α-Substituted β-Oxa Isosteres of Fosmidomycin: Synthesis and Biological Evaluation

Brücher, Karin; Illarionov, Boris; Held, Jana; Tschan, Serena; Kunfermann, Andrea; Pein, Miriam; Bacher, Adelbert; Gräwert, Tobias; Maes, Louis; Mordmüller, Benjamin; Fischer, Markus; Kurz, Thomas

doi:10.1021/jm300652f

Cited by 34 publications

(35 citation statements)

References 51 publications

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“…It is possible that fosmidomycin penetrates cells adequately of itself. The most recent studies reported a series of fosmidomycin analogs with enhanced potency against the purified enzyme and growth of the Plasmodium parasite in vitro [219]. While the activity was somewhat enhanced by bis-POM protection, the results parallel findings of limited activity of the tri-POM pro-drug squalene synthase inhibitor ER27856 in Leishmania .…”

Section: Current Applications Of Prodrug Technologymentioning

confidence: 84%

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

Wiemer

2014

Topics in Current Chemistry

147

135

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A substantial portion of metabolism involves transformation of phosphate esters, including pathways leading to nucleotides and oligonucleotides, carbohydrates, isoprenoids and steroids, and phosphorylated proteins. Because the natural substrates bear one or more negative charges, drugs that target these enzymes generally must be charged as well but small charged molecules can have difficulty traversing the cell membrane other than by endocytosis. The resulting dichotomy has stimulated abundant effort to develop effective prodrugs, compounds that carry little or no charge to enable them to transit biological membranes but then able to release the parent drug once inside the target cell. This chapter will present recent studies on advances in prodrug forms, along with representative examples of their application to marketed and developmental drugs.

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Section: Current Applications Of Prodrug Technologymentioning

confidence: 84%

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

Wiemer

2014

Topics in Current Chemistry

147

135

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“…α -Aryl-substituted β -oxa isosteres of fosmidomycin with a reverse orientation of the hydroxamic acid group were synthesized and evaluated for their inhibitory activity against recombinant 1-deoxy-d-xylulose 5-phosphate reductoisomerase (IspC) of Plasmodium falciparum and for their in vitro antiplasmodial activity against chloroquine-sensitive and resistant strains of P. falciparum . The most active derivative inhibits IspC protein of P. falciparum ( Pf IspC) with an IC 50 value of 12 nM and shows potent in vitro antiplasmodial activity [40]. …”

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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“…Behrendt et al ( 2011 ) synthesized the reverse hydroxamate based inhibitors amongst which [1-(3,4-Difluorophenyl)-4-(hydroxylamino)-4-oxobutyl] phosphonic acid is considered most effective with an IC 50 of 3 nM. Later Brücher et al ( 2012 ) synthesized α-Aryl-substituted β-oxa isosteres of Fos with a reverse orientation of the hydroxamic acid group and tested them against recombinant P. falciparum IspC and chloroquine-sensitive and resistant strains of P. falciparum . They found an inhibitory activity of these derivatives against P. falciparum IspC, with the most active derivative ((3,4-Difluorophenyl) (2-(hydroxy(methyl)amino)-2-oxoethoxy) methyl) phosphonic acid showing an IC 50 value of 12 nM and potent in-vitro anti-plasmodial activity.…”

Section: Introductionmentioning

confidence: 99%

New Insight into Isoprenoids Biosynthesis Process and Future Prospects for Drug Designing in Plasmodium

et al. 2016

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The MEP (Methyl Erythritol Phosphate) isoprenoids biosynthesis pathway is an attractive drug target to combat malaria, due to its uniqueness and indispensability for the parasite. It is functional in the apicoplast of Plasmodium and its products get transported to the cytoplasm, where they participate in glycoprotein synthesis, electron transport chain, tRNA modification and several other biological processes. Several compounds have been tested against the enzymes involved in this pathway and amongst them Fosmidomycin, targeted against IspC (DXP reductoisomerase) enzyme and MMV008138 targeted against IspD enzyme have shown good anti-malarial activity in parasite cultures. Fosmidomycin is now-a-days prescribed clinically, however, less absorption, shorter half-life, and toxicity at higher doses, limits its use as an anti-malarial. The potential of other enzymes of the pathway as candidate drug targets has also been determined. This review details the various drug molecules tested against these targets with special emphasis to Plasmodium. We corroborate that MEP pathway functional within the apicoplast of Plasmodium is a major drug target, especially during erythrocytic stages. However, the major bottlenecks, bioavailability and toxicity of the new molecules needs to be addressed, before considering any new molecule as a potent antimalarial.

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α-Substituted β-Oxa Isosteres of Fosmidomycin: Synthesis and Biological Evaluation

Cited by 34 publications

References 51 publications

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

Exploring Drug Targets in Isoprenoid Biosynthetic Pathway forPlasmodium falciparum

New Insight into Isoprenoids Biosynthesis Process and Future Prospects for Drug Designing in Plasmodium

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