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 : 002B04 ( Ncbi/Checkpoint ); précédent : 002B03; suivant : 002B05Structure-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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pubmed:26205408Le document en format XML
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<front><div type="abstract" xml:lang="en">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. </div>
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