Title
Synthesis of <tex>$\beta$</tex>- and <tex>$\gamma$</tex>-oxa isosteres of fosmidomycin and FR900098 as antimalarial candidates Synthesis of <tex>$\beta$</tex>- and <tex>$\gamma$</tex>-oxa isosteres of fosmidomycin and FR900098 as antimalarial candidates
Author
Faculty/Department
Faculty of Medicine and Health Sciences
Publication type
article
Publication
Oxford ,
Subject
Human medicine
Source (journal)
Bioorganic and medicinal chemistry. - Oxford
Volume/pages
16(2008) :6 , p. 3361-3371
ISSN
0968-0896
ISI
000255127700062
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Abstract
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.
E-info
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