Y. Ikee et al. / Bioorg. Med. Chem. Lett. 17 (2007) 942–945
945
Table 2. Antibacterial activity of 7-azetidinylquinolones and a clinically used antibiotic (MIC, lg/mL)
Compound S. aureusa S. aureusb S. aureusc E. faecalis S. pneumoniae M. catarrhalis H. influenzae E. colid E. colie P. aeruginosa
13a
13b
0.016
0.031
0.031
0.063
0.031
0.5
0.5
0.25
0.5
1
>64
16
0.5
0.25
0.5
1
0.25
0.063
0.5
0.016
0.031
0.031
0.063
0.125
0.063
60.008
60.008
60.008
60.008
60.008
0.016
0.031
0.031
0.063
0.125
0.25
0.25
0.25
0.5
1
4
4
16
13c
13d
16
16
0.5
0.125
1
>16
>16
0.5
13e
LVFXf
1
>16
>128
2
2
0.016
4
2
0.016
a Quinolone-susceptible MRSA.
b Quinolone-intermediate MRSA.
c Quinolone-resistant MRSA.
d Without AcrAB.
e With AcrAB.
f LVFX, levofloxacin.
2001, 33, S180; (f) Mitscher, L. A. Chem. Rev. 2005, 105,
559.
4. 7-Azetidinylquinolones as antibacterial agents. (a) Frigola,
In conclusion, we have demonstrated a convenient syn-
thesis of 3-sulfenylazetidine derivatives 7a–f and 3-amin-
oazetidine derivatives 12a–f utilizing ABB 3. Several
azetidine derivatives were successfully introduced into
fluoroquinolone carboxylic acid 8 to give the corre-
sponding fluoroquinolone antibiotics 9a–f and 13a–f.
Most of the synthesized fluoroquinolones exhibited
more potent antibacterial activities against Gram-posi-
tive bacteria than against Gram-negative bacteria. Espe-
cially, compounds 13a–e were fairly potent against
quinolone-susceptible MRSA in comparison with the
activities of clinically used fluoroquinolones, such as
LVFX.
´
J.; Pares, J.; Corbera, J.; Van˜o, D.; Merce, R.; Torrens, A.;
Mas, J.; Valentı, E. J. Med. Chem. 1993, 36, 801; (b)
´
`
´
´
´
Frigola, J.; Torrens, A.; Castrillo, J. A.; Mas, J.; Van˜o, D.;
Berrocal, J. M.; Calvet, C.; Salgado, L.; Redondo, J.;
´
Garcıa-Granda, S.; Valentı, E.; Quintana, J. R. J. Med.
Chem. 1994, 37, 4195; (c) Frigola, J.; Van˜o, D.; Torrens, A.;
´
´
´
´
Gomez-Gomar, A.; Ortega, E.; Garcıa-Granda, S. J. Med.
Chem. 1995, 38, 1203; (d) Kuramoto, Y.; Ohshita, Y.;
Yoshida, J.; Yazaki, A.; Shiro, M.; Koike, T. J. Med.
Chem. 2003, 46, 1905; (e) Hansen, T. M.; Gu, Y.-G.; Rehm,
T. M.; Dandliker, L. E.; Chovan, L. E.; Bui, M. H.; Nilius,
A. M.; Beutel, B. A. Bioorg. Med. Chem. Lett. 2005, 15,
2716.
5. (a) Grohe, K.; Heitzer, H. Liebigs Ann. Chem. 1987, 29; (b)
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; (c) Sanchez, J. P.; Bridges, A. J.; Bucsh, R.;
Domagala, J. M.; Hagen, S. E.; Heifetz, C. L.; Joannides,
E. T.; Sesnie, J. C.; Shapiro, M. A.; Szotek, D. L. J. Med.
Chem. 1992, 35, 361; (d) Ronald, J. C.; Thomas, A. C.;
Gregory, L. K.; James, W. Synthesis 1993, 3, 290; (e)
Wentland, M. P.; Lesher, G. Y.; Reuman, M.; Gruett, M.
D.; Singh, B.; Aldous, S. C.; Dorff, P. H.; Rake, J. B.;
Coughlin, S. A. J. Med. Chem. 1993, 36, 2801.
Acknowledgment
This work was supported in part by a Grant-in -Aid for
Scientific Research (B) (2) (Nos. 14370723 and
16390008) from the Japan Society for the Promotion
of Science.
Supplementary data
6. X-ray data for 9b: C19H17F2N5O3S, MW = 433.43, colorless
Supplementary data associated with this article can be
block, monoclinic, Space group P21/n(#14), a = 16.030(3)
˚
˚
˚
A, b = 7.443(2) A, c = 16.844(4) A, b = 112.74(2)°,
3
V = 1853.4(7) A , Z = 4, R = 0.063, Rw = 0.061. CCDC-
˚
623357 (9b) contains the supplementary crystallographic
date for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Date Centre
References and notes
1. (a) Hayashi, K.; Kumagai, T.; Nagao, Y. Heterocycles
2000, 53, 447; (b) Hayashi, K.; Ikee, Y.; Goto, S.; Shiro,
M.; Nagao, Y. Chem. Pharm. Bull. 2004, 52, 89.
7. Suzuki, Y.; Tsukamoto, K.; Hasegawa, Y.; Hiramatsu, Y.
Japan Kokai Tokkyo Koho (Japan Patent) S49-109369,
1974.
2. (a) Hayashi, K.; Sato, C.; Hiki, S.; Kumagai, T.; Tamai, S.;
Abe, T.; Nagao, Y. Tetrahedron Lett. 1999, 40, 3761; (b)
Hayashi, K.; Hiki, S.; Kumagai, T.; Nagao, Y. Heterocycles
2002, 56, 433.
3. (a) Shen, L. L.; Mitscher, L. A.; Sharma, P. N.; O’Donnell,
T. J.; Che, D. W. T.; Cooper, C. S.; Rosen, T.; Pernet, A.
G. Biochemistry 1989, 28, 3886; (b) Domagala, J. M.
J. Antimicrob. Chemother. 1994, 33, 685; (c) Drlica, K.
Curr. Opin. Microbiol. 1999, 2, 504; (d) Hooper, D. C. Clin.
Infect. Dis. 2001, 32, S9; (e) Peterson, L. R. Clin. Infect. Dis.
8. Japan Society of Chemotherapy. Chemotherapy, 1981, 29,
76.
9. (a) Wise, R.; Andrews, J. M.; Edwards, L. J. Antimicrob.
Agents Chemother. 1983, 33, 559; (b) Hayakawa, I.;
Atarashi, S.; Yokohama, S.; Imamura, M.; Sakano, K.;
Frukawa, M. Antimicrob. Agents Chemother. 1986, 29, 163;
(c) Atarashi, S.; Yokohama, S.; Yamazaki, K.; Sakano, K.;
Imamura, M.; Hayakawa, I. Chem. Pharm. Bull. 1987, 35,
1896; (d) Mitscher, L. A.; Sharma, P. N.; Chu, D. T. W.;
Shen, L. L.; Pernet, A. G. J. Med. Chem. 1987, 30, 2283.