Ghosh Arun K, Sean Fyvie W, Brindisi Margherita, Steffey Melinda, Agniswamy Johnson, Wang Yuan-Fang, Aoki Manabu, Amano Masayuki, Weber Irene T, Mitsuya Hiroaki
Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA; Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA.
Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
Bioorg Med Chem Lett. 2017 Nov 1;27(21):4925-4931. doi: 10.1016/j.bmcl.2017.09.003. Epub 2017 Sep 6.
Design, synthesis, and evaluation of a new class of HIV-1 protease inhibitors containing diverse flexible macrocyclic P1'-P2' tethers are reported. Inhibitor 5a with a pyrrolidinone-derived macrocycle exhibited favorable enzyme inhibitory and antiviral activity (K=13.2nM, IC=22nM). Further incorporation of heteroatoms in the macrocyclic skeleton provided macrocyclic inhibitors 5m and 5o. These compounds showed excellent HIV-1 protease inhibitory (K=62pM and 14pM, respectively) and antiviral activity (IC=5.3nM and 2.0nM, respectively). Inhibitor 5o also remained highly potent against a DRV-resistant HIV-1 variant.
报道了一类含有多种柔性大环P1'-P2'连接链的新型HIV-1蛋白酶抑制剂的设计、合成及评估。具有吡咯烷酮衍生大环的抑制剂5a表现出良好的酶抑制和抗病毒活性（K = 13.2 nM，IC = 22 nM）。在大环骨架中进一步引入杂原子得到大环抑制剂5m和5o。这些化合物显示出优异的HIV-1蛋白酶抑制活性（K分别为62 pM和14 pM）和抗病毒活性（IC分别为5.3 nM和2.0 nM）。抑制剂5o对一种对达芦那韦耐药的HIV-1变体也保持高效。
