Reverse Fosmidomycin Derivatives against the Antimalarial Drug Target IspC (Dxr)

Behrendt, Christoph; Kunfermann, Andrea; Illarionova, Victoria; Matheeussen, An; Pein, Miriam; Gräwert, Tobias; Kaiser, J.; Bacher, Adelbert; Eisenreich, Wolfgang; Illarionov, Boris; Fischer, Markus; Maes, Louis; Groll, M.; Kurz, Thomas

doi:10.1021/jm200694q

Cited by 56 publications

(61 citation statements)

References 34 publications

(25 reference statements)

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“…Kuntz et al (2005) synthesized two phosphonohydroxamic acids which showed inhibitory activity towards DXR as well as antibacterial activity against E. coli in vitro. Indeed, Behrendt et al (2011) very recently reported the antiplasmodial activity of IspC/Dxr inhibitors.…”

Section: The Mep Pathway As a Drug Targetmentioning

confidence: 99%

Isoprenoid biosynthesis in bacterial pathogens

et al. 2012

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Section: The Mep Pathway As a Drug Targetmentioning

confidence: 99%

Isoprenoid biosynthesis in bacterial pathogens

et al. 2012

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“…Reverse hydroxamate-based inhibitor for IspC enzyme was evaluated by Behrendt et al (2011) [37]. Fosmidomycin has been proven to be efficient in the treatment of P. falciparum malaria by inhibiting 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), an enzyme of the nonmevalonate pathway, which is absent in humans (Figure 4).…”

Section: Antimalarial Compounds Against Isoprenoid Biosynthetic Pamentioning

confidence: 99%

Exploring Drug Targets in Isoprenoid Biosynthetic Pathway forPlasmodium falciparum

Qidwai¹,

Jamal

Khan

et al. 2014

Biochemistry Research International

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Emergence of rapid drug resistance to existing antimalarial drugs in Plasmodium falciparum has created the need for prediction of novel targets as well as leads derived from original molecules with improved activity against a validated drug target. The malaria parasite has a plant plastid-like apicoplast. To overcome the problem of falciparum malaria, the metabolic pathways in parasite apicoplast have been used as antimalarial drug targets. Among several pathways in apicoplast, isoprenoid biosynthesis is one of the important pathways for parasite as its multiplication in human erythrocytes requires isoprenoids. Therefore targeting this pathway and exploring leads with improved activity is a highly attractive approach. This report has explored progress towards the study of proteins and inhibitors of isoprenoid biosynthesis pathway. For more comprehensive analysis, antimalarial drug-protein interaction has been covered.

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“…15,17 Extensive crystallographic studies on DXRs from different species have provided the structural framework needed to understand the binding of these inhibitors, 10,[18][19][20][21] as well as their α-aryl-substituted analogues. 7,22,23 Despite the lack of biological activity of fosmidomycin itself against M. tuberculosis, the well-conserved nature of the active site of DXR, 21 combined with the anti-parasite activity of some DXR inhibitors, led us to believe that our medicinal chemistry effort based on MtDXR would produce interesting compounds for use against other pathogens where the MEP pathway is essential. It also seemed possible that some fosmidomycin analogues would in fact be active against M. tuberculosis.…”

Section: Introductionmentioning

confidence: 99%

DXR Inhibition by Potent Mono- and Disubstituted Fosmidomycin Analogues

et al. 2013

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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 Cα 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) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 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 IC 50 of 40 nM. IntroductionFosmidomycin (1) and its acetyl derivative, , are natural product antibiotics with activity against a number of important pathogens. 1,2 They work by blocking the pathway for biosynthesis of isopentenyl diphosphate and dimethylallyl diphosphate that proceeds via the intermediate 2-C-methyl-D-erythritol 4-phosphate (MEP). This MEP pathway is used in Gramnegative and some Gram-positive bacteria, as well as in plant chloroplasts, algae and apicomplexan protozoa. 3 The enzymes involved are essential to the organisms possessing them, yet completely absent in humans, and they have therefore received considerable attention as potential targets for antimicrobial drug discovery. Fosmidomycin and 2 act by inhibiting the second (and first committed) step in the pathway, 4, 5 in which 1-deoxy-D-xylulose 5-phosphate (DXP) is converted to MEP by the enzyme 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR, also called IspC). A number of major pathogens are dependent upon the MEP pathway, although not all are sensitive to fosmidomycin and its analogues. For example, while both 1 and 2 inhibit the DXRs of the protozoan Plasmodium falciparum (PfDXR) 6 and Mycobacterium tuberculosis (MtDXR), 7-10 the Plasmodium species are sensitive to these antibiotics in vitro and in vivo, 6 but the mycobacteria are not. 11 The use of fosmidomycin as a single-drug treatment for P. falciparum malaria has been hampered by low bioavailability, rapid clearance from the parasite and recrudescent infection, 12 although the compound has been used more successfully in combination with clindamycin. 13 Failure to obtain biological activity against mycobacteria appears to result from poor uptake. 11Page 3 of 36 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34...

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Reverse Fosmidomycin Derivatives against the Antimalarial Drug Target IspC (Dxr)

Cited by 56 publications

References 34 publications

Isoprenoid biosynthesis in bacterial pathogens

Isoprenoid biosynthesis in bacterial pathogens

Exploring Drug Targets in Isoprenoid Biosynthetic Pathway forPlasmodium falciparum

DXR Inhibition by Potent Mono- and Disubstituted Fosmidomycin Analogues

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