Abstract
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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- Counter F. T., Ensminger P. W., Preston D. A., Wu C. Y., Greene J. M., Felty-Duckworth A. M., Paschal J. W., Kirst H. A. Synthesis and antimicrobial evaluation of dirithromycin (AS-E 136; LY237216), a new macrolide antibiotic derived from erythromycin. Antimicrob Agents Chemother. 1991 Jun;35(6):1116–1126. doi: 10.1128/aac.35.6.1116. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Firl J., Prox A., Luger P., Maier R., Woitun E., Daneck K. Epimerization of erythromycin derivatives. J Antibiot (Tokyo) 1990 Oct;43(10):1271–1277. doi: 10.7164/antibiotics.43.1271. [DOI] [PubMed] [Google Scholar]
- Kirst H. A., Sides G. D. New directions for macrolide antibiotics: pharmacokinetics and clinical efficacy. Antimicrob Agents Chemother. 1989 Sep;33(9):1419–1422. doi: 10.1128/aac.33.9.1419. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Massey E. H., Kitchell B. S., Martin L. D., Gerzon K. Antibacterial activity of 9(S)-erythromycylamine-aldehyde condensation products. J Med Chem. 1974 Jan;17(1):105–107. doi: 10.1021/jm00247a018. [DOI] [PubMed] [Google Scholar]
- Tardrew P. L., Mao J. C., Kenney D. Antibacterial activity of 2'-esters of erythromycin. Appl Microbiol. 1969 Aug;18(2):159–165. doi: 10.1128/am.18.2.159-165.1969. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Taskinen J., Ottoila P. Hydrolysis of 2'-esters of erythromycin. J Antimicrob Chemother. 1988 Jun;21 (Suppl 500):1–8. doi: 10.1093/jac/21.suppl_d.1. [DOI] [PubMed] [Google Scholar]
- Tulkens P. M. Intracellular distribution and activity of antibiotics. Eur J Clin Microbiol Infect Dis. 1991 Feb;10(2):100–106. doi: 10.1007/BF01964420. [DOI] [PubMed] [Google Scholar]