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; Junyi Liu

doi:10.1021/jm400102x

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 WangJunyi Liu

Neurology

Research output: Contribution to journal › Article

27 Scopus citations

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 language	English (US)
Pages (from-to)	3593-3608
Number of pages	16
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	9
DOIs	https://doi.org/10.1021/jm400102x
State	Published - May 9 2013

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/jm400102x

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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., ... 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, 56(9), 3593-3608. https://doi.org/10.1021/jm400102x

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 journal › Article

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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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.",

author = "Amin Li and Yabo Ouyang and Ziyun Wang and Yuanyuan Cao and Xiangyi Liu and Li Ran and Chao Li and Li Li and Liang Zhang and Kang Qiao and Weisi Xu and Yang Huang and Zhili Zhang and Chao Tian and Zhenming Liu and Shibo Jiang and Yiming Shao and Yansheng Du and Liying Ma and Xiaowei Wang and Junyi Liu",

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AU - Li, Amin

AU - Ouyang, Yabo

AU - Wang, Ziyun

AU - Cao, Yuanyuan

AU - Liu, Xiangyi

AU - Ran, Li

AU - Li, Chao

AU - Li, Li

AU - Zhang, Liang

AU - Qiao, Kang

AU - Xu, Weisi

AU - Huang, Yang

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

PY - 2013/5/9

Y1 - 2013/5/9

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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