Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 2A Nanwei Road, Xicheng District, Beijing 100050, PR China.
J Med Chem. 2011 Aug 25;54(16):5747-68. doi: 10.1021/jm200394x. Epub 2011 Aug 1.
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, EC(50)=1.8 μM, SI=9.6), 6-(cyclohexyl(methyl)amino)-7-(4-phenylthiazol-2-ylamino)quinoxalin-2(1H)-one (compound 33, EC(50)=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, EC(50)=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, EC(50)=1.82 μM, SI=9.9), and 6-(diethylamino)-7-(4-phenylthiazol-2-ylamino)quinoxalin-2(1H)-one (compound 78, EC(50)=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.
丙型肝炎病毒（HCV）感染是一个全球性的严重问题，但目前还没有有效的药物。通过对我们的特权结构库进行筛选，我们发现喹喔啉-2(1H)-酮衍生物 N-(7-(环己基（甲基）氨基)-3-氧代-3,4-二氢喹喔啉-6-基氨甲硫酰基)苯甲酰胺（化合物 1）在体外具有很强的 HCV 抑制活性。随后，进行了构效关系分析，结果表明 N-(7-(环己基（甲基）氨基)-3-氧代-3,4-二氢喹喔啉-6-基氨甲硫酰基)呋喃-2-甲酰胺（化合物 11，EC(50)=1.8 μM，SI=9.6）、6-(环己基（甲基）氨基)-7-(4-噻唑基氨基)喹喔啉-2(1H)-酮（化合物 33，EC(50)=1.67 μM，SI=37.4）、2-(环己基（甲基）氨基)-3-(4-噻唑基氨基)-7,8,9,10-四氢-5H-吡啶并[1,2-a]喹喔啉-6(6aH)-酮（化合物 60，EC(50)=1.19 μM，SI=9.27）、8-(环己基（甲基）氨基)-7-(4-噻唑基氨基)吡咯并[1,2-a]喹喔啉-4(5H)-酮（化合物 65，EC(50)=1.82 μM，SI=9.9）和 6-(二乙氨基)-7-(4-噻唑基氨基)喹喔啉-2(1H)-酮（化合物 78，EC(50)=1.27 μM，SI=17.9）对 HCV 具有活性。构效关系研究的数据表明，喹喔啉-2(1H)-酮衍生物对 HCV 具有很强的活性。
