Modeling and spectroscopic studies of synthetic diazabicyclo analogs of the HIV-1 inhibitor BMS-378806 and evaluation of their antiviral activity

Laura Legnani, Diego Colombo, Elena Cocchi, Lucrezia Solano, Stefania Villa, Lucia Lopalco, Valeria Asti, Lorenzo Diomede, Franca Marinone Albini, Lucio Toma

Research output: Contribution to journalArticlepeer-review

Abstract

Three diazabicyclo analogs of BMS-378806, in which theaxial methyl group present on its piperazine ring is replaced by a carbon bridge, were synthesized and tested, through a viral neutralization assay, on a panel of six pseudoviruses. The diazabicyclooctane and-nonane derivatives maintained a significant infectivity reduction power, whereas the diazabicycloheptane derivative was much less effective. A modeling study allowed to relate the antiviral activity to the conformational preferences of the compounds. Moreover, similarly to BMS-378806, theoretical calculations predict the existence of different conformational families corresponding to the possible arrangements at the two planar amido functions of the compounds. High-field 1H NMR spectra confirm these results, as they show two distinct series of signals. A viral neutralization assay on a panel of six HIV-related pseudoviruses allowed the determination of the antiviral activity of three diazabicyclo analogs of BMS-378806, in which the axial methyl group on its piperazine ring is replaced by a carbon bridge. The diazabicyclooctane and-nonane derivatives show a significant infectivity reduction power that is related to their conformational preference.

Original languageEnglish
Pages (from-to)287-294
Number of pages8
JournalEuropean Journal of Organic Chemistry
Issue number2
DOIs
Publication statusPublished - Jan 2011

Keywords

  • Antiviral agents
  • Inhibitors
  • Molecular modeling
  • NMR spectroscopy

ASJC Scopus subject areas

  • Organic Chemistry
  • Physical and Theoretical Chemistry

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