Discovery of Novel Boron-Containing <em>N</em>-Substituted Oseltamivir Derivatives as Anti-Influenza A Virus Agents for Overcoming N1-H274Y Oseltamivir-Resistant
To address drug resistance to influenza virus neuraminidase inhibitors (NAIs), a series of novel boron-containing <i>N</i>-substituted oseltamivir derivatives were designed and synthesized to target the 150-cavity of neuraminidase (NA). In NA inhibitory assays, it was found that most of...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-09-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/27/19/6426 |
| _version_ | 1797477907954663424 |
|---|---|
| author | Ruifang Jia Jiwei Zhang Jian Zhang Chiara Bertagnin Anna Bonomini Laura Guizzo Zhen Gao Xiangkai Ji Zhuo Li Chuanfeng Liu Han Ju Xiuli Ma Arianna Loregian Bing Huang Peng Zhan Xinyong Liu |
| author_facet | Ruifang Jia Jiwei Zhang Jian Zhang Chiara Bertagnin Anna Bonomini Laura Guizzo Zhen Gao Xiangkai Ji Zhuo Li Chuanfeng Liu Han Ju Xiuli Ma Arianna Loregian Bing Huang Peng Zhan Xinyong Liu |
| author_sort | Ruifang Jia |
| collection | DOAJ |
| description | To address drug resistance to influenza virus neuraminidase inhibitors (NAIs), a series of novel boron-containing <i>N</i>-substituted oseltamivir derivatives were designed and synthesized to target the 150-cavity of neuraminidase (NA). In NA inhibitory assays, it was found that most of the new compounds exhibited moderate inhibitory potency against the wild-type NAs. Among them, compound <b>2c</b> bearing 4-(3-boronic acid benzyloxy)benzyl group displayed weaker or slightly improved activities against group-1 NAs (H1N1, H5N1, H5N8 and H5N1-H274Y) compared to that of oseltamivir carboxylate (<b>OSC</b>). Encouragingly, <b>2c</b> showed 4.6 times greater activity than <b>OSC</b> toward H5N1-H274Y NA. Moreover, <b>2c</b> exerted equivalent or more potent antiviral activities than <b>OSC</b> against H1N1, H5N1 and H5N8. Additionally, <b>2c</b> demonstrated low cytotoxicity in vitro and no acute toxicity at the dose of 1000 mg/kg in mice. Molecular docking of <b>2c</b> was employed to provide a possible explanation for the improved anti-H274Y NA activity, which may be due to the formation of key additional hydrogen bonds with surrounding amino acid residues, such as Arg152, Gln136 and Val149. Taken together, <b>2c</b> appeared to be a promising lead compound for further optimization. |
| first_indexed | 2024-03-09T21:24:26Z |
| format | Article |
| id | doaj.art-31d58646425e4f5fae5d75af1d8c6889 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T21:24:26Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-31d58646425e4f5fae5d75af1d8c68892023-11-23T21:11:16ZengMDPI AGMolecules1420-30492022-09-012719642610.3390/molecules27196426Discovery of Novel Boron-Containing <em>N</em>-Substituted Oseltamivir Derivatives as Anti-Influenza A Virus Agents for Overcoming N1-H274Y Oseltamivir-ResistantRuifang Jia0Jiwei Zhang1Jian Zhang2Chiara Bertagnin3Anna Bonomini4Laura Guizzo5Zhen Gao6Xiangkai Ji7Zhuo Li8Chuanfeng Liu9Han Ju10Xiuli Ma11Arianna Loregian12Bing Huang13Peng Zhan14Xinyong Liu15Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, ChinaDepartment of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, ChinaInstitute of Medical Sciences, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, ChinaDepartment of Molecular Medicine, University of Padova, Via Gabelli 63, 35121 Padova, ItalyDepartment of Molecular Medicine, University of Padova, Via Gabelli 63, 35121 Padova, ItalyDepartment of Molecular Medicine, University of Padova, Via Gabelli 63, 35121 Padova, ItalyDepartment of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, ChinaDepartment of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, ChinaDepartment of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, ChinaDepartment of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, ChinaDepartment of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, ChinaInstitute of Poultry Science, Shandong Academy of Agricultural Sciences, 1 Jiaoxiao Road, Jinan 250023, ChinaDepartment of Molecular Medicine, University of Padova, Via Gabelli 63, 35121 Padova, ItalyInstitute of Poultry Science, Shandong Academy of Agricultural Sciences, 1 Jiaoxiao Road, Jinan 250023, ChinaDepartment of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, ChinaDepartment of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, ChinaTo address drug resistance to influenza virus neuraminidase inhibitors (NAIs), a series of novel boron-containing <i>N</i>-substituted oseltamivir derivatives were designed and synthesized to target the 150-cavity of neuraminidase (NA). In NA inhibitory assays, it was found that most of the new compounds exhibited moderate inhibitory potency against the wild-type NAs. Among them, compound <b>2c</b> bearing 4-(3-boronic acid benzyloxy)benzyl group displayed weaker or slightly improved activities against group-1 NAs (H1N1, H5N1, H5N8 and H5N1-H274Y) compared