Abstract
Fumagillin, an irreversible inhibitor of MetAP2, has been shown to potently inhibit growth of malaria parasites in vitro. Here, we demonstrate activity of fumagillin analogs with an improved pharmacokinetic profile against malaria parasites, trypanosomes, and amoebas. A subset of the compounds showed efficacy in a murine malaria model. The observed SAR forms a basis for further optimization of fumagillin based inhibitors against parasitic targets by inhibition of MetAP2.
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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Aminopeptidases / antagonists & inhibitors*
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Aminopeptidases / metabolism
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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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Cyclohexanes / chemical synthesis
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Cyclohexanes / chemistry*
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Cyclohexanes / pharmacology
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Fatty Acids, Unsaturated / chemical synthesis
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Fatty Acids, Unsaturated / chemistry*
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Fatty Acids, Unsaturated / pharmacology
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Metalloendopeptidases / antagonists & inhibitors*
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Metalloendopeptidases / metabolism
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Mice
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Parasitic Sensitivity Tests
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Sesquiterpenes / chemical synthesis
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Sesquiterpenes / chemistry
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Sesquiterpenes / pharmacology
Substances
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Antimalarials
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Cyclohexanes
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Fatty Acids, Unsaturated
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Sesquiterpenes
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fumagillin
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Aminopeptidases
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methionine aminopeptidase 2
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Metalloendopeptidases