Synthesis and Anti-HCV Activity Evaluation of Anilino-heterobicyclic Derivatives

• Main Authors: Huang-Kai Peng, 彭皇凱
• Other Authors: Shyh-Chyun Yang
• Format: Others
• Language: zh-TW
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/43860653366065873994

博士 === 高雄醫學大學 === 藥學研究所 === 101 === In this study, the anti-HCV activities of the synthesized series of anilinoheterobicyclic derivatives 13-30, 35-45, and 47-61 were evaluated and their biological activities were discussed. A significant result was found that these synthesized derivatives were active against HCV. Based on this outcome, the relationships of their structures and activities were further illustrated. Among anilinoquinolines, compound 25 (EC50 = 7 ?嵱) with a strong EWG substituent on C3 of phenyl ring showed anti-HCV activity against NS3/4A protease. Among anilinocoumarins, compound 39 (EC50 = 12 ?嵱) with trimethoxy substituents on the phenyl ring was the first report which demonstrated coumarin-like derivatives inhibiting viral replication through an induction of IFN-mediated anti-viral response. Among the last part of derivatives, compound 59 (EC50 = 8 ?嵱) was observed to against NS5B polymerase by a non-competitive mode of inhibition. The best binding pose which calculated by computer molecular modeling of compound 59 was located in the Thumb II Pocket of HCV RdRp. Moreover, compounds 39 and 59 displayed the synergism decreasing HCV RNA levels by combination with IFN, telaprevir, BMS790052 or PSI7977. As a consequence, it is suggested that these three series of synthesized derivatives be promising to develop as novel anti-HCV small molecule inhibitors.