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2. (a) Yee, Y. C.; Thornsberry, C. Antimicrob. Infect. Dis.
Newslett. 1995, 14, 1–18; (b) Voss, A.; Doebbeling, B. N.
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the previously described 5-hydrogen compounds (entries
7–9),3,4a–c similar in vitro potencies are seen. In particu-
lar, compound 11d (IC50 = 4 lM) is roughly equipotent
to the parent compound 1 (IC50 = 7 lM). Compound
11a (IC50 = 14 lM) where R7 = azetidine, is only 2–3
times less potent than the analogous 5-hydrogen com-
pound (13, IC50 = 5 lM). These data indicate a toler-
ance for this type of substitution at the 5-position.
Also shown in Table 1 is the antibacterial activity of
each compound. Data for levofloxacin, a second-gener-
ation quinolone antibiotic, are included as a reference.
Moderate to good antibacterial activity is seen for com-
pounds 11a,b, 12b and d against S. pneumoniae 7257, a
strain resistant to the fluoroquinolones due to mutations
in the DNA gyrase and topoisomerases IV,10 and Hae-
mophilus influenzae GYR 1435, a representative Gram-
negative pathogen. These MICs, taken together with
the biochemical assay results, provide solid evidence
that these compounds exert their antimicrobial effects
through a non-quinolone mechanism of action. A possi-
ble explanation for the lack of antibacterial activity for
11d and 12d in either of these strains could be poor cel-
lular penetration. No permeabilizer studies were done
with this group of compounds.4c
3. Dandliker, P. J.; Black-Schaefer, C.; Bui, M.; Cai, Y.;
Cao, Z.; Chovan, L. M.; Clark, R. F.; Daly, M. M.;
David, C. A.; Englund, E. E.; Hickman, R. K.; Kakavas,
S. J.; Lerner, C. G.; Merta, P.; Nilius, A. M.; Pratt, S.
D.; Ruan, X.; Saiki, A. Y.; Shen, L. L.; Soni, N. B.;
Wagner, R.; Weitzberg, M.; Xuei, X.; Zhong, P.; Beutel,
B. A. Antimicrob. Agents Chemother. 2003, 47, 3831–
3839.
4. (a) Anderson, D.; Beutel, B.; Bosse, T. D.; Cooper, C.;
Dandliker, P. J.; David, C.; Gu, Y.-G.; Hinman, M.;
Kalvin, D.; Lynch, L.; Ma, Z.; Motter, C.; Rosenberg, T.;
Sanders, W.; Tufano, M.; Wagner, R.; Weitzberg, M.;
Yong, H. U.S. Patent 6 818 654, November 16, 2004; (b)
Anderson, D.; Beutel, B.; Bosse, T. D.; Clark, R. F.;
Cooper, C.; Dandliker, P. J.; David, C.; Gu, Y.-G.;
Hansen, T. M.; Hinman, M.; Kalvin, D.; Larson, D. P.;
Lynch, L.; Ma, Z.; Motter, C.; Palazzo, F.; Rosenberg, T.;
Rehm, T.; Sanders, W.; Tufano, M. D.; Wagner, R.;
Weitzberg, M.; Yong, H.; Zhang, T. U.S. Patent Appli-
cation 20030232818, 2003; (c) Clark, R. F.; Wang, S.; Ma,
Z.; Weitzberg, M.; Motter, C.; Tufano, M. D.; Wagner,
R.; Gu, Y.-G.; Dandliker, P. J.; Lerner, C. G.; Chovan, L.
E.; Cai, Y.; Black-Schaefer, C. L.; Lynch, L.; Kalvin, D.;
Nilius, A. M.; Pratt, S. D.; Soni, N.; Zhang, T.; Zhang, X.;
Beutel, B. A. Bioorg. Med. Chem. Lett. 2004, 14, 3299–
3302.
In summary, we have developed a flexible synthetic
entry to novel 5-methoxy- and 5-hydroxy-6-fluoro-1,8-
naphthyridone-3-carboxylic acid antibiotics. Members
of this class of 1,8-naphthyridones had not previously
been evaluated as antibacterial agents. The data indicate
incorporation of a 5-methoxy group does not have a dele-
terious effect on in vitro potency and given the profound
influence the 7-position has in combination with the 5-
position,11 further exploration of this class of NRIs
should be undertaken. The 5-hydroxyl also constitutes a
new synthetic handle for this class of compounds, mak-
ing it possible to thoroughly investigate the advantages
of hydrophilic substitution at the 5-position of 1,8-naph-
thyridone antibacterials. Extension of this work will
include a comprehensive survey of 5-hydroxy, 5-alkoxy,
5-amino derivatives in combination with a wide variety
of C7 amino substitution, allowing further development
and differentiation of this novel class. Detailed accounts
of continuing studies will be reported in due course.
5. (a) Domagala, J. M.; Bridges, A. J.; Culbertson, T. P.;
Gambino, L.; Hagen, S. E.; Karrick, G.; Porter, K.;
Sanchez, J. P.; Sesnie, J. A.; Spense, F. G.; Szotek, D.;
Wemple, J. J. Med. Chem. 1991, 34, 1142–1154; (b)
Hagen, S. E.; Domagala, J. M.; Heifetz, C. L.; Johnson, J.
J. Med. Chem. 1991, 34, 1155–1161.
6. These two steps have been done with tBuONa to provide a
tBu protecting group on the C4 hydroxyl: Li, Q.; Chu, D.;
Claiborne, A.; Cooper, C.; Lee, C.; Raye, K.; Berst, K.;
Donner, P.; Wang, W.; Hasvold, L.; Fung, A.; Ma, Z.;
Tufano, M.; Flamm, R.; Shen, L.; Baranowski, J.; Nilius,
A.; Alder, J.; Meulbroek, J.; Marsh, K.; Crowell, D.; Hui,
Seif L.; Melcher, L.; Henry, R.; Spanton, S.; Faghih, R.;
Klein, L.; Tanaka, K.; Plattner, J. J. Med. Chem. 1996, 39,
3070–3088.
7. Clay, R.; Collom, T.; Karrick, G.; Wemple, J. Synthesis
1993, 290–292.
Acknowledgements
8. (a) Chu, D.; Fernandes, P.; Claiborne, A.; Gracey, E.;
Pernet, A. J. Med. Chem. 1986, 29, 2363–2369; (b) Radl,
S.; Bouzard, D. Heterocycles 1991, 34, 2143.
9. Pratt, S. D.; David, C. A.; Black-Schaefer, C.; Dandliker,
P. J.; Xuei, X.; Warrior, U.; Burns, D. J.; Zhong, P.; Cao,
Z.; Saiki, A. Y. C.; Lerner, C. G.; Chovan, L. E.; Soni, N.
B.; Nilius, A. M.; Beutel, B. A. J. Biomol. Screen. 2004, 9,
3–11.
The authors thank the Abbott High Throughput Purifi-
cation group for purification of compounds, the Hydro-
genation Laboratory, Xiaolin Zhang and Carmina
Presto for NMR interpretation and Richard Clark,
Qun Li, Moshe Weitzberg and Robert Keyes for valu-
able discussions.
10. Bruggemann, A. B.; Coffman, S. L.; Rhomberg, P.;
Hungh, H.; Almer, L.; Nilius, A. M.; Flamm, R.; Doern,
G. V. Antimicrob. Agents Chemother. 2002, 46, 680–
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11. Rolf Wagner, personal communication.