Ghosh Arun K, Fyvie W Sean, Brindisi Margherita, Steffey Melinda, Agniswamy Johnson, Wang Yuan-Fang, Aoki Manabu, Amano Masayuki, Weber Irene T, Mitsuya Hiroaki
Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN, 47907, USA.
Departments of Biology and Chemistry, Molecular Basis of Disease, Georgia State University, Atlanta, GA, 30303, USA.
ChemMedChem. 2017 Dec 7;12(23):1942-1952. doi: 10.1002/cmdc.201700614. Epub 2017 Nov 24.
The structure-based design, synthesis, and biological evaluation of a series of nonpeptidic HIV-1 protease inhibitors with rationally designed P2' ligands are described. The inhibitors are designed to enhance backbone binding interactions, particularly at the S2' subsite. Synthesis of inhibitors was carried out efficiently. The stereochemistry of alcohol functionalities of the P2' ligands was set by asymmetric reduction of the corresponding ketone using (R,R)- or (S,S)-Noyori catalysts. A number of inhibitors displayed very potent enzyme inhibitory and antiviral activity. Inhibitors 3g and 3h showed enzyme K values of 27.9 and 49.7 pm and antiviral activity of 6.2 and 3.9 nm, respectively. These inhibitors also remained quite potent against darunavir-resistant HIV-1 variants. An X-ray structure of inhibitor 3g in complex with HIV-1 protease revealed key interactions in the S2' subsite.
描述了一系列具有合理设计的P2'配体的非肽类HIV-1蛋白酶抑制剂的基于结构的设计、合成及生物学评价。这些抑制剂旨在增强主链结合相互作用，特别是在S2'亚位点。抑制剂的合成高效进行。使用(R,R)-或(S,S)-Noyori催化剂通过相应酮的不对称还原确定P2'配体醇官能团的立体化学。许多抑制剂表现出非常强的酶抑制和抗病毒活性。抑制剂3g和3h的酶K值分别为27.9和49.7 pm，抗病毒活性分别为6.2和3.9 nm。这些抑制剂对达芦那韦耐药的HIV-1变体也保持相当强的活性。抑制剂3g与HIV-1蛋白酶复合物的X射线结构揭示了S2'亚位点的关键相互作用。
