Meanwell Nicholas A, Wallace Owen B, Fang Haiquan, Wang Henry, Deshpande Milind, Wang Tao, Yin Zhiwei, Zhang Zhongxing, Pearce Bradley C, James Jennifer, Yeung Kap-Sun, Qiu Zhilei, Kim Wright J J, Yang Zheng, Zadjura Lisa, Tweedie Donald L, Yeola Suresh, Zhao Fang, Ranadive Sunanda, Robinson Brett A, Gong Yi-Fei, Wang Hwei-Gene Heidi, Spicer Timothy P, Blair Wade S, Shi Pei-Yong, Colonno Richard J, Lin Pin-Fang
Department of Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
Bioorg Med Chem Lett. 2009 Apr 1;19(7):1977-81. doi: 10.1016/j.bmcl.2009.02.040. Epub 2009 Feb 13.
The effects of introducing simple halogen, alkyl, and alkoxy substituents to the 4, 5, 6 and 7 positions of 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione, an inhibitor of the interaction between HIV gp120 and host cell CD4 receptors, on activity in an HIV entry assay was examined. Small substituents at C-4 generally resulted in increased potency whilst substitution at C-7 was readily tolerated and uniformly produced more potent HIV entry inhibitors. Substituents deployed at C-6 and, particularly, C-5 generally produced a modest to marked weakening of potency compared to the prototype. Small alkyl substituents at N-1 exerted minimal effect on activity whilst increasing the size of the alkyl moiety led to progressively reduced inhibitory properties. These studies establish a basic understanding of the indole element of the HIV attachment inhibitor pharmacophore.
1-(4-苯甲酰基哌嗪-1-基)-2-(1H-吲哚-3-基)乙烷-1,2-二酮是一种HIV gp120与宿主细胞CD4受体相互作用的抑制剂，研究了在其4、5、6和7位引入简单卤素、烷基和烷氧基取代基对HIV进入试验活性的影响。C-4位的小取代基通常会导致活性增加，而C-7位的取代很容易被耐受，并且一致地产生更有效的HIV进入抑制剂。与原型相比，C-6位尤其是C-5位的取代基通常会使活性适度至显著减弱。N-1位的小烷基取代基对活性影响最小，而增加烷基部分的大小会导致抑制特性逐渐降低。这些研究建立了对HIV附着抑制剂药效团中吲哚元素的基本认识。
