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Novel Pyridinone Derivatives As Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) with High Potency against NNRTI-Resistant HIV-1 Strains
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
2013-05-09
DOI10.1021/jm400102x
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
WOS记录号WOS:000318892500015
Citation statistics
Cited Times:19[WOS]   [WOS Record]     [Related Records in WOS]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/65894
Collection北京大学药学院_药物化学系
北京大学药学院
北京大学药学院_化学生物学系
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
GB/T 7714
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.
APA Li, Amin.,Ouyang, Yabo.,Wang, Ziyun.,Cao, Yuanyuan.,Liu, Xiangyi.,...&Liu, Junyi.(2013).Novel Pyridinone Derivatives As Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) with High Potency against NNRTI-Resistant HIV-1 Strains.JOURNAL OF MEDICINAL CHEMISTRY,56(9),3593-3608.
MLA Li, Amin,et al."Novel Pyridinone Derivatives As Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) with High Potency against NNRTI-Resistant HIV-1 Strains".JOURNAL OF MEDICINAL CHEMISTRY 56.9(2013):3593-3608.
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