Complete Characterization of the 3D Properties of the CCR5 Antagonist Vicriviroc through DFT Calculations, NMR Spectroscopy, and X-ray Analysis
Articolo
Data di Pubblicazione:
2012
Citazione:
Complete Characterization of the 3D Properties of the CCR5 Antagonist Vicriviroc through DFT Calculations, NMR Spectroscopy, and X-ray Analysis / L. Legnani, D. Colombo, S. Villa, F. Meneghetti, C. Castellano, A. Gelain, F. M. Albini, L. Toma. - In: EUROPEAN JOURNAL OF ORGANIC CHEMISTRY. - ISSN 1434-193X. - :26(2012), pp. 5069-5074. [10.1002/ejoc.201200586]
Abstract:
Vicriviroc is a piperazine-based CCR5 receptor antagonist, with better
oral availability, potency, safety, and pharmacological properties than
those of its precursor SCH-C, but whose development has been stopped. A
full evaluation of the 3D properties of vicriviroc was carried out in
order to achieve a complete knowledge of its conformational behavior
and, consequently, to identify the parameters necessary to design new,
possibly better, analogs. The theoretical study was performed at the
B3LYP/6-31G(d) level of calculations. Particular attention was focused
on the arrangement at the planar amido function and the conformational
preferences of the piperazine and piperidine rings. Several
conformational families, characterized by different through-space
contacts and comparable energy values, were located and confirmed by
high-field NMR spectroscopy. Two distinct series of signals, originating
from the barrier to rotation of the amido function, were observed in the
NMR spectrum. Moreover, a NOESY experiment provided evidence for all the
close contacts present assuring the coexistence, in solution, of
numerous conformations in equilibrium, characterized by different chair
geometries of the heterocyclic rings.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Antiviral agents; Density functional calculations; Nitrogen heterocycles; NMR spectroscopy; X-ray diffraction
Elenco autori:
L. Legnani, D. Colombo, S. Villa, F. Meneghetti, C. Castellano, A. Gelain, F.M. Albini, L. Toma
Link alla scheda completa: