Wang Jingsong, Le Nhut, Heredia Alonso, Song Haijing, Redfield Robert, Wang Lai-Xi
Institute of Human Virology, University of Maryland Biotechnology Institute, University of Maryland, 725 W. Lombard Street, Baltimore, MD 21201, USA.
Org Biomol Chem. 2005 May 7;3(9):1781-6. doi: 10.1039/b415159c. Epub 2005 Apr 12.
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.
本文描述了小分子HIV-1抑制剂4-苯甲酰基-1-[(4-甲氧基-1H-吡咯并[2,3-b]吡啶-3-基)氧代乙酰基]-2-(R)-甲基哌嗪（BMS-378806）的特定修饰及其构效关系。结果表明：i）哌嗪部分上3-甲基的存在和构型（R对S）对抗病毒活性均很重要，3-(R)-甲基衍生物显示出最高活性；ii）吲哚或氮杂吲哚环上C-4取代基的电负性似乎对活性很重要，小的供电子基团如氟或甲氧基显示出增强的活性，而硝基则降低活性；iii）吲哚环的N-1位在不失活的情况下不适合修饰；iv）吲哚或氮杂吲哚环C-4位周围的庞大基团会降低活性，这可能是由于结合时的空间位阻。我们发现，一种由间隔基连接两个BMS-378806部分的合成二价化合物在纳摩尔范围内对HIV-1感染的活性比相应的单体抑制剂提高了约5倍。但基于聚丙烯酰胺的多价化合物在高达200 nM时未显示出抑制活性。
