Tricyclononene carboxamide derivatives as novel anti-HIV-1 agents

被引：19

作者：

Dong, Ming-xin ^{[1
]}

Zhang, Jian ^{[3
]}

Peng, Xu-qing ^{[1
]}

Lu, Hong ^{[2
]}

Yun, Liu-hong ^{[4
]}

Jiang, Shibo ^{[2
]}

Dai, Qiu-yun ^{[1
]}

机构：

[1] Beijing Inst Biotechnol, Beijing 100071, Peoples R China

[2] New York Blood Ctr, Lindsley F Kimball Res Inst, New York, NY 10065 USA

[3] Shanghai Jiao Tong Univ, Key Lab Cell Differentiat & Apoptosis, Dept Pathophysiol, Chinese Minist Educ,Sch Med, Shanghai 200025, Peoples R China

[4] Bejing Inst Toxicol & Pharmacol, Beijing 100850, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 45卷 / 09期

关键词：

HIV-1; Inhibitor; Synthesis; Tricyclononene carboxamide derivatives; anti-HIV-1; activity; QSAR; NONPEPTIDE CCR5 ANTAGONIST; HIV FUSION INHIBITORS; GP41 CORE STRUCTURE; SMALL-MOLECULE; POTENT; IDENTIFICATION; DESIGN; COMFA;

D O I：

10.1016/j.ejmech.2010.05.070

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

By modifying the chemical structure of anti-orthopoxvirus compound ST-246, we designed and synthesized a series of tricyclononene carboxamide derivatives and tested their anti-HIV-1 activity and cytotoxicity. We found that benzoimidazol-containing compound 7g was highly effective in inhibiting HIV-1 R5 infection with an IC50 value of 0.41 mu M and a selectivity index of 292, but it exhibited no significant inhibitory activity on HIV-1 reverse transcriptase, integrase and protease. CoMFA was used to analyze structure-activity relationships with good predictive power (r(2) = 0.921; q(2) = 0.582). Moreover, the CoMFA model showed that the length of the molecule, the amide, and the amine moieties all played crucial roles in anti-HIV activity. These results suggest that 7g may serve as a lead for the development of novel anti-HIV-1 therapies. (C) 2010 Elsevier Masson SAS. All rights reserved.

引用

页码：4096 / 4103

页数：8

共 24 条

[1] Recent progress in antiretrovirals - lessons from resistance [J].

Adamson, Catherine S. ;

Freed, Eric O. .

DRUG DISCOVERY TODAY, 2008, 13 (9-10) :424-432

[2] A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity [J].

Baba, M ;

Nishimura, O ;

Kanzaki, N ;

Okamoto, M ;

Sawada, H ;

Iizawa, Y ;

Shiraishi, M ;

Aramaki, Y ;

Okonogi, K ;

Ogawa, Y ;

Meguro, K ;

Fujino, M .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (10) :5698-5703

[3]

CHOU TC, 1991, CALUSYN WINDOWS SOFT

[4] Therapies: Confronting the limits of success [J].

Cohen, J .

SCIENCE, 2002, 296 (5577) :2320-2324

[5] COMPARATIVE MOLECULAR-FIELD ANALYSIS (COMFA) .1. EFFECT OF SHAPE ON BINDING OF STEROIDS TO CARRIER PROTEINS [J].

CRAMER, RD ;

PATTERSON, DE ;

BUNCE, JD .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1988, 110 (18) :5959-5967

[6] Structure-based identification of small molecule antiviral compounds targeted to the gp41 core structure of the human immunodeficiency virus type 1 [J].

Debnath, AK ;

Radigan, L ;

Jiang, SB .

JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (17) :3203-3209

[7] Mechanisms of resistance and failure of treatment with maraviroc [J].

Delgado, Rafael .

ENFERMEDADES INFECCIOSAS Y MICROBIOLOGIA CLINICA, 2008, 26 :28-33

[8]

Dong B., 2006, CHIN J AIDS STD, V12, P402

[9] Novel targets for HIV therapy [J].

Greene, Warner C. ;

Debyser, Zeger ;

Ikeda, Yasuhiro ;

Freed, Eric O. ;

Stephens, Edward ;

Yonemoto, Wes ;

Buckheit, Robert W. ;

Este, Jose A. ;

Cihlar, Tomas .

ANTIVIRAL RESEARCH, 2008, 80 (03) :251-265

[10]

GUO ZM, 2002, CHIN J EXP CLIN VIRO, V16, P119

← 1 2 3 →