Synthesis and antibacterial activity of O-methylazithromycin derivatives.

Kobrehel, Gabrijela; Lazarevski, Gorjana; Ðokić, Slobodan; Kolacny-Babic, Lidija; Kucisec-Tepes, N; Cvrue, M.

doi:10.7164/antibiotics.45.527

Cited by 20 publications

(7 citation statements)

References 15 publications

(1 reference statement)

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“…It was shown that 9a-and 8a-azalide undergo facile methylation of the 12-hydroxyl group, while methylation of the 6-hydroxyl group was not observed, whereas following methylation of the 11-hydroxyl group, 6-OH is the first to be methylated. The difficulty of methylating the 6-OH group is controversial, with data already published by Kobrehel et al [39].…”

Section: New Azalide Derivativesmentioning

confidence: 96%

New research in macrolides and ketolides since 1997

Bryskier¹

1999

Expert Opinion on Investigational Drugs

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Macrolide and ketolide antibacterials remain a very dynamically active group. To overcome erythromycin A resistance within Gram-positive cocci and bacteria, novel compounds have been semi-synthesised, such as ketolides and C-4'' carbamate erythromycylamine derivatives. The continual efforts of those studying macrolides have led to molecular level investigations into the mechanism of action of these antibacterials. Among all novel derivatives, only telithromycin and AB-773 are currently under development. No real novel developments have been seen with the 15- and 16-membered ring macrolides, however, research is also continuing in this area. This review is an update of our knowledge in the field of macrolides.

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Section: New Azalide Derivativesmentioning

confidence: 96%

New research in macrolides and ketolides since 1997

Bryskier¹

1999

Expert Opinion on Investigational Drugs

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“…The methylation of the 2',4"-protected azalide 180 was investigated first by Kobrehel et al [64] and more recently by Waddell et al [65]. respectively (Scheme 35).…”

Section: -Hydroxyl [62]mentioning

confidence: 98%

Highlights of Semi-synthetic Developments from Erythromycin A

Wu¹

2000

CPD

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Earlier semi-synthetic studies of erythromycin A culminated in the discovery of two successful second generation macrolide antibiotics, azithromycin and clarithromycin, for the treatment of community-acquired bacterial infections. More recent structural modifications of erythromycin A have resulted in the discovery of novel ketolide antibiotics and new motilide prokinetic agents. This review is an account of the semi-synthetic developments from erythromycin A by chemical transformations.

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“…The structure of 12-O-methyl derivative 30a was first described as 6-O-methyl azithromycin [53]. This error was corrected later by a publication from Merck [54] and confirmed by PLIVA using X-ray structural analysis of the trimethylated compound 30d [55].…”

Section: O-substitutedmentioning

confidence: 99%

“…The first efforts were focused on the synthesis of the 6-O-methyl derivative of 8, similar to the synthesis of clarithromycin. Using benzyloxycarbonyl chloride in the presence of sodium bicarbonate, 8 was protected at the 2Ј-O-and 3Ј-Npositions to yield the di-benzyloxycarbonyl derivative 27, which was methylated with methyl iodide and sodium hydride in DMSO-THF or DMF [53]. Unfortunately, only mixtures of 11-O-and 12-O-methyl derivatives with small amounts of di-or tri-methylated products (28) were generated (Scheme 8).…”

Section: O-substitutedmentioning

confidence: 99%

“…When O-methyl derivatives of azithromycin were synthesized [53], using a benzoyloxycarbonyl group for protection, the 3Ј-N-demethyl derivative 29 was obtained, which, after removing protecting groups, had to be remethylated with formaldehyde and formic acid. 3Ј-N-Demethylazithromycin is known as one of the impurities in 8 synthesis.…”

Section: Substitution On C-3 Positionmentioning

confidence: 99%

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Azalides from Azithromycin to New Azalide Derivatives

Mutak

2007

J Antibiot

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Azalides are semi-synthetic macrolides, in which a nitrogen atom is introduced into a macrolactone ring via a Beckmann rearrangement. Starting from erythromycin, oximes, depending on the reaction conditions lactams, or bicyclic-imino-ethers were formed, which were further reduced to aminolactones. The cyclic amine 9a-became the precursor for novel, significantly more active derivatives, especially for 9-dihydro-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A with the generic name azithromycin. It showed a broad spectrum of antibacterial activity covering all significant bacteria causing respiratory tract infections. The greatest advantages of azithromycin are its unusual pharmacokinetics (high tissue distribution), metabolic stability and high tolerability. These properties have led in recent years to the widespread use of the azalide scaffold for the synthesis of new compounds with advantageous pharmacokinetics.The azalide scaffold possesses an amino and several hydroxyl groups, which could be substituted or transformed to obtain new compounds. Different derivatives were obtained by substitution on the nitrogen but a large variety of derivatives, such as ethers, esters and carbamates, were made by reactions with various hydroxyl groups. Substitutions on both nitrogen and hydroxyl or two hydroxyl groups yielded new, bridged compounds. The 4Љ-hydroxy group was oxidized to 4-oxo-, which was transformed via the oxime to 4-amino, or via epoxide to 4Љ-methylamino compounds. Cleavage of the cladinose sugar and further transformations gave 3-acyl or 3-oxo compounds, which were less active than 14-membered acylides or ketolides. Beckmann rearrangement of some 16-membered macrolide oximes yielded only 17-membered lactams, which were less active than starting macrolides, and could not be reduced to amines.Intramolecular rearrangement of azalide imino-ethers yielded 13-membered azalides. Some new 11a-azalides were obtained after oxidative cleavage of some 16-membered macrolides and additional cyclisation.

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Synthesis and antibacterial activity of O-methylazithromycin derivatives.

Cited by 20 publications

References 15 publications

New research in macrolides and ketolides since 1997

New research in macrolides and ketolides since 1997

Highlights of Semi-synthetic Developments from Erythromycin A

Azalides from Azithromycin to New Azalide Derivatives

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