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IR@PKUHSC  > 北京大学药学院  > 化学生物学系  > 期刊论文
学科主题: 药学
题名:
Design, Synthesis, and Biological Evaluation of 1-[(2-Benzyloxyl/alkoxyl)methyl]-5-halo-6-aryluracils as Potent HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors with an Improved Drug Resistance Profile
作者: Wang, Xiaowei2,3; Zhang, Jianfang4; Huang, Yang1; Wang, Ruiping4; Zhang, Liang2,3; Qiao, Kang2,3; Li, Li2,3; Liu, Chang4; Ouyang, Yabo1; Xu, Weisi1; Zhang, Zhili2,3; Zhang, Liangren; Shao, Yiming1; Jiang, Shibo5,6; Ma, Liying1; Liu, Junyi2,3
刊名: JOURNAL OF MEDICINAL CHEMISTRY
发表日期: 2012-03-08
DOI: 10.1021/jm201506e
卷: 55, 期:5, 页:2242-2250
收录类别: SCI ; IC
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Chemistry, Medicinal
研究领域[WOS]: Pharmacology & Pharmacy
关键词[WOS]: IMMUNODEFICIENCY-VIRUS TYPE-1 ; RT INHIBITORS ; POSITIONAL ADAPTABILITY ; CONFORMATIONAL-CHANGES ; DERIVATIVES ; ANALOGS ; COMPLEX ; BINDING ; RESOLUTION ; THERAPY
英文摘要:

Because the emergence of drug-resistant mutants has limited the efficacy of non-nucleoside reverse transcriptase inhibitors (NNRTIs), it is essential to develop new antivirals with better drug resistance and pharmacokinetic profiles. Here we designed and synthesized a series of 1-[(2-benzyloxyl/alkoxyl)methyl]-5-halo-6-aryluracils, the HEPT analogues, and evaluated their biological activity using nevirapine and 18 (TNK-651) as reference compounds. Most of these compounds, especially 6b, 7b, 9b, 11b, and 7c, exhibited highly potent anti-HIV-1 activity against both wild-type and NNRTI-resistant HIV-1 strains. Compound 7b, which had the highest selectivity index (SI = 38 215), is more potent than nevirapine and 18. These results suggest that the introduction of a halogen at the C-5 position may contribute to the effectiveness of these compounds against RTI-resistant variants. In addition, meta substituents on the C-6 aromatic moiety could significantly enhance activity against NNRTI-resistant HIV-1 strains. These compounds can be further developed as next-generation NNRTIs with an improved antiviral efficacy and drug-resistance profile.

语种: 英语
所属项目编号: 20972011 ; 21042009 ; 21172014 ; 30872232 ; 81172733 ; 2009ZX09301-010 ; 2011SKLID102
项目资助者: National Science Foundation of China ; Ministry of Science and Technology of China ; SKLID
WOS记录号: WOS:000301170000038
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/60692
Appears in Collections:北京大学药学院_化学生物学系_期刊论文

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作者单位: 1.Fudan Univ, Inst Med Microbiol, Shanghai 200032, Peoples R China
2.Chinese Ctr Dis Control & Prevent, State Key Lab Infect Dis Prevent & Control, Natl Ctr AIDS STD Control & Prevent NCAIDS, Beijing 102206, Peoples R China
3.Peking Univ, Sch Pharmaceut Sci, Dept Biol Chem, Beijing 100191, Peoples R China
4.Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
5.Capital Med Univ, Coll Pharmaceut Sci, Beijing 100069, Peoples R China
6.Fudan Univ, MOE MOH Key Lab Med Mol Virol, Shanghai Med Coll, Shanghai 200032, Peoples R China

Recommended Citation:
Wang, Xiaowei,Zhang, Jianfang,Huang, Yang,et al. Design, Synthesis, and Biological Evaluation of 1-[(2-Benzyloxyl/alkoxyl)methyl]-5-halo-6-aryluracils as Potent HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors with an Improved Drug Resistance Profile[J]. JOURNAL OF MEDICINAL CHEMISTRY,2012,55(5):2242-2250.
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