Design and Synthesis of Potent HIV-1 Protease Inhibitors Containing Bicyclic Oxazolidinone Scaffold as the P2 Ligands: Structure-Activity Studies and Biological and X-ray Structural Studies.
Design and Synthesis of Potent HIV-1 Protease Inhibitors Containing Bicyclic Oxazolidinone Scaffold as the P2 Ligands: Structure-Activity Studies and Biological and X-ray Structural Studies.
复制标题
DOI：
10.1021/acs.jmedchem.8b01227
复制
发表时间：
2018-11-08
影响因子：
7.3
通讯作者：
Mitsuya H
中科院分区：
文献类型：
--
作者：
Ghosh AK;Williams JN;Ho RY;Simpson HM;Hattori SI;Hayashi H;Agniswamy J;Wang YF;Weber IT;Mitsuya H
我们已经设计，合成，并评估了一类新的有效的HIV-1蛋白酶抑制剂与新的双环恶唑烷酮衍生物作为P2配体。我们已经开发了一种利用关键的邻碘酰苯甲酸介导的环化反应的对映选择性合成这些双环恶唑烷酮。几种抑制剂对HIV-1蛋白酶表现出良好至优异的活性，并在MT-4细胞中表现出显著的抗病毒活性。化合物4k显示出40 pM的酶Ki和31 nM的抗病毒IC 50。针对一组高度耐药的多药耐药HIV-1变异体评价了抑制剂4k和4l，其抗病毒活性的倍数变化与使用地瑞那韦观察到的相似。此外，两个X-射线晶体结构的相关抑制剂4a和4 e结合到HIV-1蛋白酶分别确定在1.22和1.30 μ m分辨率，并揭示了重要的相互作用的活性位点，尚未被探索。
We have designed, synthesized, and evaluated a new class of potent HIV-1 protease inhibitors with novel bicyclic oxazolidinone derivatives as the P2 ligand. We have developed an enantioselective synthesis of these bicyclic oxazolidinones utilizing a key o-iodoxybenzoic acid mediated cyclization. Several inhibitors displayed good to excellent activity toward HIV-1 protease and significant antiviral activity in MT-4 cells. Compound 4k has shown an enzyme Ki of 40 pM and antiviral IC50 of 31 nM. Inhibitors 4k and 4l were evaluated against a panel of highly resistant multidrug-resistant HIV-1 variants, and their fold-changes in antiviral activity were similar to those observed with darunavir. Additionally, two X-ray crystal structures of the related inhibitors 4a and 4e bound to HIV-1 protease were determined at 1.22 and 1.30 Å resolution, respectively, and revealed important interactions in the active site that have not yet been explored.
登录
查看更多内容
影响因子：
7.3
作者：
Ghosh AK;Osswald HL;Prato G
通讯作者：
Prato G
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
4.8
作者：
Koh, Yasuhiro;Matsumi, Shintaro;Mitsuya, Hiroaki
通讯作者：
Mitsuya, Hiroaki
影响因子：
7.3
作者：
Ghosh AK;Rao KV;Nyalapatla PR;Osswald HL;Martyr CD;Aoki M;Hayashi H;Agniswamy J;Wang YF;Bulut H;Das D;Weber IT;Mitsuya H
通讯作者：
Mitsuya H
影响因子：
5.6
作者：
Kovalevsky, Andrey Y.;Liu, Fengling;Weber, Irene T.
通讯作者：
Weber, Irene T.