6,7-Dihydroxyisoindolin-1-one and 7,8-Dihydroxy-3,4-Dihydroisoquinolin- 1(2H)-one Based HIV-1 Integrase Inhibitors.
Integrase (IN) is an essential viral enzyme required for HIV-1 replication, which has been targeted by anti-AIDS therapeutics. Integrase strand transfer inhibitors (INSTIs) represent a new class of antiretroviral agents developed for the treatment of HIV-1 infections. Important structural features that are shared by many INSTIs include a coplanar arrangement of three heteroatoms that chelate two catalytic Mg(2+) ions in the IN active site and a linked halophenyl ring that binds in the hydrophobic pocket formed by the complex of IN with viral DNA. We recently reported bicyclic 6,7-dihydroxyoxoisoindolin-1-one-based IN inhibitors. In the current study, we modified these inhibitors in three ways. First, we increased the spacer length between the metalchelating triad and the halophenyl group. Second, we replaced the indoline [5,6] bicycle with a fused dihydroxyisoquinolinones [6,6] ring system. Finally, we prepared bis-6,7-dihydroxyisoindolin-1-one-4-sulfonamides as dimeric HIV-1 IN inhibitors. These new analogues showed low micromolar inhibitory potency in in vitro HIV-1 integrase assays.
Chemical Biology Laboratory, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD 21702, USA. xuezhi.zhao@nih.gov.
Xue Zhi
XZ
Zhao
Mathieu
M
Metifiot
Steven J
SJ
Smith
Kasthuraiah
K
Maddali
Christophe
C
Marchand
Stephen H
SH
Hughes
Yves
Y
Pommier
Terrence R
TR
Burke
D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D054833:Isoindoles / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
C000609192:6,7-dihydroxyisoindolin-1-one; C000609193:7,8-dihydroxy-3,4-dihydroisoquinolin-1(2H)-one; D019428:HIV Integrase Inhibitors; D054833:Isoindoles; D019427:HIV Integrase