Investigation of the energy barrier to the rotation of amide CN bonds in ACE inhibitors by NMR, dynamic HPLC and DFT

• Published in: Journal of pharmaceutical and biomedical analysis Vol. 128; pp. 416 - 425
• Main Authors: Bouabdallah, S., Ben Dhia, M.T., Driss, M.R., Touil, S.
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 05.09.2016
• Subjects: ACE; Amides - chemistry; Angiotensin-Converting Enzyme Inhibitors - chemistry; Chromatography, High Pressure Liquid; DFT; Dynamic chromatography; Enalapril - chemistry; Enalaprilat - chemistry; Isomerism; Isomerization; Lisinopril - chemistry; Magnetic Resonance Spectroscopy; Models, Statistical; NMR; Perindopril - chemistry; Thermodynamics; Dynamic chromatography; NMR; ACE; DFT; Isomerization
• ISSN: 0731-7085; 1873-264X
• DOI: 10.1016/j.jpba.2016.05.049

•The isomerizations of Enalapril, Peindopril, Enalaprilate and Lisinopril have been investigated using NMR spectroscopic, dynamic chromatographic, unified equation and theoretical calculations.•Study of the equilibrium using HPLC, 13C RMN spectra, 1H RMN spectra and NOE DIFF.•Compare the experimental data and theoretical result.•Propose the correlation between the structure and the activity of ACE. The isomerizations of Enalapril, Perindopril, Enalaprilat and Lisinopril have been investigated using NMR spectroscopic, dynamic chromatographic, unified equation and DFT theoretical calculations. The thermodynamic parameters (ΔH, ΔS and ΔG) were determined by varying the temperature in the NMR experiments. At the coalescence temperature, we can evaluate the isomerization barrier to the rotation (ΔG≠) around the amide bond. Using dynamics chromatography and an unified equation introduced by Trap, we can determine isomerization rate constants and Gibbs activation energies. Molecular mechanics calculations also provided evidence for the presence of low energy conformers for the ACE due to restricted amide rotation. With the value of barriers (ΔE) between them of the order of (20kJmol−1), which is in agreement with the dynamic NMR results and DFT calculations.