Novel pyridinone derivatives as non-nucleoside reverse transcriptase inhibitors (NNRTIs) with high potency against NNRTI-resistant HIV-1 strains

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 & 1 others Junyi Liu

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)3593-3608
Number of pages16
JournalJournal of Medicinal Chemistry
Volume56
Issue number9
DOIs
StatePublished - May 9 2013

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Pyridones
Reverse Transcriptase Inhibitors
HIV-1
Viral Drug Resistance
A 17
RNA-Directed DNA Polymerase
Iodine
High Pressure Liquid Chromatography
Mutation
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Novel pyridinone derivatives as non-nucleoside reverse transcriptase inhibitors (NNRTIs) with high potency against NNRTI-resistant HIV-1 strains. / Li, Amin; Ouyang, Yabo; Wang, Ziyun; Cao, Yuanyuan; Liu, Xiangyi; Ran, Li; Li, Chao; Li, Li; Zhang, Liang; Qiao, Kang; Xu, Weisi; Huang, Yang; Zhang, Zhili; Tian, Chao; Liu, Zhenming; Jiang, Shibo; Shao, Yiming; Du, Yansheng; Ma, Liying; Wang, Xiaowei; Liu, Junyi.

In: Journal of Medicinal Chemistry, Vol. 56, No. 9, 09.05.2013, p. 3593-3608.

Research output: Contribution to journalArticle

Li, A, Ouyang, Y, Wang, Z, Cao, Y, Liu, X, Ran, L, Li, C, Li, L, Zhang, L, Qiao, K, Xu, W, Huang, Y, Zhang, Z, Tian, C, Liu, Z, Jiang, S, Shao, Y, Du, Y, Ma, L, Wang, X & Liu, J 2013, 'Novel pyridinone derivatives as non-nucleoside reverse transcriptase inhibitors (NNRTIs) with high potency against NNRTI-resistant HIV-1 strains', Journal of Medicinal Chemistry, vol. 56, no. 9, pp. 3593-3608. https://doi.org/10.1021/jm400102x
Li, Amin ; Ouyang, Yabo ; Wang, Ziyun ; Cao, Yuanyuan ; Liu, Xiangyi ; Ran, Li ; Li, Chao ; Li, Li ; Zhang, Liang ; Qiao, Kang ; Xu, Weisi ; Huang, Yang ; Zhang, Zhili ; Tian, Chao ; Liu, Zhenming ; Jiang, Shibo ; Shao, Yiming ; Du, Yansheng ; Ma, Liying ; Wang, Xiaowei ; Liu, Junyi. / Novel pyridinone derivatives as non-nucleoside reverse transcriptase inhibitors (NNRTIs) with high potency against NNRTI-resistant HIV-1 strains. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 9. pp. 3593-3608.
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AU - Cao, Yuanyuan

AU - Liu, Xiangyi

AU - Ran, Li

AU - Li, Chao

AU - Li, Li

AU - Zhang, Liang

AU - Qiao, Kang

AU - Xu, Weisi

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AU - Zhang, Zhili

AU - Tian, Chao

AU - Liu, Zhenming

AU - Jiang, Shibo

AU - Shao, Yiming

AU - Du, Yansheng

AU - Ma, Liying

AU - Wang, Xiaowei

AU - Liu, Junyi

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N2 - 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.

AB - 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.

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