Synthesis and Cap-Dependent Endonuclease Inhibition of Baloxavir Derivatives
Baloxavir marboxil is a creative antiviral drug for influenza A and B viruses with a novel mechanism of action. In this study, three series comprising a total of 21 previously unreported target compounds were designed and synthesized. The drug-likeness of these compounds was evaluated by molecular d...
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MDPI AG
2023-06-01
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| Online Access: | https://www.mdpi.com/2073-4352/13/7/988 |
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| author | Yiyun Wang Jiaru Wang Hui Wu Longyao Cui Zihui Meng Zhibin Xu Zhonghui Zheng Jiarong Li |
| author_facet | Yiyun Wang Jiaru Wang Hui Wu Longyao Cui Zihui Meng Zhibin Xu Zhonghui Zheng Jiarong Li |
| author_sort | Yiyun Wang |
| collection | DOAJ |
| description | Baloxavir marboxil is a creative antiviral drug for influenza A and B viruses with a novel mechanism of action. In this study, three series comprising a total of 21 previously unreported target compounds were designed and synthesized. The drug-likeness of these compounds was evaluated by molecular docking, PAINS-Remover and SwissADME. The inhibitory effect and affinity of the compounds on the cap-dependent endonuclease activity of the influenza virus were evaluated. Compounds <b>I-4, II-1~II-9</b> and compound <b>III-8</b> showed similar inhibitory activity to baloxavir (7.45 μM) on the cap-dependent endonuclease. In particular, compounds <b>I-4</b> (3.29 μM) and <b>II-2</b> (1.46 μM) showed strong cap-dependent endonuclease inhibitory activity. The structure–activity relationship studies showed that the inhibitive effect of the compounds on endonuclease was enhanced when the dibenzothiepin rings were substituted by diphenylmethyl containing chiral-center electron-withdrawing groups, dibenzocycloheptane, dihydrodibenzo[b,e]oxepin, and five-member heterocycles containing aryl substitution. |
| first_indexed | 2024-03-11T01:11:08Z |
| format | Article |
| id | doaj.art-d7f9a5ea1a1c422983d4fab95c8ffb39 |
| institution | Directory Open Access Journal |
| issn | 2073-4352 |
| language | English |
| last_indexed | 2024-03-11T01:11:08Z |
| publishDate | 2023-06-01 |
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| record_format | Article |
| series | Crystals |
| spelling | doaj.art-d7f9a5ea1a1c422983d4fab95c8ffb392023-11-18T18:52:49ZengMDPI AGCrystals2073-43522023-06-0113798810.3390/cryst13070988Synthesis and Cap-Dependent Endonuclease Inhibition of Baloxavir DerivativesYiyun Wang0Jiaru Wang1Hui Wu2Longyao Cui3Zihui Meng4Zhibin Xu5Zhonghui Zheng6Jiarong Li7School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, ChinaSchool of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, ChinaShandong Xinhua Pharmaceutical Co., Ltd., No. 1 Lutai Avenue, Zibo 255086, ChinaShandong Xinhua Pharmaceutical Co., Ltd., No. 1 Lutai Avenue, Zibo 255086, ChinaSchool of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, ChinaSchool of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, ChinaShandong Xinhua Pharmaceutical Co., Ltd., No. 1 Lutai Avenue, Zibo 255086, ChinaSchool of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, ChinaBaloxavir marboxil is a creative antiviral drug for influenza A and B viruses with a novel mechanism of action. In this study, three series comprising a total of 21 previously unreported target compounds were designed and synthesized. The drug-likeness of these compounds was evaluated by molecular docking, PAINS-Remover and SwissADME. The inhibitory effect and affinity of the compounds on the cap-dependent endonuclease activity of the influenza virus were evaluated. Compounds <b>I-4, II-1~II-9</b> and compound <b>III-8</b> showed similar inhibitory activity to baloxavir (7.45 μM) on the cap-dependent endonuclease. In particular, compounds <b>I-4</b> (3.29 μM) and <b>II-2</b> (1.46 μM) showed strong cap-dependent endonuclease inhibitory activity. The structure–activity relationship studies showed that the inhibitive effect of the compounds on endonuclease was enhanced when the dibenzothiepin rings were substituted by diphenylmethyl containing chiral-center electron-withdrawing groups, dibenzocycloheptane, dihydrodibenzo[b,e]oxepin, and five-member heterocycles containing aryl substitution.https://www.mdpi.com/2073-4352/13/7/988baloxavirderivativessynthesisinhibition |
| spellingShingle | Yiyun Wang Jiaru Wang Hui Wu Longyao Cui Zihui Meng Zhibin Xu Zhonghui Zheng Jiarong Li Synthesis and Cap-Dependent Endonuclease Inhibition of Baloxavir Derivatives Crystals baloxavir derivatives synthesis inhibition |
| title | Synthesis and Cap-Dependent Endonuclease Inhibition of Baloxavir Derivatives |
| title_full | Synthesis and Cap-Dependent Endonuclease Inhibition of Baloxavir Derivatives |
| title_fullStr | Synthesis and Cap-Dependent Endonuclease Inhibition of Baloxavir Derivatives |
| title_full_unstemmed | Synthesis and Cap-Dependent Endonuclease Inhibition of Baloxavir Derivatives |
| title_short | Synthesis and Cap-Dependent Endonuclease Inhibition of Baloxavir Derivatives |
| title_sort | synthesis and cap dependent endonuclease inhibition of baloxavir derivatives |
| topic | baloxavir derivatives synthesis inhibition |
| url | https://www.mdpi.com/2073-4352/13/7/988 |
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