title: 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.
authors.affiliation: Institute of Human Virology, University of Maryland Biotechnology Institute, University of Maryland, 725 W. Lombard Street, Baltimore, MD 21201, USA.
authors.forename: Jingsong
authors.initials: J
authors.lastname: Wang
authors.forename: Nhut
authors.initials: N
authors.lastname: Le
authors.forename: Alonso
authors.initials: A
authors.lastname: Heredia
authors.forename: Haijing
authors.initials: H
authors.lastname: Song
authors.forename: Robert
authors.initials: R
authors.lastname: Redfield
authors.forename: Lai-Xi
authors.initials: LX
authors.lastname: Wang
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D018360:Crystallography, X-Ray; D015699:HIV Envelope Protein gp120 / Q000187:drug effects*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D015699:HIV Envelope Protein gp120