Alkoxycarbonyloxyethyl ester prodrugs of FR900098 with improved in vivo antimalarial activity

Archiv der Pharmazie

Volumn 338, Issue 7, 2005, Pages 305-314

  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

Isoprenoid biosynthesis; Malaria; Plasmodium falciparum; Prodrug

Indexed keywords

3 (N ACETYL N HYDROXYAMINO)PROPYLPHOSPHONIC ACID; [3 (ACETYLHYDROXYAMINO)PROPYL] 3,7 DIMETHYL 5 OXIDE 2,4,6,8 TETRAOXA 5 PHOSPHANONANEDIOIC ACID DIETHYL ESTER; [3 (ACETYLHYDROXYAMINO)PROPYL] 3,7 DIMETHYL 5 OXIDE 2,4,6,8 TETRAOXA 5 PHOSPHANONANEDIOIC ACID DIMETHYL ESTER; [3 (ACETYLHYDROXYAMINO)PROPYL]PHOSPHONIC ACID [1 (2,2 DIMETHYLPROPIONYLOXY)ETHYL] ESTER; [3 (ACETYLHYDROXYAMINO)PROPYL]PHOSPHONIC ACID BIS[1 (ACETYLOXY)ETHYL] ESTER; ANTIMALARIAL AGENT; FOSMIDOMYCIN; ISOPRENOID; PRODRUG; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIMALARIAL ACTIVITY; ARTICLE; BIOSYNTHESIS; CARBON NUCLEAR MAGNETIC RESONANCE; DRUG EFFICACY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; MALARIA; MOUSE; NONHUMAN; PARASITEMIA; PLASMODIUM VINCKEI; PRIORITY JOURNAL; PROTON NUCLEAR MAGNETIC RESONANCE; TREATMENT OUTCOME;

ADMINISTRATION, ORAL; ALDOSE-KETOSE ISOMERASES; ANIMALS; ANTIMALARIALS; BIOLOGICAL AVAILABILITY; DOSE-RESPONSE RELATIONSHIP, DRUG; FOSFOMYCIN; MALARIA; MICE; MICE, INBRED BALB C; MULTIENZYME COMPLEXES; OXIDOREDUCTASES; PLASMODIUM; PRODRUGS; QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 22544446490     PISSN: 03656233     EISSN: None     Source Type: Journal    
DOI: 10.1002/ardp.200500976     Document Type: Article

References (15)

1. B. Greenwood, T. Mutabingwa. Nature 2002, 415, 670-672;
2. R. G. Ridley. Nature 2002, 415, 686-693.
3. H. Jomaa, J. Wiesner, S. Sanderbrand, B. Altincicek, C. Weidemeyer, M. Hintz, I. Turbachova, M. Eberl, J. Zeidler, H. K. Lichtenthaler, D. Soldati, E. Beck, Science 1999, 285, 1573-1576.
4. T. Tsuchiya, K. Ishibashi, M. Terakawa, M. Nishiyama, N. Itoh, H. Noguchi, Eur. J. Drug. Metab. Pharmacokinet. 1982, 7, 59-64.
5. A. Reichen berg, J. Wiesner, C. Weidemeyer, E. Dreiseidler, S. Sanderbrand, B. Altincicek, E. Beck, M. Schlitzer, H. Jomaa, Bioorg. Med. Chem. Lett. 2001, 11, 833-835.
6. R. Ortmann, J. Wiesner, A. Reichenberg, D. Henschker, E. Beck, H. Jomaa, M. Schlitzer, Bioorg. Med. Chem. Lett. 2003, 13, 2163-2166.
7. T. Kurz, D. Geffken, C. Wackendorff, Z. Naturforsch., B: Chem. Sci. 2003, 58b, 106-110.
8. C. E. McKenna, P. Shen, J. Org. Chem. 1981, 46, 4573-4576.
9. H. T. Serafinowska, R. J. Ashton, S. Bailey, M. R. Harnden, S. M. Jackson, D. Sutton, J. Med. Chem. 1995, 38, 1372-1379.
10. The chloroalkyl esters were prepared by reaction of acetaldehyde (or isobutyraldehyde in case of 6g) with the appropriate acid chloride. K. Fleischmann, F. Adam, W. Dürckheimer, W. Hertzsch, R. Hörlein, H. Jendralla, C. Lefebvre, P. Mackiewicz, J.-M. Roul, T. Wollmann, Liebigs Ann. 1996, 1735-1741;
11. W. S. Saari, M. B. Freedman, R. D. Hartman, S. W. King, A. W. Raab, W. C. Randall, E. L. Engelhardt, R. Hirschmann. J. Med. Chem. 1978, 21, 746-753.
12. Prepared from 1-chloroethyl carbonochloridate and methanol according to G. Barcelo, J.-P. Sent, G. Sennyey, Synthesis 1986, 8, 627-632.
13. S. Chen, C. Lin, D. S. Kwon, C. D. Walsh, J. K. Coward, J. Med Chem. 1997, 40, 3842-3850.
14. 2O (for comparison with 7a) or SSV (for comparison with the other prodrugs). Parasitaemia was monitored by Giemsa-stained blood smears. Mice were sacrificed when parasitaemia was exceeding approx. 40%. Five mice were used for each treatment group, and four mice for the untreated control group. Results were expressed as geometric mean values for each group.
15. 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 three-fold increased activity compared with FR900098.