Fused heterocycles bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 3: Optimization of [1,2,4]triazolo[1,5-a]pyrimidine core via structure-based and physicochemical property-driven approaches

被引：87

作者：

Huang, Boshi ^{[1
]}

Li, Cuicui ^{[1
]}

Chen, Wenmin ^{[1
]}

Liu, Tao ^{[1
]}

Yu, Mingyan ^{[2
]}

Fu, Lu ^{[1
]}

Sun, Yueyue ^{[1
]}

Liu, Huiqing ^{[3
]}

De Clercq, Erik ^{[4
]}

Pannecouque, Christophe ^{[4
]}

Balzarini, Jan ^{[4
]}

Zhan, Peng ^{[1
]}

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] Shandong Inst Food & Drug Control, Jinan 250101, Shandong, Peoples R China

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

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

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 92卷

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：

Triazolopyrimidines; Structure-based drug design; Biological activity; HIV-1; RT; Physicochemical properties; Molecular simulations; REVERSE-TRANSCRIPTASE INHIBITORS; REFINING APPROACH; BIOLOGICAL EVALUATION; COLORIMETRIC ASSAY; DESIGN STRATEGIES; DRUG-RESISTANCE; DERIVATIVES; DISCOVERY; SAR; DIARYLPYRIMIDINES;

D O I：

10.1016/j.ejmech.2015.01.042

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In our arduous efforts to develop new potent HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs), novel piperidine-linked [1,2,4]triazolo[1,5-a]pyrimidine derivatives were designed, synthesized and evaluated for their antiviral activities in MT-4 cell cultures. Biological results showed that all of the title compounds displayed moderate to excellent activities against wild-type (wt) HIV-1 strain (IIIB) with EC50 values ranging from 8.1 nM to 2284 nM in a cell-based assay. Among them, the most promising analog 7d possessed an EC50 value of 8.1 nM against wt HIV-1, which was much more potent than the reference drugs DDI, 3 TC, NVP and DLV. Additionally, 7d demonstrated weak activity against the double mutant HIV-1 strain (K103N + Y181C), and was more efficient than NW in a RT inhibition assay. Besides, some measured and calculated physicochemical properties of 7d, like log P and water solubility, as well as the structure activity relationships (SARs) analysis have been discussed in detail. Furthermore, the binding mode of the active compound 7d was rationalized by molecular simulation studies. (C) 2015 Elsevier Masson SAS. All rights reserved.

引用

页码：754 / 765

页数：12

共 37 条

[1] Antiviral Drug Resistance and the Need for Development of New HIV-1 Reverse Transcriptase Inhibitors [J].

Asahchop, Eugene L. ;

Wainberg, Mark A. ;

Sloan, Richard D. ;

Tremblay, Cecile L. .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2012, 56 (10) :5000-5008

[2] The Protein Data Bank [J].

Berman, HM ;

Westbrook, J ;

Feng, Z ;

Gilliland, G ;

Bhat, TN ;

Weissig, H ;

Shindyalov, IN ;

Bourne, PE .

NUCLEIC ACIDS RESEARCH, 2000, 28 (01) :235-242

[3] Discovery of Piperidine-Linked Pyridine Analogues as Potent Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors [J].

Chen, Xuwang ;

Li, Yuanyuan ;

Ding, Shufang ;

Balzarini, Jan ;

Pannecouque, Christophe ;

De Clercq, Erik ;

Liu, Huiqing ;

Liu, Xinyong .

CHEMMEDCHEM, 2013, 8 (07) :1117-1126

[4] Design, synthesis, anti-HIV evaluation and molecular modeling of piperidine-linked amino-triazine derivatives as potent non-nucleoside reverse transcriptase inhibitors [J].

Chen, Xuwang ;

Zhan, Peng ;

Liu, Xin ;

Cheng, Ziheng ;

Meng, Caicai ;

Shao, Siyuan ;

Pannecouque, Christophe ;

De Clercq, Erik ;

Liu, Xinyong .

BIOORGANIC & MEDICINAL CHEMISTRY, 2012, 20 (12) :3856-3864

[5] Recent Advances in DAPYs and Related Analogues as HIV-1 NNRTIs [J].

Chen, Xuwang ;

Zhan, Peng ;

Li, Dongyue ;

De Clercq, Erik ;

Liu, Xinyong .

CURRENT MEDICINAL CHEMISTRY, 2011, 18 (03) :359-376

[6] Molecular obesity, potency and other addictions in drug discovery [J].

Hann, Michael M. .

MEDCHEMCOMM, 2011, 2 (05) :349-355

[7] "Old Dogs with New Tricks": exploiting alternative mechanisms of action and new drug design strategies for clinically validated HIV targets [J].

Kang, Dongwei ;

Song, Yu'ning ;

Chen, Wenmin ;

Zhan, Peng ;

Liu, Xinyong .

MOLECULAR BIOSYSTEMS, 2014, 10 (08) :1998-2022

[8] Discovery of piperidin-4-yl-aminopyrimidines as HIV-1 reverse transcriptase inhibitors. N-Benzyl derivatives with broad potency against resistant mutant viruses [J].

Kertesz, Denis J. ;

Brotherton-Pleiss, Christine ;

Yang, Minmin ;

Wang, Zhanguo ;

Lin, Xianfeng ;

Qiu, Zongxing ;

Hirschfeld, Donald R. ;

Gleason, Shelley ;

Mirzadegan, Taraneh ;

Dunten, Pete W. ;

Harris, Seth F. ;

Villasenor, Armando G. ;

Hang, Julie Qi ;

Heilek, Gabrielle M. ;

Klumpp, Klaus .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (14) :4215-4218

[9] Crystal Structures of HIV-1 Reverse Transcriptase with Etravirine (TMC125) and Rilpivirine (TMC278): Implications for Drug Design [J].

Lansdon, Eric B. ;

Brendza, Katherine M. ;

Hung, Magdeleine ;

Wang, Ruth ;

Mukund, Susmith ;

Jin, Debi ;

Birkus, Gabriel ;

Kutty, Nilima ;

Liu, Xiaohong .

JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (10) :4295-4299

[10] Synthesis and biological evaluation of pyridazine derivatives as novel HIV-1 NNRTIs [J].

Li, Dongyue ;

Zhan, Peng ;

Liu, Huiqing ;

Pannecouque, Christophe ;

Balzarini, Jan ;

De Clercq, Erik ;

Liu, Xinyong .

BIOORGANIC & MEDICINAL CHEMISTRY, 2013, 21 (07) :2128-2134

← 1 2 3 4 →