P.-E. Sum et al. / Bioorg. Med. Chem. Lett. 16 (2006) 400–403
403
Table 3. Antibacterial activity of 9-(sulfonylamino)-7-(substituted)-6-demethyl-6-deoxytetracycline 9a–e
Organism
Minimal inhibitory concentration (MIC) lg/mL compound
9a
9b
9c
9d
9e
Mino
S. aureus UBMS 90-1 (tetM)
S. aureus UBMS 90-2 (tetM)
S. aureus UBMS 90-3 (sensitive)
S. aureus UBMS 88-7 (tetK)
S. aureus Smith (sensitive)
E. faecalis ATCC 29212
E. coli UBMS 88-1 (tetB)
E. coli 88-2 (sensitive)
4
0.25
0.12
0.12
1
1
32
4
0.25
0.06
0.12
8
8
0.06
4
0.25
0.25
2
2
2
0.03
0.25
0.06
2
4
32
2
4
0.12
0.06
>32
>32
ND
>32
0.03
0.25
32
0.12
0.06
8
0.06
16
8
1
>32
>32
32
>32
16
8
2
0.25
>32
2
E. coli UBMS 89-1 (tetM)
E. coli 89-2 (sensitive)
ND
16
ND
16
ND
2
5. Levy, S. B. J. Antimicrob. Chemother. 1989, 24, 1.
6. Speer, B. S.; Shoemaker, N. B.; Salyers, A. A. Clin.
Microbiol. Rev. 1992, 5, 387.
7. Sum, P.-E.; Lee, V. J.; Testa, R. T.; Hlavka, J. J.; Ellestad,
G. A.; Bloom, J. D.; Gluzman, Y.; Tally, F. P. J. Med.
Chem. 1994, 37, 184.
8. Testa, R. T.; Petersen, P. J.; Jacobus, N. V.; Sum, P.-E.;
Lee, V. J.; Tally, F. P. Antimicrob. Agents Chemother.
1993, 37, 2270.
9. Sum, P.-E.; Petersen, P. J. Bioorg. Med. Chem. Lett. 1999,
9, 1459.
In summary, the sulfonamide series is much more active
against Gram-positive bacteria than the acylated series.
The structure–activity relationship studies of these
compounds provided useful information on the structur-
al requirements for activity against Gram-negative
bacteria. It also indicated that it is possible to design
compounds with activity selectively just against Gram-
positive bacteria. The potent in vitro activity of some
of the sulfonamide derivatives (e.g., 9b,e) against resis-
tant Gram-positive bacteria makes them potential
candidates for the development of new antibiotics tar-
geting selectively just the Gram-positive pathogens.
10. Petersen, P. J.; Jacobus, N. V.; Weiss, W. J.; Sum, P.-E.;
Testa, R. T. Antimicrob. Agents Chemother. 1999, 43, 738.
11. Sum, P.-E.; Sum, F.-W.; Projan, S. J. Curr. Pharm. Des.
1998, 4, 119.
12. Broadersen, D. E.; Clemons, W. M., Jr.; Carter, A. P.;
Morgan-Warre, R. T.; Wimberly, B. T.; Ramakrishnan,
V. Cell 2000, 103, 1143.
13. Rasmussen, B. A.; Gluzman, Y.; Tally, F. P. Antimicrob.
Agents Chemother. 1994, 38, 1658.
14. Bergeron, J.; Ammirati, M.; Danley, D.; James, L.;
Norcia, M.; Retsema, J.; Strick, C. A.; Su, W.-G.;
Sutcliffe, J.; Wondrack, L. Antimicrob. Agents Chemother.
1996, 40, 2226.
Acknowledgments
We thank Ms. Nilda Jacobus and Dr. Frank Tally for
their support and the analytical chemistry group for
analytical HPLC and spectral data. We also thank Dr.
Jerauld Skotnicki and Dr. Tarek Mansour for helpful
discussion during the preparation of the manuscript.
15. Orth, P.; Schnappinger, D.; Sum, P.-E.; Ellestad, G. A.;
Hillen, W.; Saenger, W.; Hinrichs, W. J. Mol. Biol. 1999,
285, 455.
References and notes
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1991. Methods for dilution antimicrobial susceptibility
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