DXR Inhibition by Potent Mono- and Disubstituted Fosmidomycin Analogues
2013 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 56, no 15, 6190-6199 p.Article in journal (Refereed) Published
The antimalarial compound fosmidomycin targets DXR, the enzyme that catalyzes the first committed step in the MEP pathway producing the universally essential isoprenoid precursors, isopentenyl diphosphate and dimethylallyl diphosphate. The MEP pathway is used by a number of pathogens, including Mycobacterium tuberculosis and apicomplexan parasites, and differs from the classical mevalonate pathway that is essential in humans. Using a structure-based approach, we designed a number of analogues of fosmidomycin, including a series that are substituted in both the Cα and the hydroxamate positions. The latter proved to be a stable framework for the design of inhibitors that extend from the cramped substrate-binding site and can, for the first time, bridge the substrate and cofactor binding sites. A number of these compounds are more potent than fosmidomycin in terms of killing Plasmodium falciparum in an in vitro assay; the best has an IC50 of 40 nM.
Place, publisher, year, edition, pages
2013. Vol. 56, no 15, 6190-6199 p.
Mycobacterium tuberculosis, 1-deoxy-D-xylulose 5-phosphate reductoisomerase, DXR
Research subject Biology with specialization in Structural Biology; Medicinal Chemistry
IdentifiersURN: urn:nbn:se:uu:diva-196616DOI: 10.1021/jm4006498ISI: 000323082400015OAI: oai:DiVA.org:uu-196616DiVA: diva2:610506
FunderSwedish Foundation for Strategic Research Swedish Research Council
De tre (3) första författarna delar förstaförfattarskapet.2013-03-112013-03-112015-04-23Bibliographically approved