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Antimicrobial Agents and Chemotherapy, Jul 1995, 1436-1441, Vol 39, No. 7
Copyright © 1995 by the American Society for Microbiology. All rights reserved.

Antimicrobial characterization and interrelationships of dirithromycin and epidirithromycin

HA Kirst, LC Creemer, JW Paschal, DA Preston, WE Alborn Jr, FT Counter, JG Amos, RL Clemens, KA Sullivan and JM Greene
Lilly Research Laboratories, Eli Lilly and Company, Greenfield, Indiana 46140, USA.

Dirithromycin is the 9-N,11-O-oxazine adduct formed from 9(S)- erythromycylamine and 2-(2-methoxyethoxy)acetaldehyde in which the methoxyethoxymethyl substituent on the oxazine ring possesses the R configuration. Epidirithromycin is its isomer in which the methoxyethoxymethyl substituent has the opposite (S) configuration. Both compounds readily epimerize in solution, reaching an equilibrium ratio of 85:15 in favor of dirithromycin, given sufficient time. The rate of interconversion is dependent upon pH, temperature, and solvent. An enriched sample of epidirithromycin (95% purity) was synthesized by condensing erythromycylamine and 2-(2-methoxyethoxy)acetaldehyde in diethyl ether as the reaction solvent, and the product was fully characterized by nuclear magnetic resonance spectroscopy and high- pressure liquid chromatographic (HPLC) analysis. Both oxazine derivatives readily hydrolyze to erythromycylamine, so all three compounds exhibit the same antibiotic activity in vitro. In order to determine whether dirithromycin itself possesses significant antimicrobial activity without initial hydrolysis to erythromycylmine, inhibition of cell-free ribosomal protein synthesis was measured under conditions which were adapted to minimize hydrolysis, as measured by analytical HPLC in parallel experiments. Under these particular conditions, inhibition of ribosomal protein synthesis by dirithromycin was < 10% of the value measured for erythromycylamine.

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