title: Structure-activity relationship studies on quinoxalin-2(1H)-one derivatives containing thiazol-2-amine against hepatitis C virus leading to the discovery of BH6870.
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.
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 2 Nanwei Rd., Xicheng Dist., Beijing, 100050, People's Republic of China.
authors.forename: Qi-Fei
authors.initials: QF
authors.lastname: Zhong
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 2 Nanwei Rd., Xicheng Dist., Beijing, 100050, People's Republic of China.
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 2 Nanwei Rd., Xicheng Dist., Beijing, 100050, People's Republic of China. gangliu27@gmail.com.|Tsinghua-Peking Center for Life Sciences and Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Haidian Dist., Beijing, 100084, People's Republic of China. gangliu27@gmail.com.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
mesh_terms: D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D016174:Hepacivirus / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D011810:Quinoxalines / Q000737:chemistry; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000588:Amines; D000998:Antiviral Agents; D011810:Quinoxalines
keywords: Antiviral activity; Hepatitis C virus; Quinoxalinone; Structure–activity relationships