Structure-based design, synthesis, X-ray studies, and biological evaluation of novel HIV-1 protease inhibitors containing isophthalamide-derived P2-ligands.
Structure-based design, synthesis, X-ray studies, and biological evaluation of novel HIV-1 protease inhibitors containing isophthalamide-derived P2-ligands.
复制标题
DOI：
10.1016/j.bmcl.2015.05.052
复制
发表时间：
2015-11-01
影响因子：
2.7
通讯作者：
Mitsuya H
中科院分区：
文献类型：
--
作者：
Ghosh AK;Takayama J;Kassekert LA;Ella-Menye JR;Yashchuk S;Agniswamy J;Wang YF;Aoki M;Amano M;Weber IT;Mitsuya H
我们描述了一系列以间苯二甲酰胺类化合物为P2-P3配体的新型HIV-1蛋白水解酶抑制剂的设计、合成和生物学评价。我们研究了一系列非环和杂环酰胺类化合物作为扩展的P2-P3配体。这些抑制剂表现出很好到很好的HIV-1蛋白酶抑制活性。此外，一些抑制剂在MT细胞中表现出很好的抗病毒活性。化合物5N的KI为0.17 nM，抗病毒IC50为14 nM。用X-射线衍射法测定了HIV-1蛋白水解酶抑制剂50的X-射线晶体结构。这一结构揭示了活性部位抑制物-HIV-1蛋白酶相互作用的重要分子洞察力。
We describe the design, synthesis and biological evaluation of a series of novel HIV-1 protease inhibitors bearing isophthalamide derivatives as the P2–P3 ligands. We have investigated a range of acyclic and heterocyclic amides as the extended P2–P3 ligands. These inhibitors displayed good to excellent HIV-1 protease inhibitory activity. Also, a number of inhibitors showed very good antiviral activity in MT cells. Compound 5n has shown an enzyme Ki of 0.17 nM and antiviral IC50 of 14 nM. An X-ray crystal structure of inhibitor 5o-bound to HIV-1 protease was determined at 1.11 Å resolution. This structure revealed important molecular insight into the inhibitor-HIV-1 protease interactions in the active site.