Gabrijela Kobrehel

Erythromycin series. Part 11. Ring expansion of erythromycin A oxime by the Beckmann rearrangement

The synthesis of 10-dihydro-10-deoxo-11-azaerythromycin A (11) by the Beckmann rearrangement of erythromycin A oxime (2) and reduction of the imino ether so obtained (5) is described. The structure elucidation of the new ring-expanded semisynthetic erythromycins (5) and (11) has been established on the basis of their analytical and spectral data and acid-catalysed degradation into the aglycones (7) and (13), respectively. Finally, the complete structure of ring-expanded erythronolides (7) and (13) has been determined by X-ray crystallography.

Conformational analysis of azithromycin by nuclear magnetic resonance spectroscopy and molecular modelling

Abstract The conformation of azithromycin 1 in the solution was determined by NMR spectroscopy and molecular mechanics calculations and compared with its crystal structure and with some erythromycin derivatives. In solution 1 exists predominantly in a “folded-in” conformation in the C-3 to C-5 region, whereas its crystal state conformation is “folded-out”.

Synthesis and Antibacterial Activity of Isomeric 15-Membered Azalides

A series of 3-keto and 3-O-acyl derivatives of both 6-O-alkyl-8a-aza-8a-homoerythromycin A and 6-O-alkyl-9a-aza-9a-homo-erythromycin A were synthesised and tested against Gram-positive and Gram-negative bacteria. Derivatives of 8a-aza-8a-homoerythromycin A have potent antibacterial activity against not only azithromycin-susceptible strains, but also efflux (M) and inducible macrolide-lincosamide-streptogramin (iMLSB) resistant Gram-positive pathogens, while the corresponding 9a-isomers were less active. Introduction of an additional ring such as 11,12-cyclic carbonate reduced antibacterial activity of both series. 3-Keto and 3-O-(4-nitrophenyl)acetyl derivatives of 6-O-methyl-8a-aza-8a-homo-erythromycin A show typical macrolide pharmacokinetics in preliminary in vivo studies in mice, and their in vivo efficacy is demonstrated.

Conformational analysis of 9-deoxo-9a-aza-9a- and 9-deoxo-8a-aza-8a-homoerythromycin A 6,9-cyclic iminoethers

Abstract The conformation of 9a- 4 and 8a- 5 bicyclic iminoethers, the key synthetic intermediates of 15-membered AZALIDES was determined. The 2D NMR data and molecular modeling techniques were used to establish the predominant solution-state conformation. Conformational analysis suggests that in reduction of the iminoethers the smaller ring in both bicyclic compounds, as well as steric effects around the imidate group are reactivity-determined factors. The invariance in coupling constants indicates that 4 and 5 do not change conformation, when they go from a polar to a hydrophobic environment.