Jingying Qiu , Qingqing Zhou , Yueting Zou , Shuqiong Li , Lihua Yang , Wang Chen , Jian Gao , Xiaoke Gu
{"title":"具有TLR8激动作用的新型喹唑啉酮类抗hbv药物的设计与合成","authors":"Jingying Qiu , Qingqing Zhou , Yueting Zou , Shuqiong Li , Lihua Yang , Wang Chen , Jian Gao , Xiaoke Gu","doi":"10.1016/j.ejmech.2022.114159","DOIUrl":null,"url":null,"abstract":"<div><p><span>Hepatitis B virus<span> (HBV) infection is a worldwide threat to public health. In this work, a series of novel quinazolinone derivatives (</span></span><strong>5a-q</strong>) were synthesized and evaluated as novel anti-HBV agents. Among them, compound <strong>5l</strong><span> exhibited potent inhibitory effect on HBV DNA replication in both wild type and drug resistant (lamivudine and entecavir) HBV strains with IC</span><sub>50</sub> values of 0.15 and 0.10 μM, respectively. Notably, the selective index value of <strong>5l</strong><span> was high above 66.67, indicating the favorable safety profile. Molecular docking study indicated that compound </span><strong>5l</strong><span> well fitted into the binding pocket of TLR8 protein-protein interface. Dual-luciferase reporter gene assay further confirmed that compound </span><strong>5l</strong> could dose-dependently activate TLR8, thus effectively inducing the activity of TLR8-dependent NF-κB. Collectively, compound <strong>5l</strong> displayed potent anti-HBV activities and TLR8 agonist effect in vitro, and might be a potential immunomodulatory anti-HBV agent to warrant further investigation.</p></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0000,"publicationDate":"2022-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"2","resultStr":"{\"title\":\"Design and synthesis of novel quinazolinone derivatives as anti-HBV agents with TLR8 agonist effect\",\"authors\":\"Jingying Qiu , Qingqing Zhou , Yueting Zou , Shuqiong Li , Lihua Yang , Wang Chen , Jian Gao , Xiaoke Gu\",\"doi\":\"10.1016/j.ejmech.2022.114159\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p><span>Hepatitis B virus<span> (HBV) infection is a worldwide threat to public health. In this work, a series of novel quinazolinone derivatives (</span></span><strong>5a-q</strong>) were synthesized and evaluated as novel anti-HBV agents. Among them, compound <strong>5l</strong><span> exhibited potent inhibitory effect on HBV DNA replication in both wild type and drug resistant (lamivudine and entecavir) HBV strains with IC</span><sub>50</sub> values of 0.15 and 0.10 μM, respectively. Notably, the selective index value of <strong>5l</strong><span> was high above 66.67, indicating the favorable safety profile. Molecular docking study indicated that compound </span><strong>5l</strong><span> well fitted into the binding pocket of TLR8 protein-protein interface. Dual-luciferase reporter gene assay further confirmed that compound </span><strong>5l</strong> could dose-dependently activate TLR8, thus effectively inducing the activity of TLR8-dependent NF-κB. Collectively, compound <strong>5l</strong> displayed potent anti-HBV activities and TLR8 agonist effect in vitro, and might be a potential immunomodulatory anti-HBV agent to warrant further investigation.</p></div>\",\"PeriodicalId\":314,\"journal\":{\"name\":\"European Journal of Medicinal Chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.0000,\"publicationDate\":\"2022-03-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"2\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0223523422000617\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0223523422000617","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Design and synthesis of novel quinazolinone derivatives as anti-HBV agents with TLR8 agonist effect
Hepatitis B virus (HBV) infection is a worldwide threat to public health. In this work, a series of novel quinazolinone derivatives (5a-q) were synthesized and evaluated as novel anti-HBV agents. Among them, compound 5l exhibited potent inhibitory effect on HBV DNA replication in both wild type and drug resistant (lamivudine and entecavir) HBV strains with IC50 values of 0.15 and 0.10 μM, respectively. Notably, the selective index value of 5l was high above 66.67, indicating the favorable safety profile. Molecular docking study indicated that compound 5l well fitted into the binding pocket of TLR8 protein-protein interface. Dual-luciferase reporter gene assay further confirmed that compound 5l could dose-dependently activate TLR8, thus effectively inducing the activity of TLR8-dependent NF-κB. Collectively, compound 5l displayed potent anti-HBV activities and TLR8 agonist effect in vitro, and might be a potential immunomodulatory anti-HBV agent to warrant further investigation.
期刊介绍：
The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers.
A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.
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