The Journal of Antibiotics
Online ISSN : 1881-1469
Print ISSN : 0021-8820
ISSN-L : 0021-8820
SYNTHESIS, IN VITRO AND IN VIVO ACTIVITY OF NOVEL 9-DEOXO-9a-AZA-9a-HOMOERYTHROMYCIN A DERIVATIVES; A NEW CLASS OF MACROLIDE ANTIBIOTICS, THE AZALIDES
G. MICHAEL BRIGHT, ARTHUR A. NAGEL, JON BORDNER, KISHOR A. DESAI, JOSEPH N. DIBRINO, JOLANTA NOWAKOWSKA, LAWRENCE VINCENT, RICHARD M. WATROUS, FRANK C. SCIAVOLINO, ARTHUR R. ENGLISH, JAMES A. RETSEMA, MARGARET R. ANDERSON, LORI A. BRENNAN, ROBERTA J. BOROVOY, CAROLINE R. CIMOCHOWSKI, JAMES A. FAIELLA, ARTHUR E. GIRARD, DENNIS GIRARD, CAROL HERBERT, MARY MANOUSOS, RACHEL MASON
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JOURNAL FREE ACCESS

1988 Volume 41 Issue 8 Pages 1029-1047

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Abstract

A series of erythromycin A-derived semisynthetic antibiotics, featuring incorporation of a basic nitrogen atom into a ring expanded (15-membered) macrocyclic lactone, have been prepared and biologically evaluated. Semisynthetic modifications focused upon (1) varied substitution at the macrocyclic ring nitrogen and (2) epimerization or amine substitution at the C-4" hydroxyl site within the cladinose sugar. In general, the new azalides exhibit improved Gram-negative potency, expanding the spectrum of erythromycin A to fully include Haemophilus influenzae and Neisseria gonorrhoeae. When compared to erythromycin A, the azalides exhibit substantially increased half-life and area-under-the-curve values in all species studied. The overall in vitro/in vitro performance of N-methyl, C-4" epimers 3a and 9; and C-4" amine 11 identify these compounds as the most interesting erythromycin A-superior agents. Compound 3a has been advanced to clinical study.

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© Japan Antibiotics Research Association
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The Journal of Antibiotics, Series A

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