Synthesis and antibacterial activity of novel 6-O-substituted erythromycin A derivatives

doi:10.1016/S0960-894X(00)00106-2

Bioorganic & Medicinal Chemistry Letters

Volume 10, Issue 8, April 2000, Pages 815-819

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Abstract

A series of novel 6-O-substituted erythromycin A derivatives has been synthesized. Good in vitro antibacterial activity has been demonstrated for analogues incorporating a variety of structural features. The methodology disclosed is expected to find application in the design of future macrolide antibiotics that target the prevalent bacterial resistance problem.

References (15)

(a) Chu, D. T. W. Exp. Opin. Invest. Drugs 1995, 4, 65. (b) Lartey, P. A.; Perun, T. In Studies in Natural Products...
P Kurath et al.
Experienta
(1971)
Z Itoh et al.
Am. J. Physiol.
(1984)
(a) Morimoto, S.; Takahashi, Y.; Watanabe, Y.; Omura, S. J. Antibiot. 1984, 37, 187. (b) Watanabe, Y.; Morimoto, S.;...
S Morimoto et al.
J. Antibiot.
(1990)
(a) Fernandes, P. B.; Baker, W. R.; Freiberg, L. A.; Hardy, D. J.; McDonald, E. D. Antimicrob. Agents Chemother. 1989,...
(a) Neu, H. C. Science 1992, 257, 1064. (b) Appelbaum, P. C. Clin. Infect. Dis., 1992, 15, 77. (c) Katz, L.; Chu, D. T....

There are more references available in the full text version of this article.

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Citation Excerpt :
Therefore, continuous efforts should be devoted to this family. It is known that an allyl group could serve as templates for a variety of further modification, such as Heck reaction and functional transformation [18,19]. Moreover, incorporation of 11,12-carbonate could improve activities than the parent 11,12-diol and other analogues [20].
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Synthesis and antibacterial activity of novel 6-O-substituted erythromycin A derivatives

Abstract

Experienta

Am. J. Physiol.

J. Antibiot.