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

Bioorganic and Medicinal Chemistry Letters

Volumn 13, Issue 13, 2003, Pages 2163-2166

  Ortmann, Regina ^a   Wiesner, Jochen ^b   Reichenberg, Armin ^b   Henschker, Dajana ^b   Beck, Ewald ^b   Jomaa, Hassan ^b   Schlitzer, Martin ^a  

^a UNIVERSITY OF MUNICH   (Germany)

^b JUSTUS LIEBIG UNIVERSITY   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

1 DEOXY DEXTRO XYLULOSE 5 PHOSPHATE REDUCTOISOMERASE; 3 (N ACETYL N HYDROXYAMINO)PROPYLPHOSPHONIC ACID; ACETIC ACID DERIVATIVE; ANTIMALARIAL AGENT; FOSMIDOMYCIN; ISOMERASE; PRODRUG; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BIOSYNTHESIS; CONTROLLED STUDY; DRUG EFFICACY; DRUG POTENCY; DRUG SYNTHESIS; ENZYME INHIBITION; MOUSE; NONHUMAN; PARASITEMIA; PLASMODIUM VINCKEI;

PLASMODIUM VINCKEI; RODENTIA;

EID: 0037871840     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(03)00354-8     Document Type: Article

References (17)

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14. 1H NMR, MS and microanalysis.
15. Prodrugs were dissolved in DMSO at 150 mg/mL and further diluted in SSV (standard suspension vehicle; 0.9% NaCl, 0.5% Na-carboxymethylcellulose, 0.5% benzyl alcohol, 0.4% Tween 80). FR900098 was dissolved in SSV. Parasitaemia was monitored by Giemsa-stained blood smears. Mice were sacrificed when parasitaemia was exceeding approx 40%. Four mice were used for each treatment group, and three mice for the control group. Results were expressed as geometric mean values for each group.
16. 2, 1 mM NADPH, 0.3 mM DOXP, and 1 μg/mL DOXP reductoisomerase from Escherichia coli. The mixture was incubated with a dilution series of the plasma samples on a 96-well microtiter plate, and the reaction started by addition of DOXP. The decrease of absorption was monitored at 340 nm using a SpectraMax 340PC microplate reader (Molecular Devices, Ismaning). The plasma concentrations were calculated from the enzyme inhibition values obtained with FR900098 standard solutions analyzed in parallel.
17. When calculating the dosages in molar units instead of mass units (40 mg/kg FR900098=0.18 mmol/kg; 20 mg/kg 7e=0.054 mmol/kg), 7e has 3-fold increased activity compared with FR900098.