Quinoxalin-2(1H)-One Derivatives As Inhibitors Against Hepatitis C Virus

• Published in: Journal of medicinal chemistry 2011-08, Vol.54 (16), p.5747-5768
• Main Authors: Liu, Rui, Huang, Zhuhui, Murray, Michael G, Guo, Xiaoyong, Liu, Gang
• Format: Article
• Language: English
• Subjects: Cell Line, Tumor; Dose-Response Relationship, Drug; Hepacivirus - drug effects; Humans; Models, Chemical; Models, Molecular; Molecular Structure; Quinoxalines - chemical synthesis; Quinoxalines - chemistry; Quinoxalines - pharmacology; Structure-Activity Relationship; Virus Replication - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm200394x

Hepatitis C virus (HCV) infection is a serious problem worldwide, but no effective drugs are currently available. Through screening of our privileged structure library, quinoxalin-2(1H)-one derivative N-(7-(cyclohexyl(methyl)amino)-3-oxo-3,4-dihydroquinoxalin-6-ylcarbamothioyl)benzamide (compound 1) was identified as potent HCV inhibitor in vitro. Subsequently, a structure–activity relationship analysis was carried out that showed N-(7-(cyclohexyl(methyl)amino)-3-oxo-3,4-dihydroquinoxalin-6-ylcarbamothioyl)furan-2-carboxamide (compound 11, EC50 = 1.8 μM, SI = 9.6), 6-(cyclohexyl(methyl)amino)-7-(4-phenylthiazol-2-ylamino)quinoxalin-2(1H)-one (compound 33, EC50 = 1.67 μM, SI = 37.4), 2-(cyclohexyl(methyl)amino)-3-(4-phenylthiazol-2-ylamino)-7,8,9,10-tetrahydro-5H-pyrido[1,2-a]quinoxalin-6(6aH)-one (compound 60, EC50 = 1.19 μM, SI = 9.27), 8-(cyclohexyl(methyl)amino)-7-(4-phenylthiazol-2-ylamino)pyrrolo[1,2-a]quinoxalin-4(5H)-one (compound 65, EC50 = 1.82 μM, SI = 9.9), and 6-(diethylamino)-7-(4-phenylthiazol-2-ylamino)quinoxalin-2(1H)-one (compound 78, EC50 = 1.27 μM, SI = 17.9) acted against HCV. The data from the structure–activity relationship study suggests that quinoxalin-2(1H)-one derivatives exhibited potent activity against HCV.