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Title
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Synthesis of - and -oxa isosteres of fosmidomycin and FR900098 as antimalarial candidates
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Author
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Abstract
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| To expand the structureactivity relationships of fosmidomycin and FR900098, two potent antimalarials interfering with the MEP-pathway, we decided to replace a methylene group in β-position of the phosphonate moiety of these leads by an oxygen atom. β-oxa-FR900098 (11) proved equally active as the parent compound. When applied to 4-[hydroxyl(methyl)amino]-4-oxobutyl phosphonic acid, featuring a hydroxamate instead of the retrohydroxamate moiety, a β-oxa modification yielded a derivative (13) with superior activity against the Plasmodium falciparum 3D7 strain than fosmidomycin, while a γ-oxa modification resulted in less active derivatives. A bis(pivaloyloxymethyl)ester of phosphonate 13 proved twice as active in inhibiting cultured parasites as a similar prodrug of FR900098. |
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Language
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English
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Source (journal)
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Bioorganic and medicinal chemistry. - Oxford
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Publication
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Oxford
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2008
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ISSN
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0968-0896
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DOI
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10.1016/J.BMC.2007.12.001
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Volume/pages
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16
:6
(2008)
, p. 3361-3371
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ISI
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000255127700062
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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