1540
G. Sbardella et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1537–1541
both wild-type and MDR mutant strains as well as
against MAC. Surprisingly para-substitution proved
more effective than meta-substitution. Moreover the
introduction of the pyrrole moiety as a spacer between
oxazolidinone pharmacophore and phenyl ring or as a
replacement of the latter group resulted in a diminished
antimycobacterial activity. Both results suggest that the
alteration of the geometry of PNU100480 lead to less
favorable interactions of synthesized compounds with the
mycobacterial target.
Sarnaik, H.; Charavaryamath, C.; Rao, B. S.; Raheem,
M. A.; Das, J.; Iqbal, J.; Rajagopalan, R. J. Med. Chem.
2002, 45, 3953. (e) Cui, Y.; Yang, Y.; Chen, K.; Ji, R.;
Zhang, S. Bioorg. Med. Chem. Lett. 2003, 13, 2311.
12. See also: Gadwood, R. C.; Shinabarger, D. A. in Annual
Reports in Medicinal Chemistry; Academic Press: New
York, 2000; Vol. 35, pp 135–144.
13. (a) Genin, M. J.; Hutchinson, D. K.; Allwine, D. A.;
Hester, J. B.; Emmert, D. E.; Garmon, S. A.; Ford, C. W.;
Zurenko, G. E.; Hamel, J. C.; Schaadt, R. D.; Stapert, D.;
Yagi, B. H.; Friis, J. M.; Shobe, E. M.; Adams, W. J. J.
Med. Chem. 1998, 41, 5144. (b) Genin, M. J.; Allwine,
D. A.; Anderson, D. J.; Barbachyn, M. R.; Emmert, D. E.;
Garmon, S. A.; Graber, D. R.; Grega, K. C.; Hester, J. B.;
Hutchinson, D. K.; Morris, J.; Reischer, R. J.; Ford,
C. W.; Zurenko, G. E.; Hamel, J. C.; Schaadt, R. D.;
Stapert, D.; Yagi, B. H. J. Med. Chem. 2000, 43, 953.
14. (a) Riedl, B. US Patent 5,843,967, 1998; Chem. Abstr.
1995, 124, 261021. (b) Riedl, B. US Patent 5,698,574,
1997; Chem. Abstr. 1995, 124, 289520. (c) Riedl, B. Eur-
opean Patent 789,026, 1997; Chem. Abstr. 1997, 127,
220651. (d) Riedl, B. US Patent 5,827,857, 1998; Chem.
Abstr. 1997, 127, 149139. (e) Stolle, A. US Patent
5,869,659, 1999; Chem. Abstr. 1997, 127, 176421. (f) Riedl,
B. US Patent 5,684,023, 1997; Chem. Abstr. 1995, 124,
261020. (g) Bartel, S. World Patent 9,937,641, 1999;
Chem. Abstr. 1999, 131, 129999.
15. 1a: MS (EI, 70 ev) m/z: 299; IR (cmꢁ1, KBr) 1714
(CH3C¼O), 1722 (C¼O), 3282 (NH); 1H NMR
(200 MHz, CDCl3) d 1.986 (3H, s); 3.627(3H, m, over-
lapped signals); 3.956 (1H, t, J=9.0 Hz); 4.679 (1H, m);
6.098 (1H, m, exchang. with D2O); 6.302 (1H, dd, J=3.3,
1.8 Hz); 6.950 (1H, dd, J=3.3, 2.6 Hz); 7.218 (2H, m,
overlapped signals); 7.346 (4H, m, overlapped signals).
Anal. calcd for C16H17N3O3: C, 64.20, H, 5.72, N, 14.04;
Found C, 64.34, H, 5.74, N, 13.91.
References and notes
1. Duncan, K. Chem. Ind. 1997, 861.
3. Barbachyn, M. R.; Ford, C. W. Angew. Chem., Int. Ed.
2003, 42, 2010 and references cited therein.
4. Brickner, S. J. Curr. Pharmaceut. Dess. 1996, 2, 175.
5. Ford, C. W.; Hamel, J. C.; Wilson, D. M.; Moerman,
J. K.; Stapert, D.; Yancey, R. J., Jr.; Hutchinson, D. K.;
Barbachyn, M. R.; Brickner, S. J. Antimicrobial Agents
and Chemotherapy 1996, 40, 1508.
6. (a) Stevens, D. L.; Herr, D.; Lampiris, H.; Hunt, J. L.;
Batts, D. H.; Hafkin, B. Clinical Infectious Diseases 2002,
34, 1481. (b) Perry, C. M.; Javis, B. Drugs 2001, 61, 525.
(c) Norrby, R. Exp. Opin. Pharmacother. 2001, 2, 293. (d)
Clemett, D.; Markham, A. Drugs 2000, 59, 815.
7. (a) Lin, A. H.; Murray, R. W.; Vidmar, T. J.; Marotti,
K. R. Antimicrob. Agents Chemother. 1997, 41, 2127. (b)
Diekema, D. J.; Jones, R. N. The Lancet 2001, 358, 1975.
(c) 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. Chemo-
ther. 1997, 41, 2132.
8. (a) Aoki, H.; Ke, L.; Poppe, S. M.; Poel, T. J.; Weaver,
E. A.; Gadwood, R. C.; Thomas, R. C.; Shinabarger,
D. L.; Gonaza, M. C. Antimicrob. Agents Chemother.
2002, 46, 1080. (b) Kloss, P.; Xiong, L.; Mankin, A. S.;
Shinabarger, D. L.; Mankin, A. S. J. Mol. Biol. 1999, 294,
93. (c) Bobkova, E. V.; Yan, Y. P.; Jordan, D. B.; Kurilla,
M. G.; Pompliano, D. L.; Jordan, D. B. J. Biol. Chem.
2003, 278, 9802.
