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Table 2. Inhibition values for E. coli DNA gyrase (wild type and
fluoroquinolone resistanta) and mammalian topoisomerase II
Compd
Wild type
gyrase
IC50, mg/mL
Quinolone
resistant gyrase
IC50, mg/mL
Topo II
IC50, mg/mL
5a
5b
5c
5d
6.4
3.2
63
31
3.2
51.2
>102
>500
>500
12.8
38
150
>500
250
>600
Levofloxacin
aFluoroquinolone DNA gyrase was characterized as Ser83 to Trp
mutant.
10. Graul, A.; Rabasseda, X.; Castaner, J. Drugs Future 1999,
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1987, 24, 453.
As seen in their antibacterial activity, analogues 5c and
5d were notably less active in inhibiting topoisomerases.
This non-fluorinated series of Levofloxacin analogues
are equivalent or less potent than the parent molecule.
In contrast to some non-fluorinated analogues where
the N1 moiety is a cyclopropyl, there is a substantial
decrease in activity versus known agents. The loss of
freedom of movement at N1 and C8 appears to be
responsible for these diminished results.
17. Johnson, D. R.; Szoteck, D. L.; Domagala, J. M.; Stick-
ney, T. M.; Michel, A.; Kampf, J. W. J. Heterocycl. Chem.
1992, 29, 1481.
Acknowledgements
18. Fedij, V.; Lenoir, E. A.III; Suto, M. J.; Zeller, J. R.;
Wemple, J. Tetrahedron: Asymmetry 1994, 5, 1131.
19. Moon, S. H.; Lee, S. Synth. Commun. 1998, 28, 3919.
20. Roychoudhury, S.; Twinem, T. L.; Makin, K. M.; McIn-
tosh, E. J.; Ledoussal, B.; Catrenich, C. E. Journal of Anti-
microbial Chemotherapy 2001, 48, 29.
21. Kimura, Y.; Atarashi, S.; Takahashi, M.; Hayakawa, I.
Chem. Pharm. Bull. 1994, 42, 1442.
22. Manuscript in prepation.
23. Ledoussal, B.; Almstead, J. I.; Flaim, S. M.; Gallagher, C.
P.; Gray, J. L.; Hu, E. X.; Kim, N. K.; McKeever, H. D.;
Miley, C. J.; Twinem, T. L.; Zheng, S. X. 37th Interscience
Conference on Antimicrobial Chemotherapy, San Francisco,
1999, Abstr. No. F0544.
We would like to thank Tiehong Huang for the pre-
parative HPLC purification of compounds 5c and 5d.
References and Notes
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