Substituent effects on P2-cyclopentyltetrahydrofuranyl urethanes: Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors

被引：18

作者：

Ghosh, Arun K. ^{[1
,2
]}

Chapsal, Bruno D. ^{[1
,2
]}

Steffey, Melinda ^{[1
,2
]}

Agniswamy, Johnson ^{[3
]}

Wang, Yuan-Fang ^{[3
]}

Amano, Masayuki ^{[4
,5
]}

Weber, Irene T. ^{[3
]}

Mitsuya, Hiroaki ^{[4
,5
,6
]}

机构：

[1] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA

[2] Purdue Univ, Dept Med Chem, W Lafayette, IN 47907 USA

[3] Georgia State Univ, Dept Biol, Atlanta, GA 30303 USA

[4] Kumamoto Univ, Dept Hematol, Grad Sch Med & Pharmaceut Sci, Kumamoto 8608556, Japan

[5] Kumamoto Univ, Dept Infect Dis, Grad Sch Med & Pharmaceut Sci, Kumamoto 8608556, Japan

[6] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 06期

基金：

美国国家卫生研究院;

关键词：

HIV-1 protease inhibitors; P2; ligand; Drug resistance; Design and synthesis; X-ray crystal structure; DRUG-RESISTANT MUTANTS; BIOLOGICAL EVALUATION; P2-LIGANDS; BACKBONE;

D O I：

10.1016/j.bmcl.2012.01.061

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The design, synthesis, and biological evaluation of novel C3-substituted cyclopentyltetrahydrofuranyl (Cp-THF)-derived HIV-1 protease inhibitors are described. Various C3-functional groups on the Cp-THF ligand were investigated in order to maximize the ligand-binding site interactions in the flap region of the protease. Inhibitors 3c and 3d have displayed the most potent enzyme inhibitory and antiviral activity. Both inhibitors have maintained impressive activity against a panel of multidrug resistant HIV-1 variants. A high-resolution X-ray crystal structure of 3c-bound HIV-1 protease revealed a number of important molecular insights into the ligand-binding site interactions. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：2308 / 2311

页数：4

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