Design, synthesis, and biological evaluation of novel trifluoromethyl indoles as potent HIV-1 NNRTIs with an improved drug resistance profile

被引：45

作者：

Jiang, Hai-Xia ^{[1
]}

Zhuang, Dao-Min ^{[2
]}

Huang, Ying ^{[1
]}

Cao, Xing-Xin ^{[1
]}

Yao, Jian-Hua ^{[1
]}

Li, Jing-Yun ^{[2
]}

Wang, Jian-Yong ^{[3
]}

Zhang, Chen ^{[1
]}

Jiang, Biao ^{[1
,3
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Organ Chem, CAS Key Lab Synthet Chem Nat Subst, Shanghai 200032, Peoples R China

[2] Beijing Inst Microbiol & Epidemiol, State Key Lab Pathogen & Biosecur, Dept AIDS Res, Beijing, Peoples R China

[3] Chinese Acad Sci, Shanghai Adv Res Inst, Shanghai 201210, Peoples R China

来源：

ORGANIC & BIOMOLECULAR CHEMISTRY | 2014年 / 12卷 / 21期

基金：

中国国家自然科学基金;

关键词：

NONNUCLEOSIDE REVERSE-TRANSCRIPTASE; ETRAVIRINE-CONTAINING REGIMEN; INHIBITORS; MUTATIONS; DISCOVERY; TOXICITY; FAILURE; ANALOGS; TMC125; AGENTS;

D O I：

10.1039/c3ob42186d

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

novel series of trifluoromethyl indole derivatives have been designed, synthesized and evaluated for anti-HIV-1 activities in MT-2 cells. The hydrophobic constant, acute toxicity, carcinogenicity and mutagenicity were predicted. Trifluoromethyl indoles 10i and 10k showed extremely promising activities against WT HIV-1 with IC50 values at the low nanomolar level, similar to efavirenz, better than nevirapine, and also possessed higher potency towards the drug-resistant mutant strain Y181C than nevirapine. Preliminary SAR and docking studies of detailed binding mode provided some insights for discovery of more potent NNRTIs.

引用

页码：3446 / 3458

页数：13

共 48 条

[1] TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1 [J].

Andries, K ;

Azijn, H ;

Thielemans, T ;

Ludovici, D ;

Kukla, M ;

Heeres, J ;

Janssen, P ;

De Corte, B ;

Vingerhoets, J ;

Pauwels, R ;

de Béthune, MP .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2004, 48 (12) :4680-4686

[2]

[Anonymous], J MED CHEM

[3]

Banks R. E., 1994, ORGANOFLUORINE CHEM

[4] Computationally-Guided Optimization of a Docking Hit to Yield Catechol Diethers as Potent Anti-HIV Agents [J].

Bollini, Mariela ;

Domaoal, Robert A. ;

Thakur, Vinay V. ;

Gallardo-Macias, Ricardo ;

Spasov, Krasimir A. ;

Anderson, Karen S. ;

Jorgensen, William L. .

JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (24) :8582-8591

[5] High-resolution structures of HIV-1 reverse transcriptase/TMC278 complexes: Strategic flexibility explains potency against resistance mutations [J].

Das, Kalyan ;

Bauman, Joseph D. ;

Clark, Arthur D., Jr. ;

Frenkel, Yulia V. ;

Lewi, Paul J. ;

Shatkin, Aaron J. ;

Hughes, Stephen H. ;

Arnold, Eddy .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (05) :1466-1471

[6] Anti-HIV chemotherapy: Current state of the art [J].

De Clercq, E .

MEDICINAL CHEMISTRY RESEARCH, 2004, 13 (6-7) :439-478

[7] A microwave-assisted, propylphosphonic anhydride (T3P®) mediated one-pot Fischer indole synthesis [J].

Desroses, Matthieu ;

Wieckowski, Krzysztof ;

Stevens, Marc ;

Odell, Luke R. .

TETRAHEDRON LETTERS, 2011, 52 (34) :4417-4420

[8] Discovery of dimeric inhibitors by extension into the entrance channel of HIV-1 reverse transcriptase [J].

Ekkati, Anil R. ;

Bollini, Mariela ;

Domaoal, Robert A. ;

Spasov, Krasimir A. ;

Anderson, Karen S. ;

Jorgensen, William L. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2012, 22 (04) :1565-1568

[9] Design and Synthesis of Conformationally Constrained Inhibitors of Non-Nucleoside Reverse Transcriptase [J].

Gomez, Robert ;

Jolly, Samson J. ;

Williams, Theresa ;

Vacca, Joseph P. ;

Torrent, Maricel ;

McGaughey, Georgia ;

Lai, Ming-Tain ;

Felock, Peter ;

Munshi, Vandna ;

DiStefano, Daniel ;

Flynn, Jessica ;

Miller, Mike ;

Yan, Youwei ;

Reid, John ;

Sanchez, Rosa ;

Liang, Yuexia ;

Paton, Brenda ;

Wan, Bang-Lin ;

Anthony, Neville .

JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (22) :7920-7933

[10] Synthetic chemistry-led creation of a difluorinated biaryl ether non-nucleoside reverse transcriptase inhibitor [J].

Jones, Lyn H. ;

Randall, Amy ;

Barba, Oscar ;

Selby, Matthew D. .

ORGANIC & BIOMOLECULAR CHEMISTRY, 2007, 5 (21) :3431-3433

← 1 2 3 4 5 →