Design and Synthesis of Highly Potent HIV-1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure-Activity Studies, Biological and X-ray Structural Analysis.
Design and Synthesis of Highly Potent HIV-1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure-Activity Studies, Biological and X-ray Structural Analysis.
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DOI：
10.1021/acs.jmedchem.8b00298
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发表时间：
2018-05-24
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;R Nyalapatla P;Kovela S;Rao KV;Brindisi M;Osswald HL;Amano M;Aoki M;Agniswamy J;Wang YF;Weber IT;Mitsuya H
介绍了一类新型HIV-1蛋白水解酶抑制剂的设计、合成和生物学评价，其中P2配体为立体化学定义的稠合三环聚醚，P2‘配体为多种磺胺类化合物。研究了不同的环大小和不同的取代基效应，以增强蛋白酶活性部位的配体-主链相互作用。以这种前所未有的融合6-5-5环系为P2配体，以氨基苯并噻唑为P2‘配体，以二氟苯甲基为P1配体的抑制剂5c和5d，对一组高度耐药的HIV-1变异体表现出优异的酶抑制效力和良好的抗病毒活性。以Pauson-Khandd环化反应为关键步骤，以光学活性的形式高效地合成了这些抑制剂的伞状P2配体。利用脂肪酶催化的酶促拆分方法有效地拆分了外消旋醇。抑制物结合的HIV-1蛋白水解酶的两个高分辨X射线结构揭示了与HIV-1蛋白酶骨架原子的广泛相互作用，并提供了对这些新的抑制物结合性质的分子洞察力。
The design, synthesis, and biological evaluation of a new class of HIV-1 protease inhibitors containing stereochemically defined fused tricyclic polyethers as the P2 ligands and a variety of sulfonamide derivatives as the P2′ ligands, are described. A number of ring sizes and various substituent effects were investigated to enhance the ligand-backbone interactions in the protease active site. Inhibitors 5c and 5d containing this unprecedented fused 6-5-5 ring system as the P2 ligand, an aminobenzothiazole as the P2′ ligand and a difluorophenylmethyl as the P1 ligand exhibited exceptional enzyme inhibitory potency and maintained excellent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The umbrella-like P2 ligand for these inhibitors has been synthesized efficiently in an optically active form using a Pauson-Khand cyclization reaction as the key step. The racemic alcohols were resolved efficiently using a lipase catalyzed enzymatic resolution. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors.
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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：
1.8
作者：
GHOSH, AK;CHEN, Y
通讯作者：
CHEN, Y
影响因子：
3.5
作者：
Ghosh, Arun K.;Dawson, Zachary L.;Mitsuya, Hiroaki
通讯作者：
Mitsuya, Hiroaki
DOI：
10.1016/b978-0-12-397176-0.00013-3
发表时间：
2013-01-01
期刊：
INTRODUCTION TO BIOLOGICAL AND SMALL MOLECULE DRUG RESEARCH AND DEVELOPMENT: THEORY AND CASE STUDIES
影响因子：
--
作者：
Ghosh, Arun K.;Chapsal, Bruno D.
通讯作者：
Chapsal, Bruno D.
影响因子：
3.6
作者：
BIANCHI, D;CESTI, P;BATTISTEL, E
通讯作者：
BATTISTEL, E