Abstract
We report a series of novel inhibitors of protein farnesyltransferase based on the 2-oxotetrahydroquinoline scaffold. We developed an efficient synthesis of these compounds. These compounds show selective inhibtion of the malaria versus human farnesyltransferase and inhibit the growth of the malaria parasite in the low nanomolar range. Some of the compounds are at least an order of magnitude more stable to metabolic degradation than the corresponding tetrahydroquinolines.
MeSH terms
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Alkyl and Aryl Transferases / antagonists & inhibitors*
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Alkyl and Aryl Transferases / chemistry
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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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Crystallography, X-Ray
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Drug Stability
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Humans
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In Vitro Techniques
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Mice
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Microsomes, Liver / metabolism
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Models, Molecular
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Molecular Structure
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Plasmodium falciparum / drug effects*
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Plasmodium falciparum / enzymology
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Quinolines / chemical synthesis*
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Quinolines / chemistry
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Quinolines / pharmacology
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Rats
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Structure-Activity Relationship
Substances
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Antimalarials
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Quinolines
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Alkyl and Aryl Transferases
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p21(ras) farnesyl-protein transferase