2394
M. Takhi et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2391–2395
Table 2. In vivo efficacy in a systemic mouse infection model by oral
route
5. (a) Abi-Hanna, P.; Frank, A. L.; Quinn, J. P.; Kelkar, S.;
Schreck-enberger, P. C.; Hayden, M. K.; Marcinak, J. F.
Clin. Infect. Dis. 2000, 30, 630; (b) Collignon, P. J. Infect.
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R.; Veal, D.; Harbour, C. J. Clin. Microbiol. 2000, 38,
2378; (d) Cookson, B. D. Infect. Control Hosp. Epidemiol.
2000, 21, 398.
6. Clemett, D.; Markham, A. Drug 2000, 59, 815.
7. (a) Gravestock, M. B.; David, G. A.; Betts, M. J.; Dennis,
M.; Hatter, G.; McGregor, A.; Swain, M. L.; Wilson, R.
G.; Woods, L.; Wookey, A. Bioorg. Med. Chem. Lett.
2003, 13, 4179; (b) Philips, O. A.; Udo, E. E.; Ali, A. A.
M.; Samuel, S. M. Bioorg. Med. Chem. 2005, 13, 4113; (c)
Jang, S. Y.; Ha, Y. H.; Ko, S. W.; Lee, W.; Lee, J.; Kim,
S.; Kim, Y. W.; Lee, W. K.; Ha, H. J. Bioorg. Med. Chem.
Lett. 2004, 12, 3881; (d) Lee, C. S.; Allwine, D. A.;
Barbachyn, M. R.; Grega, K. C.; Dolak, L. A.; Ford, C.
W.; Jensen, R. M.; Seest, E. P.; Hamel, J. C.; Schaadt, R.
D.; Stapert, D.; Yagi, B. H.; Zurenko, G. E.; Genin, M. J.
Bioorg. Med. Chem. 2001, 9, 3243; (e) Griera, R.; Llopart,
C. C.; Amat, M.; Bosch, J.; Castilo, J. C. D.; Huguet, J.
Bioorg. Med. Chem. Lett. 2005, 15, 2515.
Compd
ED50 (mg/kg/day)
9d
9e
32.2 (18.6–56.8)a
12.1 (8.0–18.4)
18.3 (12.5–26.8)
22.1 (14.2–36.3)
21.2 (15.1–29.6)
32.2 (18.6–56.8)
5.3 (2.6–9.0)
9f
9h
9i
9j
Linezolid
a Numbers in parentheses are 95% confidence ranges.
corresponding oxocarbonyl derivatives 9a, 9b, 9c, and 9d.
This can be attributed to the change in electronic charac-
ter and lipophilicity of the molecules.16 Among the two
O-linked analogs 9k and 9l, the activity of 9l was compa-
rable to that of Linezolid against Gram-positive patho-
gens. In all the cases, compounds having difluoro
substitution on phenyl ring (9b, 9d, 9f, 9h, 9j, and 9l)
showed enhanced activity compared to their monofluoro
congeners (9a, 9c, 9e, 9g, 9i and 9k).
8. Shinabarger, D. L.; Marotti, K. R.; Murray, R. W.; Lin,
A. H.; Melchoir, E. P.; Swaney, S. M.; Dunyak, D. S.;
Demyan, W. F.; Buysse, J. M. Antimicrob. Agents
Chemother. 1997, 41, 2132.
9. Kloss, P.; Xiong, L.; Mankin, A. S.; Shinabarger, D. L.;
Mankin, A. S. J. Mol. Biol. 1999, 294, 93.
Selected oxazolidinones 9d, 9e, 9f, 9h, 9i, and 9j
were evaluated for in vivo efficacy in a lethal sys-
temic mouse infection model by oral route, employ-
ing S. aureus ATCC 29213 as the infectious
organism (Table 2). These compounds protected the
mice from infection following oral administration,
however, at higher doses compared to Linezolid de-
spite their potent in vitro antibacterial profile. This
difference in in vivo efficacy may be due to the sub-
optimal pharmacokinetics.
