2610
P.-E. Sum et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2607–2610
Table 2. In vitro antibacterial activity of selected benzoxazole deri-
vatives
disaccharide moiety might not be essential for
antibacterial activity.
Compd
Organism; (MIC) mg/mL
Piper 5b 5d 5m 7b
Acknowledgements
S. aureus (GC 1131) MRSA
S. aureus (GC 4541) MRSA
S. aureus (GC 4542) MRSA
S. aureus (GC 4543) MSSA
S. aureus (GC 4544) MSSA
S. aureus (GC 4545) MSSA
S. aureus (GC 2216) MSSA
Staphylococcus hemolyticus (GC 4546) MRCNS >64
SCN (GC 4547) MRCNS
SCN (GC 4548) MRCNS
SCN (GC 4549) MSCNS
SCN (GC 6257) MSCNS
SCN (GC 4551) MSCNS
Enterococcus faecalis (GC 4552) VSE
E. faecalis (GC 4553) VSE
E. faecalis (GC 4554) VSE
E. faecalis (GC 2242) VRE
E. faecalis (GC 4555) VSE
Enterococcus faecium (GC 2243) VRE
E. faecium (GC 4556) VSE
E. faecium (GC 4557) VSE
E. faecium (GC 4558) VRE
Streptococcus pyogenes (GC 4563)
Streptococcus agalactiae (GC4564)
Streptococcus pneumoniae (GC 4565) PSSP
Bacillus cereus (GC 4561) assay organism
Micrococcus lutea (GC 4562)
E. faecalis (GC 2691) VSE
E. faecalis (GC 6189) VRE
E. faecalis (GC 3059) VRE
S. pneumoniae (GC 1894) PRSP
S. pneumoniae (GC 6242) PSSP
S. aureus (GC 3051) GISA
>64
>64
64
1
8
8
8 16
8
8
8
4
8
4
8
4
8
4
4
2
4
8
4
8
4
8
8
8
4
4
1
4
4
8
1
8
8
8
4
4
4
4
4
4
4
2
4
2
8
1
4
2
1
1
4
2
4
16
16
16
8
8
2
4
2
4
8
1
16
16
16
32
8
8
4
4
Analytical support provided by analytical group is
gratefully acknowledged. We thank Drs. Jerry Skot-
nicki, Patricia Bradford, Russ Dushin, and Haiyin He
for helpful discussion. We also thank Dr. Subas Sakya
for exploring early nitration reactions.
8
8
8
8
8
4
4
4
8
8
8
8
8
4
8
4
4
8
4
>64
16
32
4
4
2
>64
1
2
1
64
1
References and Notes
2 16
4
8
64 64
16 16
32 64
32 32
32 64
16 32
64 64
4
8
1. Sum, P.-E.; How, D.; Torres, N.; Petersen, P. J.; Lenoy, E.;
Weiss, W. J.; Mansour, T. S. Bioorg. Med. Chem. Lett. 2003,
13, 1151.
2. De Voe, S. E.; Kunstmann, M. P. U.S. Patent 3,495,004,
1970: Chem. Abstr. 1970, 72, 131101
3. (a) He, H.; Bernan, V.; Williamson, R. T.; Graziani, E. I.;
Shen, B.; Greenstein, M.; Carter, G. T. 41st Interscience
Conference on Antimicrobial Agents and Chemotherapy,
Chicago, IL, Dec 16–19, 2001; abstract F-1147. (b) He, H.;
Williamson, R. T.; Shen, B.; Graziani, E. I.; Yang, H. Y.;
Sakya, S. M.; Petersen, P. J.; Carter, G. T. J. Am. Chem. Soc.
2002, 124, 9729.
4. Petersen, P. J.; Weiss, W. J.; Lenoy, E. B.; He, H.; Testa, R.
T.; Bradford, P. A. 41st Interscience Conference on Anti-
microbial Agents and Chemotherapy, Chicago, IL, Dec 16–19,
2001; abstract F-1148.
0.12
>64
ꢁ0.06 16
0.12 32
8
8
16 16
4
8
ꢁ0.06 32 16
1
32 64
2
32 32
32 32
64 64
32 16
ꢁ0.06
2
2
2
2
2
5. (a) Kiselyov, A. S. Tetrahedron Lett. 1999, 40, 4119. (b)
Bougrin, K.; Loupy, A.; Souflaoui, M. Tetrahedron 1998, 54,
8055.
ꢁ0.06 32
64 8 16
0.5 8 16
8
6. A typical benzoxazole reaction is as follows: To a solution
of 2TFA salt of 4 (0.121 g) in DMF was added 3-(4-methyl-
phenoxy)benzaldehyde (0.106 g) and DDQ (0.057 g). The
reaction was stirred at rt for 2 h and was triturated with ace-
tonitrile and ether and the solid collected, purified by reverse-
S. aureus (GC 3066) GISA
MRSA (methicillin-resistant S. aureus); MSSA (methicillin-susceptible S.
aureus); MRCNS (methicillin-resistant Coagulase-negative Staphylo-
cocci); MSCNS (methicillin-susceptible Coagulase-negative Staphylo-
cocci); VRE (vancomycin-resistant Enterococci); PRSP (penicillinresistant
Strep. pneumoniae); GISA (glycopeptide tntermediate S. aureus); Piper
(piperacillin).
phase HPLC to give 5m. MS (ES), m/z 590 (M+2H)2+
.
7. Compound 6 was prepared as follows: To a solution of 4 in
DMSO was added 1.10 equiv of 1,1-thiocarbonyldiimidazole.
The reaction was stirred at rt for 1 h, triturated with diethyl
ether and the solid filtered. To a stirred solution of crude
compound 6 in DMF was added N,N-diisopropylethylamine
(2 equiv) and benzyl bromide. The reaction mixture was stir-
red for 1 h and triturated with diethyl ether and the solid col-
lected. The product was purified by reverse-phase HPLC to
including vancomycin-resistant isolates, good activity
was observed (MICs 2–16 mg/mL). The compound
also demonstrated good streptococcal activity (MIC
2–8 mg/mL).
give 7c. MS (ES), m/z 560 (M+2H)2+
.
8. A suspension of 8 in THF was treated with 2,3,4,6-tetra-O-
benzoyl-b-d-glucopyranosyl isothiocyanate (300 mg) and the
mixture stirred at rt for several days (followed by ES/MS). The
mixture was diluted with diethyl ether and solid collected. The
solid then dissolved in MeOH and treated with mercuric chloride
(350 mg). The reaction was stirred for 18 h and diluted with di-
ethyl ether and the solid collected. The product was purified by
In summary, a series of benzoxazole derivatives of
mannopeptimycin-b and its aglycone were synthesized
to explore SAR. 5b, 5d, 5m, and 7b showed improved
activity against a number of pathogens when compared
to the parent compound 2. The good activities demon-
strated by these derivatives suggested that the mannosyl
reverse-phase HPLC to give 9. M S (ES),m/z 795.9 (M+2H)2+
.