A. Foroumadi et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4536–4539
4539
modulation in many cases exerted a positive effect: for
example, compounds 5a and 6a were more active than
non-bromo substituted analogues against all of the test-
ed Gram-positive strains. Compound 6a was the most
potent antibacterial against Gram-positive among the
studied 5-bromo- and non-bromo-substituted thiophene
derivatives and other previously described N-substituted
piperazinyl quinolone series 4.12–16 Nevertheless, the
effect of bromo-substitution was dependent on the
other substituents.
the quinolone ring and piperazine moiety points out that
compound 6a exerts significant in vitro antibacterial
activity against Gram-positive bacteria and it was more
potent than the reference drugs against S. aureus, S. epi-
dermidis and B. subtilis. These data demonstrated the
importance of the attached moiety to piperazine ring
to obtain potent antibacterial agents.
Acknowledgments
This work was supported by a Grant from Iran National
Science Foundation (INSF).
These results demonstrated that the introduction of
thiophen-2-yl or 5-bromothiophen-2-yl group instead
of phenyl, substituted phenyl and furan-2-yl group at
2 position of 2-oxoethyl or 2-oximinoethyl moiety at-
tached to the piperazine ring in 7-piperazinyl quinolones
improved the overall antibacterial activity against
Gram-positive bacteria.
References and notes
1. Witte, W. J. Antimicrob. Chemother. A 1999, 44, 1.
2. Hooper, D. C. Lancet Infect. Dis. 2002, 2, 530.
3. Beermann, D.; Kuhlmann, J.; Dalhoff, A.; Zeiler, H. J.
Quinolone Antibacterials; Springer: New York, 1998.
4. De Sarro, A.; De Sarro, G. Curr. Med. Chem. 2001, 8, 371.
5. Hooper, D. C. Drugs 1999, 58, 7.
6. Gootz, T. D.; Brighty, K. E. Med. Res. Rev. 1996, 16, 433.
7. Domagala, J. M. J. Antimicrob. Chemother. 1994, 33, 685.
8. Tillotson, G. S. J. Med. Microbiol. 1996, 44, 320.
9. Domagala, J. M.; Heifetz, C. L.; Hutt, M. P.; Mich, T. F.;
Nichols, J. B.; Solomon, M.; Worth, D. F. J. Med. Chem.
1988, 31, 991.
10. Chu, D. T. W.; Fernandes, P. B.; Claiborne, A. K.;
Pihuleac, E.; Nordeen, C. W.; Maleczka, R. E.; Pernet, A.
G. J. Med. Chem. 1985, 28, 1558.
11. Shen, L. L.; Mitscher, L. A.; Sharma, P. N.; OÕDonnell, T.
J.; Chu, D. W. T.; Cooper, C. S.; Rosen, T.; Pernet, A. G.
Biochemistry 1989, 28, 3886.
12. Foroumadi, A.; Emami, S.; Davood, A.; Moshafi, M. H.;
Sharifian, A.; Tabatabaiee, M.; Tarhimi Farimani, H.;
Sepehri, G.; Shafiee, A. Pharm. Sci. 1997, 3, 559.
13. Foroumadi, A.; Emami, S.; Haghighat, P.; Moshafi, M.
H. Pharm. Pharmacol. Commun. 1999, 5, 591.
14. Foroumadi, A.; Davood, A.; Mirzaei, M.; Emami, S.;
Moshafi, M. H. Boll. Chim. Farm. 2001, 140, 411.
15. Foroumadi, A.; Soltani, F.; Emami, S.; Davood, A. Boll.
Chim. Farm. 2002, 141, 247.
16. Mirzaei, M.; Foroumadi, A. Pharm. Pharmacol. Commun.
2000, 6, 351.
17. Kondo, H.; Sakamoto, F.; Koders, Y.; Tsukamoto, G.
J. Med. Chem. 1986, 29, 2020.
Differences in the moiety present at N-1 position or at
C-7 position markedly influence both microbiological
and pharmacokinetic properties.23 Generally, the 7-pip-
erazinyl quinolones (ciprofloxacin, norfloxacin and
enoxacin) have better Gram-negative than Gram-
positive antimicrobial potency. In contrast, from our
biological results, it is evident that N-[2-(5-bromothio-
phen-2-yl)-2-oxoethyl] derivatives of piperazinyl quino-
lones 5–7 exhibited more potent antibacterial activity
against Gram-positive rather than Gram-negative bacte-
ria. This change of antibacterial profile may be due to
the change of selectivity to target enzyme. Recently it
was investigated that the mode of action of quinolones
involves interaction with both DNA gyrase, the original-
ly recognized drug target and topoisomerase IV, a relat-
ed type II topoisomerase.5 In a bacterial cell, these two
enzymes often differ in their relative sensitivities to many
quinolones, and commonly DNA gyrase is more sensi-
tive in Gram-negative bacteria and topoisomerase IV
more sensitive in Gram-positive bacteria. It seems that
topoisomerase IV is the primary target of the quinolones
(5–7) with bulky functional group at N-4 position of
piperazine ring. Thus, the improvement of overall anti-
bacterial activity of these compounds against Gram-po-
sitive bacteria might be a result of better interaction with
topoisomerase IV rather than with DNA gyrase.
18. Fang, K.-C.; Chen, Y.-L.; Sheu, J.-Y.; Wang, T.-C.;
Tzeng, C.-C. J. Med. Chem. 2000, 43, 3809.
19. Sheu, J.-Y.; Chen, Y.-L.; Tzeng, C.-C. Helv. Chim. Acta
2003, 86, 2481.
In conclusion, we have described a convenient synthesis
of N-[2-(5-bromothiophen-2-yl)-2-oxoethyl] and N-[2-
(5-bromothiophen-2-yl)-2-oximinoethyl] derivatives of
piperazinyl quinolones 5–7 and biological studies have
shown that many of these derivatives were highly potent
as antibacterial agents especially against Gram-positive
bacteria. First approach in the series of new N-[2-(5-
bromothiophen-2-yl)-2-oxoethyl] derivatives of piperaz-
inyl quinolones bearing different structural features on
´
20. Buu-Ho¨ı; Nguyen-Hoan Rec. Trav. Chim. 1949, 68, 5.
21. Mullen, G. B.; Mitchell, J. T.; Allen, S. D.; Georgieu, V. S.
J. Pharm. Sci. 1988, 77, 1050.
22. Baron, E. J.; Finegold, S. M. Bailey and ScottÕs Diagnostic
Microbiology, 8th ed.; C.V. Mosby: St. Louis, 1990; pp
184–188.
23. Von Rosenstiel, N.; Adam, D. Drugs 1994, 47, 872.