Issue 9, 2005

Modification and structure–activity relationship of a small molecule HIV-1 inhibitor targeting the viral envelope glycoprotein gp120

Abstract

This paper describes selected modification and structure–activity relationship of the small molecule HIV-1 inhibitor, 4-benzoyl-1-[(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)oxoacetyl]-2-(R)-methylpiperazine (BMS-378806). The results revealed: i) that both the presence and configuration (R vs. S) of the 3-methyl group on the piperazine moiety are important for the antiviral activity, with the 3-(R)-methyl derivatives showing the highest activity; ii) that the electronegativity of the C-4 substituent on the indole or azaindole ring seems to be important for the activity, with a small, electron-donating group such as a fluoro or a methoxy group showing enhanced activity, while a nitro group diminishes the activity; iii) that the N-1 position of the indole ring is not eligible for modification without losing activity; and iv) that bulky groups around the C-4 position of the indole or azaindole ring diminish the activity, probably due to steric hindrance in the binding. We found that a synthetic bivalent compound with two BMS-378806 moieties being tethered by a spacer demonstrated about 5-fold enhanced activity in an nM range against HIV-1 infection than the corresponding monomeric inhibitor. But the polyacrylamide-based polyvalent compounds did not show inhibitory activity at up to 200 nM.

Graphical abstract: Modification and structure–activity relationship of a small molecule HIV-1 inhibitor targeting the viral envelope glycoprotein gp120

Article information

Article type
Paper
Submitted
01 Oct 2004
Accepted
29 Mar 2005
First published
12 Apr 2005

Org. Biomol. Chem., 2005,3, 1781-1786

Modification and structure–activity relationship of a small molecule HIV-1 inhibitor targeting the viral envelope glycoprotein gp120

J. Wang, N. Le, A. Heredia, H. Song, R. Redfield and L. Wang, Org. Biomol. Chem., 2005, 3, 1781 DOI: 10.1039/B415159C

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