Modeling and Spectroscopic Studies of Synthetic Diazabicyclo Analogs of the HIV-1 Inhibitor BMS-378806 and Evaluation of Their Antiviral Activity

• Published in: European Journal of Organic Chemistry 2011-01, Vol.2011 (2), p.287-294
• Main Authors: Legnani, Laura, Colombo, Diego, Cocchi, Elena, Solano, Lucrezia, Villa, Stefania, Lopalco, Lucia, Asti, Valeria, Diomede, Lorenzo, Marinone Albini, Franca, Toma, Lucio
• Format: Article
• Language: English
• Subjects: Antiviral agents; Chemistry; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Inhibitors; Molecular modeling; NMR spectroscopy; Organic chemistry; Preparations and properties
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201001073

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.