Conformational study of fosinopril sodium in solution using NMR and molecular modeling

Abstract

Two conformers of fosinopril sodium in methanol were unambiguously established using 2D NMR methods and variable-temperature NMR experiments. Differences in their conformational structure were shown to be related to the rotational energy barrier about the amide bond and hydrophobic interaction. The relationship between the 3D structure and activity is discussed. It is suggested that the trans-conformer may be more biologically active owing to its stacking structure and strong hydrophobic interaction and the cis-conformer could be more easily hydrolyzed because of its extended structure.

Conformational Analysis of R207910, a New Drug Candidate for the Treatment of Tuberculosis, by a Combined NMR and Molecular Modeling Approach

“…Although its conformation cannot be perfectly accounted for neither by the NMR data, which 'sees' an average conformation, nor by the conformational analysis, which omits some thermodynamic factors, the small distance deviations indicate that the model represents faithfully the most stable conformation of A1 in solution. The distances of 4.64 and 4.45 found by molecular modeling between protons Ph(o) and Ha¢, and between protons A and E, respectively, are too large to generate visible correlation peaks in the ROESY spectra and are in agreement with the absence of correlation peaks for these protons (13). Taken together, the above results confirm that compound R207910 (A1) belongs to the (RS, SR) couple of diastereoisomers as suggested by the qualitative spectra analysis.…”

“…The present study refers to experiments made in CDCl 3 , the solvent that showed a better signal separation. All NMR experiments were carried out by using a Bruker Avance DRX 400 spectrometer (Bruker, Wissembourg, France) equipped with a reverse double-resonance ( 1 H, 13 C, SEI) probe head with z-gradients and operating at 400 MHz for proton and 100 MHz for carbon. The 1D and 2D NMR spectra were obtained at temperature of 298 K. The complete assignment of all protons and carbons was underwent by 2D experiments: COSY ( 1 H-1 H; 9), HMQC ( 1 H, 13 C; 10), and HMBC ( 1 H, 13 C; 11), all performed with gradients into Icon-NMR and with automatic calculation of spectral width.…”

“…Additional ab initio calculation was performed with emphasis on the strength of the observed intramolecular hydrogen bond. Simultaneously, a complete structural identification has been carried out by a set of monodimensional and bidimensional 1 H- 13 C-NMR experiments. Determination of inter-proton distances has been achieved by a series of 1 H-1 H ROESY NMR experiments with different mixing times followed by a volume quantification of the correlations peaks.…”

Determination of the Three-dimensional Structure of Gynoside A in Solution using NMR and Molecular Modeling

“…The quaternary carbon atoms were identified by HMBC. The assignments of 1 H-and 13 C-NMR resonances in the two solutions are listed in Table 1. …”

“…All NMR experiments were performed at 300K on a BRUKER AV400 spectrometer equipped with a 5 mm gradient inverse broadband probe. MD simulations [13][14][15][16][17] were carried out by weak coupling in a temperature bath with a relaxation time of 100fs. No cutoff distance was used for all possible interactions.…”