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 |
|---|---|
| Pages (from-to) | 3593-3608 |
| Number of pages | 16 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 56 |
| Issue number | 9 |
| DOIs | |
| State | Published - May 9 2013 |
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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 journal › Article
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TY - JOUR
T1 - Novel pyridinone derivatives as non-nucleoside reverse transcriptase inhibitors (NNRTIs) with high potency against NNRTI-resistant HIV-1 strains
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.
UR - http://www.scopus.com/inward/record.url?scp=84877704978&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84877704978&partnerID=8YFLogxK
U2 - 10.1021/jm400102x
DO - 10.1021/jm400102x
M3 - Article
C2 - 23540737
AN - SCOPUS:84877704978
VL - 56
SP - 3593
EP - 3608
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 9
ER -