2,2'-Dithiobisbenzamides and 2-benzisothiazolones, two new classes of antiretroviral agents: SAR and mechanistic considerations.
Substituted 2,2'-dithiobisbenzamides and 2-benzisothiazolones were prepared and shown to possess low microM activity with high therapeutic indices against HIV-1, HIV-2 and SIV in cell culture. The mechanism of antiviral action was determined to be directed toward the nucleocapsid protein (NCp7), which contains two zinc fingers and plays vital roles in the viral life cycle. The "active sulfides" of this study cause the extrusion of zinc from these zinc fingers. Structure-activity relationships of the 2,2'-dithiobisbenzamides reveal that the disulfide bond and the ortho benzamide functional groups are essential for activity, with the best compounds having a carboxylic acid, carboxamide, or sulfonamide substituent. The 2-benzisothiazolones are formed from the disulfides both chemically and in vivo and their SAR mimics that of the 2,2'-dithiobisbenzamides. The antiviral activity of the disulfides may require cyclization to the isothiazolones. Two agents, PD 159206 and PD 161374, which showed good antiviral activity, physical properties, and excellent pharmacokinetics in mice, were selected for advanced studies.
Domagala
J M
JM
Department of Chemistry, Parke Davis Pharmaceutical Research, Division of Warner Lambert Company, Ann Arbor, Michigan 48105, USA.
Gogliotti
R
R
Sanchez
J P
JP
Stier
M A
MA
Musa
K
K
Song
Y
Y
Loo
J
J
Reily
M
M
Tummino
P
P
Harvey
P
P
Hupe
D
D
Sharmeen
L
L
Mack
D
D
Scholten
J
J
Saunders
J
J
McQuade
T
T
D000478:Alkylation; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D002460:Cell Line; D004220:Disulfides / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D051379:Mice; D019590:Nucleocapsid Proteins / Q000187:drug effects; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D013854:Thioamides / Q000737:chemistry / Q000494:pharmacology
D019380:Anti-HIV Agents; D001549:Benzamides; D004220:Disulfides; D019590:Nucleocapsid Proteins; D013844:Thiazoles; D013854:Thioamides; C015539:thiobenzamide