Alkoxycarbonyloxyethyl Ester Prodrugs of FR900098 with Improved In Vivo Antimalarial Activity

Ortmann, Regina; Wiesner, Jochen; Reichenberg, Armin; Henschker, Dajana; Beck, Ewald; Jomaa, Hassan; Schlitzer, Martin

doi:10.1002/ardp.200500976

Cited by 50 publications

(32 citation statements)

References 14 publications

(10 reference statements)

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“…10 Also, the phosphonate moiety has been altered to produce prodrugs with improved oral bioavailability. 11,12,13 Interestingly, modifications addressing the three carbon spacer are scarce. The objective of this work was to synthesize a series of fosmidomycin or FR900098 analogues containing a phenyl moiety in the α-position.…”

Section: [Figure 1]mentioning

confidence: 99%

Synthesis of α-substituted fosmidomycin analogues as highly potent Plasmodium falciparum growth inhibitors

Haemers

Wiesner

Poecke

et al. 2006

Bioorganic & Medicinal Chemistry Letters

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confidence: 99%

Synthesis of α-substituted fosmidomycin analogues as highly potent Plasmodium falciparum growth inhibitors

Haemers

Wiesner

Poecke

et al. 2006

Bioorganic & Medicinal Chemistry Letters

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100

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“…= 10.6 mmol (4 mg) kg À1 ). [432,433] In addition to the compounds mentioned above, several more DXR inhibitors have been reported. However, these compounds have only been evaluated against the isolated enzyme (most of which are less active than fosmidomycin (136)), but not against P. falciparum.…”

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confidence: 99%

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

2007

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Since ancient times, humankind has had to struggle against the persistent onslaught of pathogenic microorganisms. Nowadays, malaria is still the most important infectious disease worldwide. Considerable success in gaining control over malaria was achieved in the 1950s and 60s through landscaping measures, vector control with the insecticide DDT, and the widespread administration of chloroquine, the most important antimalarial agent ever. In the late 1960s, the final victory over malaria was believed to be within reach. However, the parasites could not be eradicated because they developed resistance against the most widely used and affordable drugs of that time. Today, cases of malaria infections are on the rise and have reached record numbers. This review gives a short description of the malaria disease, briefly addresses the history of antimalarial drug development, and focuses on drugs currently available for malaria therapy. The present knowledge regarding their mode of action and the mechanisms of resistance are explained, as are the attempts made by numerous research groups to overcome the resistance problem within classes of existing drugs and in some novel classes. Finally, this review covers all classes of antimalarials for which at least one drug candidate is in clinical development. Antimalarial agents that are solely in early development stages will be addressed in a separate review.

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“…Although significant research efforts have focused on identifying synthetic derivatives of these compounds with improved efficacy, such compounds are cost-prohibitive (11,33,34). We have recently characterized the biosynthetic pathway for FR-900098 and have reconstituted the pathway through heterologous expression of the biosynthetic genes in E. coli, opening new avenues for the production of derivative compounds by genetic manipulation (12,13).…”

Section: Discussionmentioning

confidence: 99%

New N-Acetyltransferase Fold in the Structure and Mechanism of the Phosphonate Biosynthetic Enzyme FrbF

Bae

Cobb

DeSieno

et al. 2011

Journal of Biological Chemistry

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The enzyme FrbF from Streptomyces rubellomurinus has attracted significant attention due to its role in the biosynthesis of the antimalarial phosphonate FR-900098. The enzyme catalyzes acetyl transfer onto the hydroxamate of the FR-900098 precursors cytidine 5-monophosphate-3-aminopropylphosphonate and cytidine 5-monophosphate-N-hydroxy-3-aminopropylphosphonate. Despite the established function as a bona fide N-acetyltransferase, FrbF shows no sequence similarity to any member of the GCN5-like N-acetyltransferase (GNAT) superfamily. Here, we present the 2.0 Å resolution crystal structure of FrbF in complex with acetyl-CoA, which demonstrates a unique architecture that is distinct from those of canonical GNAT-like acetyltransferases. We also utilized the co-crystal structure to guide structure-function studies that identified the roles of putative active site residues in the acetyltransferase mechanism. The combined biochemical and structural analyses of FrbF provide insights into this previously uncharacterized family of N-acetyltransferases and also provide a molecular framework toward the production of novel N-acyl derivatives of FR-900098.

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Alkoxycarbonyloxyethyl Ester Prodrugs of FR900098 with Improved In Vivo Antimalarial Activity

Cited by 50 publications

References 14 publications

Synthesis of α-substituted fosmidomycin analogues as highly potent Plasmodium falciparum growth inhibitors

Synthesis of α-substituted fosmidomycin analogues as highly potent Plasmodium falciparum growth inhibitors

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

New N-Acetyltransferase Fold in the Structure and Mechanism of the Phosphonate Biosynthetic Enzyme FrbF

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