Design, synthesis and preliminary SAR studies of novel N-arylmethyl substituted piperidine-linked aniline derivatives as potent HIV-1 NNRTIs

被引：23

作者：

Zhang, Lingzi ^{[1
]}

Zhan, Peng ^{[1
]}

Chen, Xuwang ^{[1
]}

Li, Zhenyu ^{[1
]}

Xie, Zhoumeng ^{[1
]}

Zhao, Tong ^{[1
]}

Liu, Huiqing ^{[3
]}

De Clercq, Erik ^{[2
]}

Pannecouque, Christophe ^{[2
]}

Balzarini, Jan ^{[2
]}

Liu, Xinyong ^{[1
]}

机构：

[1] Shandong Univ, Sch Pharmaceut Sci, Dept Med Chem, Key Lab Chem Biol,Minist Educ, Jinan 250012, Shandong, Peoples R China

[2] Katholieke Univ Leuven, Rega Inst Med Res, B-3000 Louvain, Belgium

[3] Shandong Univ, Inst Pharmacol, Sch Med, Jinan 250012, Shandong, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2014年 / 22卷 / 01期

基金：

中国国家自然科学基金; 高等学校博士学科点专项科研基金;

关键词：

HIV-1; AIDS; NNRTIs; Synthesis; Anti-HIV-1; activity; REVERSE-TRANSCRIPTASE INHIBITORS; COLORIMETRIC ASSAY; ANTAGONISTS; DISCOVERY; AIDS; DNA;

D O I：

10.1016/j.bmc.2013.10.033

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A series of novel N-arylmethyl substituted piperidine-linked aniline derivatives were designed, synthesized and evaluated for their anti-HIV activity in MT-4 cells. All the new compounds showed moderate to potent activities against wild-type (wt) HIV-1 with an EC50 range from 0.022 to 2.1 mu M. Among them, compound 5a6 (EC50 = 0.022 +/- 0.0091 mu M, SI > 10,770) was confirmed to be the most potent and selective inhibitor, which proved more potent than DDI and DLV in a cell-based assay against wt HIV-1, and more efficient than NVP in an RT (reverse transcriptase) assay. Besides, it is worth noting that compound 7a1 retained moderate inhibitory activity (EC50 = 4.8 +/- 0.95 mu M) against the HIV-1 double RT mutant strain (K103N/Y181C). The preliminary structure-activity relationship was discussed and rationalized by molecular simulation. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：633 / 642

页数：10

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