9. Barbachyn, M. R.; Hutchinson, D. K.; Brickner, S. J.;
Cynamon, M. H.; Kilburn, J. O.; Klemens, S. P.; Glick-
man, S. E.; Grega, K. C.; Hendges, S. K.; Toops, D. S.;
Ford, C. W.; Zurenko, G. E. J. Med. Chem. 1996, 39, 680.
10. (a) Artico, M.; Mai, A.; Sbardella, G.; Massa, S.; Lampis,
G.; Deidda, D.; Pompei, R. Bioorg. Med. Chem. Lett.
1998, 8, 1493. (b) Artico, M.; Mai, A.; Sbardella, G.;
Massa, S.; Musiu, C.; Lostia, S.; Demontis, F.; La Colla,
P. Bioorg. Med. Chem. Lett. 1999, 9, 1651. (c) Ragno, R.;
Marshall, G. R.; Di Santo, R.; Costi, R.; Massa, S.;
Pompei, R.; Artico, M. Bioorg. Med. Chem. 2000, 8, 1423.
(d) Sbardella, G.; Mai, A.; Artico, M., manuscript in
preparation.
11. (a) See for example: Tucker, J. A.; Allwine, D. A.; Grega,
K. C.; Barbachyn, M. R.; Klock, J. L.; Adamski, J. L.;
Brickner, S. J.; Hutchinson, D. K.; Ford, C. W.; Zurenko,
G. E.; Conradi, R. A.; Burton, P. S.; Jensen, R. M. J.
Med. Chem. 1998, 41, 3727. (b) Tokuyama, R.; Takaha-
shi, Y.; Tomita, Y.; Suzuki, T.; Yoshida, T.; Iwasaki, N.;
Kado, N.; Okezaki, E.; Nagata, O. Chem. Pharm. Bull.
2001, 49, 347. (c) Yu, D.; Huiyuan, G. Bioorg. Med.
Chem. Lett. 2002, 12, 857. (d) Selvakumar, N.; Srinivas,
D.; Khera, M. K.; Kumar, M. S.; Mamidi, R. N.;
1b: MS (EI, 70 ev) m/z: 317.12; IR (cmꢁ1, KBr) 1716
(CH3 C¼O), 1724 (C¼O), 3279 (NH); 1H NMR
(200 MHz, CDCl3) d 2.006 (3H, s); 3.661 (3H, m, over-
lapped signals); 3.968 (1H, t, J=9.3 Hz); 4.786 (1H, m);
6.387(1H, m); 6.537(1H, m, exchang. with D 2O); 6.920
(1H, m); 7.250 (5H, m, overlapped signals). Anal. calcd
for C16H16FN3O3: C, 60.56, H, 5.08, F, 5.99, N, 13.24;
Found C, 60.64, H, 5.13, F, 5.75, N, 13.04.
1c: MS (EI, 70 ev) m/z: 317.12; IR (cmꢁ1, KBr) 1744
(CH3C¼O, C¼O), 3294 (NH); 1H NMR (200 MHz,
CDCl3) d 1.988 (3H, s); 3.643 (3H, m, overlapped signals);
3.946 (1H, t, J=8.9 Hz); 4.753 (1H, m); 6.343 (1H, m);
7.118 (7H, m, overlapped signals). Anal. calcd for
C16H16FN3O3: C, 60.56, H, 5.08, F, 5.99, N, 13.24; Found
C, 60.68, H, 5.13, F, 5.88, N, 13.07.
1d: MS (EI, 70 ev) m/z: 317.12; IR (cmꢁ1, KBr) 1696
(CH3C¼O), 1714 (C¼O), 3303 (NH); 1H NMR
(200 MHz, CDCl3) d 2.009 (3H, s); 3.625 (3H, m, over-
lapped signals); 3.962 (1H, t, J=9.0 Hz); 4.787 (1H, m);
6.319 (1H, dd, J=2.9, 1.6 Hz); 6.563 (1H, m, exchang.
with D2O); 6.880 (1H, m); 7.075 (3H, m, overlapped sig-
nals); 7.271 (2H, m, overlapped signals). Anal. calcd for
C16H16FN3O3: C, 60.56, H, 5.08, F, 5.99, N, 13.24; Found
C, 60.38, H, 5.01, F, 6.15, N, 13.45.
1e: MS (EI, 70 ev) m/z: 402.17; IR (cmꢁ1, KBr) 1725
(CH3C¼O, C¼O), 3290 (NH); 1H NMR (200 MHz,
CDCl3) d 1.981 (3H, s); 3.040 (4H, m); 3.629 (3H, m,
overlapped signals); 3.857(5H, m, overlapped signals);
4.748 (1H, m); 6.283 (2H, m); 7.013 (5H, m, overlapped
signals). Anal. calcd for C20H23FN4O4: C, 59.69, H, 5.7 6, F,
4.72, N, 13.92; Found C, 59.78, H, 5.84, F, 4.50, N, 13.78.
1f: MS (EI, 70 ev) m/z: 418.15; IR (cmꢁ1, KBr) 1735
(CH3C¼O, C¼O), 3280 (NH); 1H NMR (200 MHz,