Conformational analysis of major metabolites of macrolide antibiotics roxithromycin and erythromycin A with different biological properties by NMR spectroscopy and molecular dynamics

Abstract

The drugs roxithromycin 1 and erythromycin 2 differ in their ability to produce a hepatotoxic effect or drug interactions involving macrolide antibiotics. The major metabolite of 1, RU39001 (3) does not induce hepatic cytochrome P-450 while the metabolite of 2, erythralosamine (4) has greater interaction properties either in vitro or in vivo with the cytochrome P-450 system. A combination of NMR spectroscopy and molecular dynamics (MD) has shown that the conformations of 1 and 2, in CDCl₃ solution, undergo an interesting conformational reorganization. The movement of the macrocycle induces five different orientations of the desosamine sugar. The use of MD simulation has facilitated the identification of conformations of their major metabolites in solution as predicted by NMR spectroscopy. There is a significant proportion of an active conformation for 4 and a conformation which can be related to the inhibition of cytochrome P-450 for 3. These results also demonstrate the importance of the nature of hydrogen bonding for 1 and its metabolite 3 which may also explain some of the biological differences observed for 1 and 3 with respect to erythromycin 2 and its metabolite 4. Similarly, the ionization of the amino group favouring one inactive conformation could allow changes in the motion and in the reactivity of the desosamine unit.