Novel Pyridinone Derivatives As Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) with High Potency against NNRTI-Resistant HIV-1 Strains

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• 作者：Amin Li ; Yabo Ouyang ; Ziyun Wang ; Yuanyuan Cao ; Xiangyi Liu ; Li Ran ; Chao Li ; Li Li ; Liang Zhang ; Kang Qiao ; Weisi Xu ; Yang Huang ; Zhili Zhang ; Chao Tian ; Zhenming Liu ; Shibo Jiang ; Yiming Shao ; Yansheng Du ; Liying Ma ; Xiaowei Wang ; Junyi Liu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：May 9, 2013
• 年：2013
• 卷：56
• 期：9
• 页码：3593-3608
• 全文大小：606K
• 年卷期：v.56,no.9(May 9, 2013)
• ISSN：1520-4804

文摘

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.