NDLI: Structure–activity relationship studies on quinoxalin-2(1H)-one derivatives containing thiazol-2-amine against hepatitis C virus leading to the discovery of BH6870

Content Provider	Springer Nature Link
Author	Zhong, Qi Fei Liu, Rui Liu, Gang
Copyright Year	2015
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 ( $$\hbox {EC}_{50} = 0.21\, μ \hbox {M}$$ ) and a good cell safety index (SI $$= 47.19$$ ). 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.
Starting Page	829
Ending Page	853
Page Count	25
File Format	PDF
ISSN	13811991
Journal	Molecular Diversity
Volume Number	19
Issue Number	4
e-ISSN	1573501X
Language	English
Publisher	Springer International Publishing
Publisher Date	2015-07-24
Publisher Place	Cham
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Antiviral activity Hepatitis C virus Quinoxalinone Structure–activity relationships Biochemistry Organic Chemistry Polymer Sciences Pharmacy
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Medicine Drug Discovery Molecular Biology Physical and Theoretical Chemistry Information Systems Catalysis Inorganic Chemistry

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