10. (a) Tsirodas, S.; Gold, H. S.; Sakoulas, G.; Eliopoulas, G.
M.; Wennerstein, C.; Venkataraman, L.; Moellering, R.
C., Jr.; Ferro, M. J. Lancet 2001, 358, 207; (b) Johnson, A.
P.; Tysall, L.; Stockdale, M. W.; Woodford, N.; Kauf-
mann, M. E.; Warner, M.; Livermoore, D. M.; Asboth,
F.; Alleberger, F. J. Eur. J. Clin. Microbial. Infect. Dis.
2002, 21, 751.
11. (a) Selvakumar, N.; Srinivas, D.; Khera, M. K.; Kumar,
M. S.; Mamidi, R. N. V. S.; Sarnaik, H.; Charavaryamath,
C.; Rao, B. S.; Raheem, M. A.; Das, J.; Iqbal, J.;
Rajagopalan, R. J. Med. Chem. 2002, 45, 3953; (b) Das, J.;
Rao, C. V. L.; Sastry, T. V. R. S.; Roshiah, M.; Sankar, P.
G.; Khadeer, A.; Kumar, M. S.; Mallik, A.; Selvakumar,
N.; Iqbal, J.; Trehan, S. Bioorg. Med. Chem. Lett. 2005,
15, 337; (c) Selvakumar, N.; Raheem, M. A.; Khera, M.
K.; Rajale, T. V.; Kumar, M. S.; Kandepu, S.; Das, J.;
Rajagopalan, R.; Iqbal, J.; Trehan, S. Bioorg. Med. Chem.
Lett. 2003, 13, 4169.
In summary, introduction of N-hydroxyacetamidine
group to the oxazolidinones afforded a potent series
with in vitro antibacterial activity comparable or superi-
or to Linezolid against Gram-positive and clinically sig-
nificant Gram-negative bacteria. Some of the analogs
from this series also exhibited in vivo activity in a lethal
mouse infection model when administered orally, but
were less efficacious than Linezolid.
12. Solubility of compound 9a in MQ water was determined
by UV-spectrophotometry method at 25 °C after 4 h
shaking. The water solubility of 9a was found to be
5.07 mg/mL, whereas the solubility of Linezolid is
3.06 mg/mL under the same conditions.
Acknowledgments
We thank Dr. R. Rajagopalan, President, Discovery Re-
search, Dr. Reddy’s Laboratories Ltd, for his constant
encouragement and valuable suggestions. We would
also like to thank Analytical Department for spectral
data and Formulation Department for solubility data.
13. Hutchinson, D. K.; Brickner, S. J.; Barbachyn, M. R.;
Gammill, R. B. PCT Int. Appl. WO 93/23384.
14. Typical procedure (9l): To a solution of compound 11b
(330 mg, 0.79 mmol) in ethanol (30 mL) were added
hydroxylamine hydrochloride (219 mg, 3.19 mmol) and
saturated aqueous solution of sodium carbonate (250 mg).
The mixture was refluxed for overnight and the solvent
was removed under vacuum. The residue was diluted with
ethylacetate and washed with water and brine successively.
The organic layers were dried over sodium sulfate. The
solvent was evaporated under reduced pressure and the
crude product was purified by column chromatography
over silica gel using 3% MeOH/CHCl3 as eluent. Com-
pound 9l was obtained as a white solid (210 mg, 59%). 1H
NMR (DMSO-d6): d 8.97 (s, 1H, D2O exchangeable), 8.69
(d, J = 1.9 Hz, 1H), 7.28 (d, J = 11.5 Hz, 2H), 6.37 (d, J =
1.9 Hz, 1H), 5.28 (s, 2H, D2O exchangeable), 5.10–5.05
(m, 1H), 4.50–4.42 (m, 2H), 4.16 (t, J = 9.1 Hz, 1H), 3.88
References and notes
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