The conformations of the macrolide antibioticserythromycin A, azithromycin and clarithromycin in aqueous solution: a 1H NMR study

Abstract

The conformations of the macrolide antibiotics erythromycin A, clarithromycin and azithromycin in aqueous solution have been determined. All three drugs were found to exist predominantly in a “folded-out” conformation with the sugars in the chair–chair up–up form. In the case of clarithromycin this result is in agreement with the published literature; previous reports suggest that the erythromycin A sugars adopt boat conformations and that azithromycin has a significant folded-in contribution. The discrepancies are discussed in full. Erythromycin A 9-ketone was found to be flexible in the C6–C12 region. We present evidence for a new minor conformation (the 8-endo folded-out conformation) intermediate between the folded-out and folded-in conformations. Evidence for traces of other minor conformations is presented for erythromycin and azithromycin, whereas clarithromycin is conformationally very stable.