Optimization of a 1,5-dihydrobenzo[b][1,4] diazepine-2,4-dione series of HIV capsid assembly inhibitors 1: Addressing configurational instability through scaffold modification
Optimization of a 1,5-dihydrobenzo[b][1,4] diazepine-2,4-dione series of HIV capsid assembly inhibitors 1: Addressing configurational instability through scaffold modification
复制标题
DOI：
10.1016/j.bmcl.2013.03.073
复制
发表时间：
2013-06-01
影响因子：
2.7
通讯作者：
Simoneau, Bruno
中科院分区：
文献类型：
--
作者：
Fader, Lee D.;Landry, Serge;Simoneau, Bruno
描述了1,5-二氢苯并[b][1,4]二氮平-2,4-二酮系列HIV-1衣壳组装抑制剂的优化，该抑制剂在C3位置具有不稳定的立体中心。为了防止外消旋作用，化合物1的C3位进行季铵化反应得到了化合物2，该化合物在我们的衣壳分解实验中是无活性的。对这一发现的一个可能的解释是由硅分析揭示的，预测C3位置季铵化后生物活性构象的能量急剧增加。用氮原子取代二氮平环的C3得到1,5-二氢苯[f][1,3,5]-三氮平-2,4-二酮类似物4是耐受良好的。在C3位置引入刚性螺环体系，得到构型稳定的1,5-二氢苯并[b][1,4]二氮平-2,4-二酮类似物5，它能够在没有严重能量损失的情况下获得生物活性构象，并抑制衣壳组装。初步的构效关系（SAR）和x射线晶体学数据表明，1,5-二氢苯并[b][1,4]二氮平-2,4-二酮系列HIV-1衣壳组装抑制剂的知识可以转移到这些新的支架上。(C) 2013 Elsevier Ltd.版权所有。
The optimization of a 1,5-dihydrobenzo[b][1,4] diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly that possess a labile stereocenter at C3 is described. Quaternization of the C3 position of compound 1 in order to prevent racemization gave compound 2, which was inactive in our capsid disassembly assay. A likely explanation for this finding was revealed by in silico analysis predicting a dramatic increase in energy of the bioactive conformation upon quaternization of the C3 position. Replacement of the C3 of the diazepine ring with a nitrogen atom to give the 1,5-dihydro-benzo[f][1,3,5]-triazepine-2,4-dione analog 4 was well tolerated. Introduction of a rigid spirocyclic system at the C3 position gave configurationally stable 1,5-dihydrobenzo[b][1,4] diazepine-2,4-dione analog 5, which was able to access the bioactive conformation without a severe energetic penalty and inhibit capsid assembly. Preliminary structure-activity relationships (SAR) and X-ray crystallographic data show that knowledge from the 1,5-dihydrobenzo[ b][1,4] diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly can be transferred to these new scaffolds. (C) 2013 Elsevier Ltd. All rights reserved.