Evaluation of a non-prime site substituent and warheads combined with a decahydroisoquinolin scaffold as a SARS 3CL protease inhibitor
Evaluation of a non-prime site substituent and warheads combined with a decahydroisoquinolin scaffold as a SARS 3CL protease inhibitor
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DOI：
10.1016/j.bmc.2018.12.019
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发表时间：
2018-12
影响因子：
3.5
通讯作者：
K. Ohnishi;Y. Hattori;Kazuya Kobayashi;K. Akaji
中科院分区：
文献类型：
--
作者：
K. Ohnishi;Y. Hattori;Kazuya Kobayashi;K. Akaji
一种非主要位置的取代基和弹头与十氢异喹啉支架相结合，被评价为一种新型的严重急性呼吸综合征(SARS)胰凝乳素样蛋白酶(3CLpro)的抑制剂。十氢异喹啉支架被证明是与SARS 3CLpro的S2位点相互作用的有效疏水中心，但S3到S4位点缺乏相互作用被认为是具有中等抑制活性的主要原因。在这项研究中，评估了支架上额外的非黄金位置取代基的效果以及几种弹头的效果。为了引入所需的非主位取代基，在十氢异喹啉支架上引入了氨基官能团，并通过Pd(II)催化的非对映选择性环的形成来构建支架。合成的十氢异喹啉抑制剂与非主位取代基结合时，对SARS-3CLpro3的抑制活性约为2.4倍。目前的结果不仅表明了预期的与SARS 3CL蛋白的额外相互作用，而且还表明了含有稠环体系作为疏水支架的新抑制剂和新弹头(如硫代缩醛)的可能性。
A non-prime site substituent and warheads combined with a decahydroisoquinolin scaffold was evaluated as a novel inhibitor for severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CLpro). The decahydroisoquinolin scaffold has been demonstrated to be an effective hydrophobic center to interact with S2 site of SARS 3CLpro, but the lack of interactions at S3 to S4 site is thought to be a major reason for the moderate inhibitory activity. In this study, the effects of an additional non-prime site substituent on the scaffold as well as effects of several warheads are evaluated. For the introduction of a desired non-prime site substituent, amino functionality was introduced on the decahydroisoquinolin scaffold, and the scaffold was constructed by Pd(II) catalyzed diastereoselective ring formation. The synthesized decahydroisoquinolin inhibitors showed about 2.4 times potent inhibitory activities for SARS 3CLprowhen combined with a non-prime site substituent. The present results indicated not only the expected additional interactions with the SARS 3CLprobut also the possibility of new inhibitors containing a fused-ring system as a hydrophobic scaffold and a new warhead such as thioacetal.