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.
Authors:
- Arthur A. NagelANArthur A. Nagel
- Jon BordnerJBJon Bordner
- Kishor A. DesaiKDKishor A. Desai
- Joseph N. DibrinoJDJoseph N. Dibrino
- Jolanta NowakowskaJNJolanta Nowakowska
- Lawrence VincentLVLawrence Vincent
- Richard M. WatrousRWRichard M. Watrous
- Frank C. SciavolinoFSFrank C. Sciavolino
- Arthur R. EnglishAEArthur R. English
- James A. RetsemaJRJames A. Retsema
- Margaret R. AndersonMAMargaret R. Anderson
- 1 January 1988
- journal article
- research article
- Published by Japan Antibiotics Research Association in The Journal of Antibiotics
- Vol. 41 (8) , 1029-1047
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 vivo 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.Keywords
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