Abstract
Design of inhibitors for N-myristoyltransferase (NMT), an enzyme responsible for protein trafficking in Plasmodium falciparum , the most lethal species of parasites that cause malaria, is described. Chemistry-driven optimization of compound 1 from a focused NMT inhibitor library led to the identification of two early lead compounds 4 and 25, which showed good enzyme and cellular potency and excellent selectivity over human NMT. These molecules provide a valuable starting point for further development.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acyltransferases / antagonists & inhibitors*
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Acyltransferases / genetics
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Antimalarials / chemical synthesis*
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Antimalarials / chemistry
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Antimalarials / pharmacology
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Benzofurans / chemical synthesis*
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Benzofurans / chemistry
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Benzofurans / pharmacology
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Crystallography, X-Ray
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Drug Design
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Humans
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Models, Molecular
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Mutagenesis, Site-Directed
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Mutation
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Piperidines / chemical synthesis*
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Piperidines / chemistry
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Piperidines / pharmacology
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Plasmodium falciparum / drug effects
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Plasmodium falciparum / enzymology*
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Protein Conformation
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Antimalarials
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Benzofurans
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Piperidines
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Acyltransferases
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glycylpeptide N-tetradecanoyltransferase