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I. H. Kim et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1181–1184
Table 1. Antibacterial activities of spirorifamycins 2a–f and 3a–e as compared to rifabutin (MIC: lg/mL)
Compound
R
S. aureus CB190a
S. aureus CB372b
S. aureus CB370c
Rifabutin
0.031
0.026
0.016
0.003
0.006
0.063
0.063
0.016
0.013
0.031
0.063
0.063
15.6
7.81
1.95
1.95
15.6
7.81
0.98
7.81
0.98
3.91
>62.5
7.81
>62.5
>62.5
>62.5
32
2a
2b
2c
2d
2e
2f
Boc
Me
Bn
Allyl
>62.5
>62.5
15.6
i-Bu
Quinolin-3-yl methyl
3a
3b
3c
3d
3e
Boc
Me
>62.5
>62.5
>62.5
31.3
Bn
i-Bu
Quinolin-3-yl methyl
>62.5
a ATCC # 29213 a wild-type, rifamycin-sensitive strain of S. aureus.
b Laboratory-derived variant of ATCC # 29213 (CB190) bearing an rpoB Asp471Tyr mutation that confers intermediate rifamycin resistance.
c Laboratory-derived variant of ATCC # 29213 (CB190) bearing an rpoB His481Tyr mutation that confers high-level rifamycin resistance.
D’Ambrieres, S. G.; Lachaud, S.; Laurin, P.; Le Martret,
O.; Loyau, V.; Tessot, N.; Pejac, J. M.; Perrn, S. Bioorg.
Med. Chem. Lett. 1999, 9, 3075.
Table 2. In vivo activity of selected spirorifamycins tested against a
wild-type S. aureus strain ATCC # 6538 in an acute lethal mouse
model of septicemia (ED50: mg/kg)
7. New rifabutin analogs were recently reported to have
better in vitro anti-tuberculosis activity than rifabutin and
rifampin: Barluenga, J.; Aznar, F.; Garcia, A-B.; Cabal,
M-P.; Palacios, J.; Menendez, M. Bioorg. Med. Chem.
Lett. 2006, 16, 5717.
8. (a) Harald, G. Chem. Rev. 2003, 103, 2795; (b) Che
Emmanuel, M. J.; Frye, L. L.; Hickey, E. R.; Liu, W.;
Morwick, T. M.; Spreno, D. M.; Sun, S.; Thomson, D. S.;
Ward, Y. D.; Young, E. R. WO Patent 0119816, 2001; (c)
Pyne, S. G. Tetrahedron Lett. 1987, 28, 4737; (d) Carboni,
B.; Benalil, A.; Vaultier, M. J. Org. Chem. 1993, 58, 3736.
9. Stahl, G. L.; Walter, R.; Smith, C. W. J. Org. Chem. 1978,
43, 2285.
Compound
ED50 (po)
ED50 (sc)
Rifabutin
0.6
<0.1
0.3
2b
2e
2f
>10
<0.1
5.0
0.6
0.6
of a rifamycin agent without the resistance development
liability and that could be employed in monotherapy
would be expected to be highly prized as a new addition
to the antimicrobial armamentarium.
10. (a) Akiyama, T.; Shima, H.; Ozaki, S. Tetrahedron Lett.
1991, 32, 5593; (b) Koh, K.; Ben, R. N.; Durst, T.
Tetrahedron Lett. 1994, 35, 375.
Acknowledgment
11. (a) Marchi, E.; Montecchi, L. US Patent 4,341,785, 1982;
(b) March, E.; Montecchi, L.; Venturini, A. P.; Mascel-
lani, G.; Brufani, M. J. Med. Chem. 1985, 28, 960.
12. Matsuoka, M.; Makino, Y.; Takei, T.; Kitao, T. Chem.
Lett. 1980, 743.
The authors would like to acknowledge helpful input
from Dr. A. Simon Lynch during preparation of this
manuscript.
13. Analytical characterization of 3d. ESI-MS m/z 847
(M+H+); HPLC: single peak at retention time 3.37 min
(Xterraꢂ MS C18 3.5 lm; 2.1 · 30 mm column, 8 min
gradient elution, 0 to 100% solvent B in solvent A; solvent
A: 0.1% formic acid in water; solvent B: 0.1% formic acid
in methanol); 1H NMR (400 MHz, CDCl3) d 13.73 (s,
1H), 8.14 (s, 1H), 7.31 (br s, 1H), 6.44 (dd, J = 10.8 and
16.0 Hz, 1H), 6.25 (d, J = 10.4 Hz, 1H), 6.10 (dd, J = 16.0
and 6.4 Hz, 1H), 6.01 (dd, J = 12.8 and 0.8 Hz, 1H), 5.09
(dd, J = 6.0 and 12.4 Hz, 1H), 4.97 (d, J = 9.6 Hz, 1H),
3.83 (d, J = 5.6 Hz, 2H), 3.76 (d, J = 10.0 Hz, 2H), 3.56 (br
s, 2H), 3.39 (br d, J = 6.0 Hz, 2H), 3.20 (br d, J = 12.0 Hz,
2H), 3.05 (s, 3H), 3.05–3.00 (m, 1H), 2.82 (m, 2H), 2.40–
2.34 (m, 1H), 2.25 (s, 3H), 2.07 (s, 3H), 2.06–1.62 (m, 6H),
2.03 (d, J = 3.6 Hz, 6H), 2.02 (s, 3H), 1.71 (s, 3H), 1.03 (d,
J = 6.8 Hz, 3H), 1.03–1.02 (m, 1H), 0.85 (d, J = 7.2 Hz,
3H), 0.65 (d, J = 7.2 Hz, 3H), 0.01 (d, J = 7.2 Hz, 3H).
14. Staphylococcus aureus in 5% porcine gastric mucin in PBS
was given at a dose of 50 times the LD50 intraperitoneally
(ip) to mice. Survival was monitored for the next 4 days
for drug-treated and control groups. ED50s were calculat-
ed based on three doses with five mice in each dose group.
References and notes
1. (a) Flosss, H. G.; Yu, T.-W. Chem. Rev. 2005, 105, 621; (b)
Brufani, M. J. Mol. Biol. 1974, 87, 409.
2. (a) American Thoracic Society Document. Am. J. Respir.
Crit. Care Med. 2003, 167, 603–662; (b) Zavasky, D-M.;
Sande, M. A. J. Am. Med. Assoc. 1998, 279, 1575; (c)
Zimmerli, W.; Widmer, A. F.; Blatter, M.; Frei, R.;
Ochsner, P. E. J. Am. Med. Assoc. 1998, 279, 1537; (d)
Darouichi, R. O. N. Engl. J. Med. 2004, 350, 1422.
3. (a) Heldman, A. W. Am. J. Med. 1996, 101, 68; (b) Wilson,
W. R. et al. J. Am. Med. Assoc. 1995, 274, 1706.
4. (a) Karchmer, A. W.; Archer, G. L.; Dismukes, W. E. Rev.
Infect. Dis. 1983, S543; (b) Zumia, A.; Grange, J. M.
Lancet Infect. Dis. 2001, 1(Suppl. 3), 199.
5. Bishai, W. R.; Graham, N. M. H.; Harrington, S.; Page,
C.; Moore-Rice, K.; Hooper, N.; Chaisson, R. E. N. Engl.
J. Med. 1996, 334, 1573.
6. (a) Ma, Z. Curr. Med. Chem. 2002, 1, 15; (b) Denis, A.;
Agouridas, C.; Auger, J-M.; Benedetti, Y.; Bonnefoy, A.;
Bretin, F.; Chantot, J-F.; Dussarat, A.; Fromentin, C.;