to that of oseltamivir carboxylate (<b>OSC</b>). Encouragingly, <b>2c</b> showed 4.6 times greater activity than <b>OSC</b> toward H5N1-H274Y NA. Moreover, <b>2c</b> exerted equivalent or more potent antiviral activities than <b>OSC</b> against H1N1, H5N1 and H5N8. Additionally, <b>2c</b> demonstrated low cytotoxicity in vitro and no acute toxicity at the dose of 1000 mg/kg in mice. Molecular docking of <b>2c</b> was employed to provide a possible explanation for the improved anti-H274Y NA activity, which may be due to the formation of key additional hydrogen bonds with surrounding amino acid residues, such as Arg152, Gln136 and Val149. Taken together, <b>2c</b> appeared to be a promising lead compound for further optimization.https://www.mdpi.com/1420-3049/27/19/6426influenzaneuraminidase inhibitorsoseltamivir derivatives150-cavityboronic acid |
| spellingShingle | Ruifang Jia Jiwei Zhang Jian Zhang Chiara Bertagnin Anna Bonomini Laura Guizzo Zhen Gao Xiangkai Ji Zhuo Li Chuanfeng Liu Han Ju Xiuli Ma Arianna Loregian Bing Huang Peng Zhan Xinyong Liu Discovery of Novel Boron-Containing <em>N</em>-Substituted Oseltamivir Derivatives as Anti-Influenza A Virus Agents for Overcoming N1-H274Y Oseltamivir-Resistant Molecules influenza neuraminidase inhibitors oseltamivir derivatives 150-cavity boronic acid |
| title | Discovery of Novel Boron-Containing <em>N</em>-Substituted Oseltamivir Derivatives as Anti-Influenza A Virus Agents for Overcoming N1-H274Y Oseltamivir-Resistant |
| title_full | Discovery of Novel Boron-Containing <em>N</em>-Substituted Oseltamivir Derivatives as Anti-Influenza A Virus Agents for Overcoming N1-H274Y Oseltamivir-Resistant |
| title_fullStr | Discovery of Novel Boron-Containing <em>N</em>-Substituted Oseltamivir Derivatives as Anti-Influenza A Virus Agents for Overcoming N1-H274Y Oseltamivir-Resistant |
| title_full_unstemmed | Discovery of Novel Boron-Containing <em>N</em>-Substituted Oseltamivir Derivatives as Anti-Influenza A Virus Agents for Overcoming N1-H274Y Oseltamivir-Resistant |
| title_short | Discovery of Novel Boron-Containing <em>N</em>-Substituted Oseltamivir Derivatives as Anti-Influenza A Virus Agents for Overcoming N1-H274Y Oseltamivir-Resistant |
| title_sort | discovery of novel boron containing em n em substituted oseltamivir derivatives as anti influenza a virus agents for overcoming n1 h274y oseltamivir resistant |
| topic | influenza neuraminidase inhibitors oseltamivir derivatives 150-cavity boronic acid |
| url | https://www.mdpi.com/1420-3049/27/19/6426 |
| work_keys_str_mv | AT ruifangjia discoveryofnovelboroncontainingemnemsubstitutedoseltamivirderivativesasantiinfluenzaavirusagentsforovercomingn1h274yoseltamivirresistant AT jiweizhang discoveryofnovelboroncontainingemnemsubstitutedoseltamivirderivativesasantiinfluenzaavirusagentsforovercomingn1h274yoseltamivirresistant AT jianzhang discoveryofnovelboroncontainingemnemsubstitutedoseltamivirderivativesasantiinfluenzaavirusagentsforovercomingn1h274yoseltamivirresistant AT chiarabertagnin discoveryofnovelboroncontainingemnemsubstitutedoseltamivirderivativesasantiinfluenzaavirusagentsforovercomingn1h274yoseltamivirresistant AT annabonomini discoveryofnovelboroncontainingemnemsubstitutedoseltamivirderivativesasantiinfluenzaavirusagentsforovercomingn1h274yoseltamivirresistant AT lauraguizzo discoveryofnovelboroncontainingemnemsubstitutedoseltamivirderivativesasantiinfluenzaavirusagentsforovercomingn1h274yoseltamivirresistant AT zhengao discoveryofnovelboroncontainingemnemsubstitutedoseltamivirderivativesasantiinfluenzaavirusagentsforovercomingn1h274yoseltamivirresistant AT xiangkaiji discoveryofnovelboroncontainingemnemsubstitutedoseltamivirderivativesasantiinfluenzaavirusagentsforovercomingn1h274yoseltamivirresistant AT zhuoli discoveryofnovelboroncontainingemnemsubstitutedoseltamivirderivativesasantiinfluenzaavirusagentsforovercomingn1h274yoseltamivirresistant AT chuanfengliu discoveryofnovelboroncontainingemnemsubstitutedoseltamivirderivativesasantiinfluenzaavirusagentsforovercomingn1h274yoseltamivirresistant AT hanju discoveryofnovelboroncontainingemnemsubstitutedoseltamivirderivativesasantiinfluenzaavirusagentsforovercomingn1h274yoseltamivirresistant AT xiulima discoveryofnovelboroncontainingemnemsubstitutedoseltamivirderivativesasantiinfluenzaavirusagentsforovercomingn1h274yoseltamivirresistant AT ariannaloregian discoveryofnovelboroncontainingemnemsubstitutedoseltamivirderivativesasantiinfluenzaavirusagentsforovercomingn1h274yoseltamivirresistant AT binghuang discoveryofnovelboroncontainingemnemsubstitutedoseltamivirderivativesasantiinfluenzaavirusagentsforovercomingn1h274yoseltamivirresistant AT pengzhan discoveryofnovelboroncontainingemnemsubstitutedoseltamivirderivativesasantiinfluenzaavirusagentsforovercomingn1h274yoseltamivirresistant AT xinyongliu discoveryofnovelboroncontainingemnemsubstitutedoseltamivirderivativesasantiinfluenzaavirusagentsforovercomingn1h274yoseltamivirresistant |