Examination of halogen substituent effects on HIV-1 integrase inhibitors derived from 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-ones and 4,5-dihydroxy-1H-isoindole-1,3(2H)-diones.
Using 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one and 4,5-dihydroxy-1H-isoindole-1,3(2H)-dione based HIV-1 integrase inhibitors as display platforms, we undertook a thorough examination of the effects of modifying the halogen substituents on a key benzyl ring that is hypothesized to bind in a hydrophobic pocket of the integrase.DNA complex. Data from this study suggest that in general dihalo-substituted analogues have higher potency than monohalo-substituted compounds, but that further addition of halogens is not beneficial.
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, MD 21702, United States.
Xue Zhi
XZ
Zhao
Kasthuraiah
K
Maddali
B Christie
BC
Vu
Christophe
C
Marchand
Stephen H
SH
Hughes
Yves
Y
Pommier
Terrence R
TR
Burke
D002478:Cells, Cultured; D019427:HIV Integrase / Q000737:chemistry / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006219:Halogens / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D054833:Isoindoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D019428:HIV Integrase Inhibitors; D006219:Halogens; D054833:Isoindoles; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1