Acyloxyalkyl ester prodrugs of FR900098 with improved in vivo anti-malarial activity

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

doi:10.1016/s0960-894x(03)00354-8

Cited by 76 publications

(59 citation statements)

References 13 publications

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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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“…These include modifications of the phosphonate group that yield phosphonate prodrugs expected to enhance oral availability. 22,23 Different acyl group substituents have also been prepared, as well as modifications of the hydroxamate group and of the three-carbon spacer (see, for example, references [24][25][26] and other work cited therein).…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and X-ray Crystallographic Studies of α-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-d-xylulose 5-Phosphate Reductoisomerase

et al. 2011

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The natural antibiotic fosmidomycin acts via inhibition of 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. Fosmidomycin is active on Mycobacterium tuberculosis DXR (MtDXR), but it lacks antibacterial activity probably because of poor uptake. α-Aryl substituted fosmidomycin analogues have more favorable physicochemical properties and are also more active in inhibiting malaria parasite growth. We have solved crystal structures of MtDXR in complex with 3,4-dichlorophenyl substituted fosmidomycin analogues; these show important differences compared to our previously described forsmidomycin–DXR complex. Our best inhibitor has an IC50 = 0.15 μM on MtDXR but still lacked activity in a mycobacterial growth assay (MIC > 32 μg/mL). The combined results, however, provide insights into how DXR accommodates the new inhibitors and serve as an excellent starting point for the design of other novel and more potent inhibitors, particularly against pathogens where uptake is less of a problem, such as the malaria parasite.

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“…[78] Increased oral bioavailability resulted from the synthesis of prodrug derivatives of FR900098 in which the phosphonate moiety was masked as a biolabile aryl function (33) or with double esters (34, Figure 11). [93,94] …”

Section: Tafenoquinementioning

confidence: 99%

New Antimalarial Drugs

et al. 2003

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Approximately 40% of the world population live in areas with the risk of malaria. Each year, 300-500 million people suffer from acute malaria, and 0.5-2.5 million die from the disease. Although malaria has been widely eradicated in many parts of the world, the global number of cases continues to rise. The most important reason for this alarming situation is the rapid spread of malaria parasites that are resistant to antimalarial drugs, especially chloroquine, which is by far the most frequently used. The development of new antimalarial drugs has been neglected since the 1970s owing to the end colonialism, changes in the areas of military engagement, and the restricted market potential. Only in recent years, in part supported by public funding programs, has interest in the development of antimalarial drugs been renewed. New data available from the recently sequenced genome of the malaria parasite Plasmodium falciparum and the application of methods of modern drug design promise to bring significant development in the fight against this disease.

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Acyloxyalkyl ester prodrugs of FR900098 with improved in vivo anti-malarial activity

Cited by 76 publications

References 13 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

Design, Synthesis, and X-ray Crystallographic Studies of α-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-d-xylulose 5-Phosphate Reductoisomerase

New Antimalarial Drugs

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