Li Xingnan, Vince Robert
Department of Medicinal Chemistry, College of Pharmacy, and Center for Drug Design, Academic Health Center, University of Minnesota, 8-123A WDH, 308 Harvard Street SE, Minneapolis, MN 55455, USA.
Bioorg Med Chem. 2006 May 1;14(9):2942-55. doi: 10.1016/j.bmc.2005.12.013. Epub 2006 Jan 4.
Since alpha,gamma-diketo acid (DKA) compounds were identified as potent and selective inhibitors for HIV integrase, numerous structural modification studies have been carried out to search for a clinical candidate as a supplement for the highly active antiretroviral therapy regimen. Due to the lack of structural information on inhibitor-integrase interactions, a comprehensive structure-activity relationship study is necessary. Most of the reported modification studies on the key alpha,gamma-diketo acid pharmacophore focused on substituting the carboxylate moiety with its bioisosteres or other electron-pair bearing heterocycles. We were interested in studying the conformation and geometry of the central diketo moiety. A series of carbazolone-containing alpha,gamma-diketo acids were designed and synthesized by applying conformational restraint onto the open-chain form of the diketo acid. These compounds showed anti-integrase activity in the low micromolar range, and integrase assay results indicated that the geometry of the diketo acid moiety is crucial to potency. Carbazol-1-one containing DKA analogs (7-8) showed a 2- to 3-fold increase in activity compared with those of carbazol-4-one containing DKA analogs (5 and 6). Alkylation of carbazol-4-one DKA nitrogen (6a-c) led to a loss of activity, suggesting this nitrogen atom may directly interact with the active site of integrase. The halogens (7b-d) and para-fluorobenzyl substituents (8a-d) on carbazol-1-one ring had little effect on potency.
自从α,γ-二酮酸（DKA）化合物被鉴定为HIV整合酶的强效和选择性抑制剂以来，已经开展了大量的结构修饰研究，以寻找一种临床候选药物作为高效抗逆转录病毒治疗方案的补充。由于缺乏抑制剂与整合酶相互作用的结构信息，因此有必要进行全面的构效关系研究。大多数已报道的关于关键α,γ-二酮酸药效团的修饰研究都集中在用其生物电子等排体或其他含电子对的杂环取代羧酸根基团。我们对研究中心二酮部分的构象和几何形状感兴趣。通过对二酮酸的开链形式施加构象限制，设计并合成了一系列含咔唑酮的α,γ-二酮酸。这些化合物在低微摩尔范围内显示出抗整合酶活性，整合酶测定结果表明二酮酸部分的几何形状对活性至关重要。与含咔唑-4-酮的DKA类似物（5和6）相比，含咔唑-1-酮的DKA类似物（7-8）的活性提高了2至3倍。咔唑-4-酮DKA氮原子的烷基化（6a-c）导致活性丧失，这表明该氮原子可能直接与整合酶的活性位点相互作用。咔唑-1-酮环上的卤素（7b-d）和对氟苄基取代基（8a-d）对活性影响很小。
