Conformational evaluation of fusidic acid derivatives by 750 MHz 1H NMR and VCD

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Abstract

Fusidic acid (1a) is a commercial antibiotic widely used in therapy for methicillin-resistant Staphylococcus aureus infections. Although the history of spectroscopic and conformational characteristics of 1a is long and old, the complete 1H NMR parameters set assignment remains incomplete due to the large signal superposition in most conventionally used NMR spectrometers. Thus, in the present study the 750 MHz 1H NMR spectra of the two methyl acetylfusidates 1b and 1c were completely assigned by means of total-line-shape-fitting calculations using the PERCH iterative spectra analysis. The task was facilitated taking advantage of the data for 3β-acetoxypregna-Δ5,16‑dien-20-one and cholesteryl benzoate, thereby allowing to obtain excellent correlations between experimental vicinal coupling constants with values calculated by the Altona program. It turned out that the vicinal coupling constant values were not compatible with the published boat conformation of B-ring. Thus, a vibrational circular dichroism study of 1b and 1c, using density functional theory calculated spectra to compare with experimental spectra, revealed that ring B in these trans-syn-trans 29-nor-protostane triterpenoids exists in equilibrium between two twisted boat conformers. This is very useful for future docking calculations to test the antibiotic in front of proteins to find further specific pharmacological applications.

Original languageEnglish
Article number130578
JournalJournal of Molecular Structure
Volume1240
DOIs
StatePublished - 15 Sep 2021

Keywords

  • 750 1H NMR
  • Fusidic acid
  • Iterative 1H NMR analysis
  • PERCH spin–spin simulation
  • Vibrational circular dichroism

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