DXR Inhibition by Potent Mono- and Disubstituted Fosmidomycin Analogues

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• 作者：Anna M. Jansson ; Anna Wi臋ckowska ; Christofer Bj枚rkelid ; Samir Yahiaoui ; Sanjeewani Sooriyaarachchi ; Martin Lindh ; Terese Bergfors ; Shyamraj Dharavath ; Matthieu Desroses ; Surisetti Suresh ; Mounir Andaloussi ; Rautela Nikhil ; Sharma Sreevalli ; Bachally R. Srinivasa ; Mats Larhed ; T. Alwyn Jones ; Anders Karl茅n ; Sherry L. Mowbray
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：August 8, 2013
• 年：2013
• 卷：56
• 期：15
• 页码：6190-6199
• 全文大小：455K
• 年卷期：v.56,no.15(August 8, 2013)
• ISSN：1520-4804

文摘

The antimalarial compound fosmidomycin targets DXR, the enzyme that catalyzes the first committed step in the MEP pathway, producing the 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 C伪 and the hydroxamate positions. The latter proved to be a stable framework for the design of inhibitors that extend from the polar and cramped (and so not easily druggable) 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.