Antibacterial activity of 9(S)-erythromycylamine-aldehyde condensation products

Massey, E. H.; Kitchell, Barbara S.; Martin, Luigi De; Gerzon, Koert

doi:10.1021/jm00247a018

Cited by 44 publications

(17 citation statements)

References 3 publications

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“…Since its introduction into clinical practice by McGuire ct al. [1952], erythro mycin has proved to be safe, and effective for the treatment of commonly encoun tered infections caused by staphylococci, streptococci, H. influenzae, Campylobacter, Legionella, Listeria, Bordetella, Mycoplas ma, Rickettsia, Chlamydia and a number of anaerobic bacteria [Elhariff ct al., 1985;Gribble and Anthony, 1982;Massey et al, 1974;Modai, 1988;Tardew et al, 1969;Washington and Wilson, 1985;Garcia-Rodriguez et al, 1989], Since erythromycin is known to degrade under acidic conditions [Kurath et al, 1971], its passage through the stomach can result in loss of antibacte rial activity. Therefore, there has been considerable interest in the development and evaluation of new derivatives of eryth romycin with improved chemical, biolog ical and pharmacokinetic properties and has resulted in a number of products some of which have progressed to clinical trials [Kirst and Sides, 1989a, b;Hardy et al, 1988;Fernandez and Hardy, 1988;Naik and Ruck, 1989;Rolston et al, 1990;Hoppe and Eichorn, 1989].…”

Section: Discussionmentioning

confidence: 99%

In vitro Activity of LY281389 and Comparison with Erythromycin and Oral Beta-Lactams

Qadri¹,

Ueno²,

Frayha³

1991

Chemotherapy

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LY281389 is a new 14-member ring macrolide which is presently being developed for possible clinical use against bacterial infections. We compared the in vitro activity of LY281389 with erythromycin, ampicillin, augmentin and cephalexin against 610 clinical isolates. The new drug inhibited 97 and 11% of methicillin-sensitive and methicillin-resistant Staphylococcus aureus isolates, respectively, 59% of coagulase-negative staphylococci, 63% of enterococci and 74% of Haemophilus influenzae. All the 171 isolates of Streptococcus Lancefield group A, group B and Streptococcus pneumoniae were susceptible to LY281389 at MIC values ranging between 0.03 and 0.24 μg/ml. In vitro activity of LY281389 against the bacteria tested was comparable to that of erythromycin.

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Section: Discussionmentioning

confidence: 99%

In vitro Activity of LY281389 and Comparison with Erythromycin and Oral Beta-Lactams

Qadri¹,

Ueno²,

Frayha³

1991

Chemotherapy

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“…The earliest of these modifications was roxithromycin, selected as the candidate with the best therapeutic index from a new series of oxime derivatives synthesized at Roussel-Uclaf (J. F. Chantot Erythromycylamine is an older derivative of erythromycin, formally the result of reductive amination of the C-9 ketone; however, both it and its N-benzylidene derivative gave extremely low levels in blood when administered orally to humans (53). Dirithromycin, a new oxazine formed from erythromycylamine and (2-methoxyethoxy)acetaldehyde, was selected by Boehringer-Ingelheim on the basis of high levels in tissues (52).…”

mentioning

confidence: 99%

New directions for macrolide antibiotics: structural modifications and in vitro activity

Kirst

Sides

1989

Antimicrob Agents Chemother

152

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“…3). However, these compounds failed to increase concentrations of antibiotic in serum after oral administration to humans (23).…”

Section: Resultsmentioning

confidence: 98%

Synthesis and antimicrobial evaluation of dirithromycin (AS-E 136; LY237216), a new macrolide antibiotic derived from erythromycin

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Ensminger

Preston

et al. 1991

Antimicrob Agents Chemother

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Dirithromycin is a 9-N-ll-O-oxazine derivative which is formed by condensation of 9(S)-erythromycylamine with 2-(2-methoxyethoxy)acetaldehyde. Dirithromycin is hydrolyzed, either under acidic conditions or in vivo, to its major active metabolite, 9(S)-erythromycylamine. The antimicrobial spectrum of dirithromycin is similar to that of erythromycin; both antibiotics are active against gram-positive bacteria, Legionella spp., Helicobacter pylori, and Chlamydia trachomatis. Comparable results were obtained for each antibiotic in MIC and MBC determinations and in the potential development of resistance in vitro. The effects of human serum, bacterial growth media, test methodology, and inoculum size on MICs were similar for each antibiotic. In standard mouse protection studies, dirithromycin was more efficacious than erythromycin against experimental infections after subcutaneous administration of antibiotic. These results were consistent with pharmacokinetic studies in rodents, which showed that dirithromycin gave more persistent concentrations of antibiotic in serum and tissues than were achieved with erythromycin. These studies indicate that dirithromycin possesses antimicrobial activity comparable to that of erythromycin in vitro but is more active than erythromycin in vivo, which may be attributable to the persistence of antimicrobial activity in the tissue(s) of the test animals.Erythromycin is an important antimicrobial agent whose role in chemotherapy is well established. It has now assumed even greater importance because of its activity against such increasingly prevalent pathogens as Legionella, Helicobacter (formerly Campylobacter), Mycoplasma, and Chlamydia species (5,25,35). During the past decade, substantial efforts have been devoted to structural modifications of erythromycin in order to improve upon its biological properties (10, 18). Dirithromycin ( Fig. 1) is a novel derivative of erythromycin which was initially discovered at Karl Thomae GmbH (22). Although its spectrum of antimicrobial activity is similar to that of erythromycin, dirithromycin exhibits higher and more prolonged concentrations in tissues than does erythromycin (6). This report describes our initial results of the synthesis and antimicrobial evaluation of dirithromycin.(These results were presented in part at the 28th Interscience Conference on Antimicrobial Agents and Chemotherapy, Los Angeles, Calif., 23 to 26 October 1988 [7a, 7b].) MATERIALS AND METHODS Synthesis of dirithromycin. 9(S)-Erythromycylamine (Fig. 2, compound 7) (18.5 g, 25.2 mmol) and 2-(2-methoxyethoxy) acetaldehyde (Fig. 2, compound 4) (4.4 g, 37 mmol) were dissolved in acetonitrile (55 ml). The reaction mixture was stirred for 18 h and cooled to 0 to 5°C. The solid was filtered, washed with cold acetonitrile, and dried to yield 16.6 g (79%) of dirithromycin (Fig. 2, compound 8). Dirithromycin was recrystallized from ethanol-water by dissolving it (3.0 g) in ethanol (12 ml) at 30°C and slowly adding water (28 ml). The mixture was cooled, and the solid was filter...

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Antibacterial activity of 9(S)-erythromycylamine-aldehyde condensation products

Cited by 44 publications

References 3 publications

In vitro Activity of LY281389 and Comparison with Erythromycin and Oral Beta-Lactams

In vitro Activity of LY281389 and Comparison with Erythromycin and Oral Beta-Lactams

New directions for macrolide antibiotics: structural modifications and in vitro activity

Synthesis and antimicrobial evaluation of dirithromycin (AS-E 136; LY237216), a new macrolide antibiotic derived from erythromycin

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