Discovery of novel diarylpyrimidines as potent HIV NNRTIs via a structure-guided core-refining approach

被引：25

作者：

Li, Xiao ^{[1
]}

Chen, Wenmin ^{[1
]}

Tian, Ye ^{[1
]}

Liu, Huiqing ^{[2
]}

Zhan, Peng ^{[1
]}

De Clercq, Erik ^{[3
]}

Pannecouque, Christophe ^{[3
]}

Balzarini, Jan ^{[3
]}

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

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

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 80卷

基金：

高等学校博士学科点专项科研基金; 中国国家自然科学基金;

关键词：

HIV-1; HIV-2; DAPY; Anti-HIV activities; Structure-activity relationships; Molecular modeling; REVERSE-TRANSCRIPTASE INHIBITORS; ACTIVE ANTIRETROVIRAL THERAPY; BIOLOGICAL EVALUATION; VIROLOGICAL FAILURE; DERIVATIVES; DESIGN; ANALOGS;

D O I：

10.1016/j.ejmech.2014.04.036

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Guided by crystal structures of HIV-1 RT/DAPY complex and molecular modeling studies, a series of novel DAPY derivatives were rationally designed, synthesized and evaluated for their anti-HIV activities. Among them, 16 compounds significantly inhibited HIV-1 IIIB replication with EC50 values lower than 66 nM. Particularly, compound 7a was the most potent inhibitor against HIV-1 wild-type and double RT mutant HIV-1 strain K103N/Y181C, with an EC50 value of 2.5 nM (SI = 13,740) and 0.33 mu M (SI = 107), respectively. Unexpectedly, compound 8c was found to show moderate anti-HIV-2 potency (EC50 = 5.57 mu M). Preliminary structure-activity relationships (SARs) and molecular modeling of these new analogues were also discussed in detail. (C) 2014 Elsevier Masson SAS. All rights reserved.

引用

页码：112 / 121

页数：10

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