Structure-activity relationship studies on quinoxalin-2(1H)-one derivatives containing thiazol-2-amine against hepatitis C virus leading to the discovery of BH6870.
Identifieur interne : 001239 ( Main/Exploration ); précédent : 001238; suivant : 001240Structure-activity relationship studies on quinoxalin-2(1H)-one derivatives containing thiazol-2-amine against hepatitis C virus leading to the discovery of BH6870.
Auteurs : Qi-Fei Zhong [République populaire de Chine] ; Rui Liu [République populaire de Chine] ; Gang Liu [République populaire de Chine]Source :
- Molecular diversity [ 1573-501X ] ; 2015.
Descripteurs français
- KwdFr :
- MESH :
- pharmacocinétique : Amines.
- pharmacologie : Antiviraux.
- synthèse chimique : Amines, Antiviraux.
- Amines, Antiviraux, Hepacivirus, Humains, Lignée cellulaire, Quinoxalines, Relation structure-activité, Réplication virale, Structure moléculaire.
English descriptors
- KwdEn :
- Amines (chemical synthesis), Amines (chemistry), Amines (pharmacokinetics), Antiviral Agents (chemical synthesis), Antiviral Agents (chemistry), Antiviral Agents (pharmacology), Cell Line, Hepacivirus (drug effects), Humans, Molecular Structure, Quinoxalines (chemistry), Structure-Activity Relationship, Virus Replication (drug effects).
- MESH :
- chemical , chemical synthesis : Amines, Antiviral Agents.
- chemical , chemistry : Amines, Antiviral Agents, Quinoxalines.
- chemical , pharmacokinetics : Amines.
- chemical , pharmacology : Antiviral Agents.
- drug effects : Hepacivirus, Virus Replication.
- Cell Line, Humans, Molecular Structure, Structure-Activity Relationship.
Abstract
Chronic hepatitis C virus infection represents a serious global public health problem, typically resulting in fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. Based on our previous discovery of lead compound 2 (Liu et al. J Med Chem 54:5747-5768, 2011), 35 new quinoxalinone derivatives were explored in this study. Outline of the structure-activity relationships (SARs) revealed that compound BH6870 (36) showed high anti-HCV potency ([Formula: see text]) and a good cell safety index (SI [Formula: see text]). SARs analysis indicated that quinoxalin-2(1H)-one containing a 4-aryl-substituted thiazol-2-amine moiety was optimal for antiviral activity. Introducing a hydrogen-bond acceptor (such as ester or amide group) at the C-3 position of quinoxalin-2(1H)-one was beneficial for the antiviral potency, and especially, N,N-disubstituted amide was far superior to N-monosubstituted amide. Incorporation of more than one halogen (fluorine or chlorine atom) or a strong electron-withdrawing group on the benzene ring of the thiazole-phenyl moiety might reduce electron atmosphere density further and resulted in a dramatical loss of activity. The NH-group of the lactam moiety was clearly required for anti-HCV activity. Design and synthesis of quinoxalin-2(1H)-one derivatives as new non-nucleoside small-molecule HCV inhibitors. BH6870 (36), showing higher antiviral potency and a good cell safety index, was identified.
DOI: 10.1007/s11030-015-9610-6
PubMed: 26205408
Affiliations:
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Le document en format XML
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Medical Sciences and Peking Union Medical College, 2 Nanwei Rd., Xicheng Dist., Beijing, 100050, People's Republic of China. gangliu27@gmail.com.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 2 Nanwei Rd., Xicheng Dist., Beijing, 100050</wicri:regionArea><wicri:noRegion>100050</wicri:noRegion></affiliation></author></analytic><series><title level="j">Molecular diversity</title><idno type="eISSN">1573-501X</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amines (chemical synthesis)</term><term>Amines (chemistry)</term><term>Amines (pharmacokinetics)</term><term>Antiviral Agents (chemical synthesis)</term><term>Antiviral Agents (chemistry)</term><term>Antiviral Agents (pharmacology)</term><term>Cell 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Based on our previous discovery of lead compound 2 (Liu et al. J Med Chem 54:5747-5768, 2011), 35 new quinoxalinone derivatives were explored in this study. Outline of the structure-activity relationships (SARs) revealed that compound BH6870 (36) showed high anti-HCV potency ([Formula: see text]) and a good cell safety index (SI [Formula: see text]). SARs analysis indicated that quinoxalin-2(1H)-one containing a 4-aryl-substituted thiazol-2-amine moiety was optimal for antiviral activity. Introducing a hydrogen-bond acceptor (such as ester or amide group) at the C-3 position of quinoxalin-2(1H)-one was beneficial for the antiviral potency, and especially, N,N-disubstituted amide was far superior to N-monosubstituted amide. Incorporation of more than one halogen (fluorine or chlorine atom) or a strong electron-withdrawing group on the benzene ring of the thiazole-phenyl moiety might reduce electron atmosphere density further and resulted in a dramatical loss of activity. The NH-group of the lactam moiety was clearly required for anti-HCV activity. Design and synthesis of quinoxalin-2(1H)-one derivatives as new non-nucleoside small-molecule HCV inhibitors. BH6870 (36), showing higher antiviral potency and a good cell safety index, was identified. </div></front></TEI><affiliations><list><country><li>République populaire de Chine</li></country></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Zhong, Qi Fei" sort="Zhong, Qi Fei" uniqKey="Zhong Q" first="Qi-Fei" last="Zhong">Qi-Fei Zhong</name></noRegion><name sortKey="Liu, Gang" sort="Liu, Gang" uniqKey="Liu G" first="Gang" last="Liu">Gang Liu</name><name sortKey="Liu, Rui" sort="Liu, Rui" uniqKey="Liu R" first="Rui" last="Liu">Rui Liu</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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