M. Tabart et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1329–1331
1331
The characteristic of this series of benzo[f][1,7]naphtyr-
idones, just like in benzo[b]naphtyridone previous series,
is that the MICs of the compounds tested are identical
against quinolone-resistant and quinolone-sensitive S.
aureus strains. This result suggests that the mechanism
of action of these derivatives in the Gram-positive
strains tested is different from that of quinolones.
antibacterial agents with a Gram positive spectrum of
activity that could be developed for topical use. They
show no cross resistance with major classes of anti-
biotics, especially with quinolones. Their antibacterial
and physico-chemical properties make them particularly
suitable for topical antibacterial use.
Structure–activity relationship analysis in this series
shows that a combination of a lipophilic cyclic amine
and a fluorine (or a fluorine and a chlorine) as sub-
stituants in positions 7, 8 and 9 of the tricycle gives rise
to the desired property, that is antibacterial activity on
quinolone-resistant strains. A non-basic N-phenyl sub-
stituted piperazine such as in compounds 12, 14, 153
and 16 gives good results (like in RP60556A, benzo[b]-
naphtyridone series), but a piperazine is not mandatory
for the activity against resistant strains since lipophilic
cyclic amines such as 3,3-dimethylpiperidine in com-
pound 17 or 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane
(commercially available from Aldrich) in compound 13
give similar results.
References and Notes
1. Witte, W. J. Antimicrob. Chemother. 1999, 14, 1.
2. Marchese, A.; Schito, G. C.; Debbia, E. A. J. Chemother.
2000, 12 (Suppl. 2), 12.
3. Chopra, I.; Hodgson, J.; Metcalf, B. Antimicrob. Agents
Chemother. 1997, 41, 497.
4. Voss, A.; Doebbeling, B. Int. J. Antimicrob. Agents 1995, 5,
101.
5. Herwaldt, L. A. American Journal of Medicine 1999, 106,
11S.
6. Parras, F.; Guerrero, M.; Bouza, E.; Blazquez, M.; Mor-
eno, S.; Cruz Menarguez, M.; Cercenado, E. Antimicrob.
Agents Chemother. 1995, 39, 175.
7. Ward, A.; Campoli-Richards, D. M. Drugs 1986, 32, 425.
8. Turnidge, J. Int. J. Antimicrob. Agents 1999, 12 (Suppl. 2),
S23.
9. Cookson, B. D. J. Antimicrob. Chemother. 1998, 41 (1), 11.
10. Turnidge, J.; Collignon, P. Int. J. Antimicrob. Agents
1999, 12 (Suppl. 2), S35.
11. Tabart, M.; Picaut, G.; Desconclois, J. F.; Dutka-Malen,
S.; Huet, Y.; Berthaud, N. Bioorg. Med. Chem. Lett. 2001, 11,
919.
The compounds from Table 1 are active against Gram-
positive cocci (staphylococci and steptococci, MIC
range 1–16 mg/L) without cross-resistance with quino-
lones, b-lactams, MLSB (macrolides, lincosamides,
streptogramin Bgroup), mupirocin and fusidic acid,
and are active against anaerobes.
12. Desconclois, J. F.; Girard, P.; Picaut, G.; Tabart, M.;
Wentzler, S. Patent WO 0037 467 A1, June 29, 2000.
13. Lesher, G., Patent US 3 300 499, Jan 24, 1967.
14. Desconclois, J. F.; Genevois-Borella, A.; Girard, P.; Kry-
venko, M.; Lavergne, M.; Malleron, J.; Picaut, G.; Tabart,
M.; Wentzler, S. Patent WO 0102396 A1, Jan 11, 2001.
Conclusion
This new series of benzo[f][1,7] derivatives shows many
similarities with the benzo[b]naphtyridone series pre-
viously described: the compounds are interesting new