural optimization of 4(1H)-quinolone ester derivatives, a new series of antimalarials related to the endochins. Herein, we report the lead optimization of 4(1H)-quinolones with a focus on improving both antimalarial potency and bioavailability. These studies led to the development of orally efficacious antimalarials including quinolone analogue 20g, a promising candidate for further optimization.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Antimalarials / administration & dosage*
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Antimalarials / chemical synthesis
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Antimalarials / chemistry*
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Antimalarials / pharmacokinetics
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Biological Availability
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Female
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Hep G2 Cells
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Humans
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Malaria, Falciparum / drug therapy*
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Malaria, Falciparum / parasitology
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Mice
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Mice, Inbred ICR
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Nuclear Magnetic Resonance, Biomolecular
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Parasitemia / drug therapy
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Parasitemia / parasitology
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Plasmodium falciparum / isolation & purification*
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Quinolines / administration & dosage*
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Quinolines / chemical synthesis
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Quinolines / chemistry*
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Quinolines / pharmacokinetics
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Spectrometry, Mass, Electrospray Ionization
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Spectroscopy, Fourier Transform Infrared
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Structure-Activity Relationship