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学科主题: 药学
题名:
Novel Pyridinone Derivatives As Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) with High Potency against NNRTI-Resistant HIV-1 Strains
作者: Li, Amin1; Ouyang, Yabo3; Wang, Ziyun2; Cao, Yuanyuan1; Liu, Xiangyi1; Ran, Li2; Li, Chao1; Li, Li1; Zhang, Liang1; Qiao, Kang2; Xu, Weisi3; Huang, Yang3; Zhang, Zhili1; Tian, Chao1; Liu, Zhenming2; Jiang, Shibo4,5,6; Shao, Yiming3; Du, Yansheng7; Ma, Liying3; Wang, Xiaowei1; Liu, Junyi1,2
刊名: JOURNAL OF MEDICINAL CHEMISTRY
发表日期: 2013-05-09
DOI: 10.1021/jm400102x
卷: 56, 期:9, 页:3593-3608
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 ; DRUG-RESISTANCE ; POSITIONAL ADAPTABILITY ; BIOLOGICAL EVALUATION ; ETRAVIRINE TMC125 ; WILD-TYPE ; DESIGN ; PREVENTION ; COMPLEXES ; SERIES
英文摘要:

Novel 6-substituted-4-cycloalkyloxy-pyridin-2(1H)-ones were synthesized as non-nucleoside reverse transcriptase inhibitors (NNRTIs), and their biological activity was evaluated. Most of the compounds, especially 26 and 22, bearing a 3-isopropyl and 3-iodine group, respectively, exhibited highly potent activity against wild-type HIV-1 strains and those resistant to reverse transcriptase inhibitors (RTIs). The diastereoisomers of 26-trans and 26-cis were synthesized separately and confirmed with HPLC and NOESY spectra. The 26-trans isomers had an activity about 400-fold more potent than that of 26-cis. The pair of 26-trans enantiomers, one of the most potent inhibitors with EC50 of 4 nM and selectivity index (SI) of 75000, was highly effective against a panel of RTIs-resistant strains with single (Y181C and K103N) or double (A17) mutations in reverse transcriptase. The results suggest that these novel pyridinone derivatives have the potential to be further developed as new antiretroviral drugs with improved antiviral efficacy and drug resistance profile.

语种: 英语
所属项目编号: 21172014 ; 20972011 ; 21042009 ; 30872232 ; 812111023 ; 81172733 ; 2009ZX09301-010 ; 2011SICLID102
项目资助者: National Natural Science Foundation of China ; Ministry of Science and Technology of China ; SKLID
WOS记录号: WOS:000318892500015
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/65894
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.Peking Univ, Dept Biol Chem, Sch Pharmaceut Sci, Beijing 100191, Peoples R China
3.Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
4.Chinese Ctr Dis Control & Prevent, Natl Ctr AIDS STD Control & Prevent NCAIDS, State Key Lab Infect Dis Prevent & Control, Beijing 102206, Peoples R China
5.Fudan Univ, Lab Med Mol Virol, Shanghai Med Coll, Minist Educ, Shanghai 200032, Peoples R China
6.Fudan Univ, Lab Med Mol Virol, Shanghai Med Coll, Minist Hlth, Shanghai 200032, Peoples R China
7.Indiana Univ Sch Med, Dept Neurol, Indianapolis, IN 46202 USA

Recommended Citation:
Li, Amin,Ouyang, Yabo,Wang, Ziyun,et al. Novel Pyridinone Derivatives As Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) with High Potency against NNRTI-Resistant HIV-1 Strains[J]. JOURNAL OF MEDICINAL CHEMISTRY,2013,56(9):3593-3608.
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