Journal of Computer-Aided Molecular Design

, Volume 18, Issue 1, pp 1–11

Theoretical study of selective methylation in the synthesis of azithromycin

Article

DOI: 10.1023/B:JCAM.0000022560.75389.c5

Cite this article as:
Duran, D., Aviyente, V. & Baysal, C. J Comput Aided Mol Des (2004) 18: 1. doi:10.1023/B:JCAM.0000022560.75389.c5
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Abstract

Azithromycin is a 15-membered macrolide antibiotic which is active in vitro against clinically important gram-negative bacteria. In this study, the selectivity of the methylation mechanism was analyzed computationally on the 2′-OCbz-3′-NMeCbz derivative of azithromycin in vacuum and in DMF. We have shown that the methylation of the hydroxy group on C-6 is energetically unfavorable compared to the other hydroxy groups in vacuum; the softness values further showed that the C-6 anion is not reactive towards CH3I in the methylation mechanism. To understand the effect of the solvent on the methylation process, detailed molecular dynamics simulations were performed in DMF using the anions at the C-4′′, C-6, C-11 and C-12 positions. We find the conformations of the anions not to be affected by the presence of the solvent. The radial distribution functions of the solvent molecules around the O of the anions demonstrate that DMF molecules cluster around the C-6 anion. The relative strength of the anion–solvent interactions reveal that the solvent molecules provide the largest stabilization to the C-6 anion and prevent the methylation at this position. The latter descriptor was found to be an important factor in explaining the experimentally observed selectivity towards the methylation of the C-4′′, C-6, C-11 and C-12 anions.

azalide antibioticsconformational analysismethylationmolecular dynamicssolvent effect

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  1. 1.Chemistry Department, Faculty of Art and SciencesBogaziçi UniversityBebek, IstanbulTurkey
  2. 2.Laboratory of Computational Biology, Faculty of Engineering and Natural SciencesSabanci University, OrhanliTuzla, IstanbulTurkey