Design, synthesis and biological evaluation of N2,N4-disubstituted-1,1,3-trioxo-2H,4H-pyrrolo[1,2-b][1,2,4,6]thiatriazine derivatives as HIV-1 NNRTIs

被引：8

作者：

Chen, Wenmin ^{[1
]}

Zhan, Peng ^{[1
]}

De Clercq, Erik ^{[2
]}

Pannecouque, Christophe ^{[2
]}

Balzarini, Jan ^{[2
]}

Jiang, Xin ^{[1
]}

Liu, Xinyong ^{[1
]}

机构：

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

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2013年 / 21卷 / 22期

基金：

中国国家自然科学基金;

关键词：

HIV; Reverse transcriptase; NNRTIs; Thienothiadiazine; Pyrrolothiatriazine; Heterocycle; Drug design; REVERSE-TRANSCRIPTASE INHIBITORS; IMMUNODEFICIENCY-VIRUS TYPE-1; AGENTS; ETRAVIRINE; RESISTANT; INFECTION; ANALOGS; POTENT; REPLICATION; EFAVIRENZ;

D O I：

10.1016/j.bmc.2013.09.009

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 N-2,N-4-disubstituted-1,1,3-trioxo-2H,4H-pyrrolo[1,2-b][1,2,4,6]thiatriazine derivatives (PTTDs) was designed and synthesized by a facile route. The biological assay results showed that five most potent compounds displayed inhibitory activity against HIV-1 at low micromolar concentrations (EC50 = 5.1-8.9 mu M). Structure-activity relationship analysis indicated that N-2-(3-halogenated-benzyl) analogues were more potent than N-2-(unsubstituted-benzyl) analogues. The N-4-substitutions contributed to the antiviral activity in the following order: 2-/3-cyano substituted benzyl > 2-/3-halogenated benzyl > non-substituted benzyl > 4-halogenated benzyl. Docking studies of the representative compound revealed the binding conformation of these compounds and provided critical insights for the further development of PTTD analogues. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：7091 / 7100

页数：10

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