标题：Fused heterocycles bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 4: Design, synthesis and biological evaluation of novel imidazo[1,2-a]pyrazines
作者：Huang, Boshi; Liang, Xin; Li, Cuicui; Chen, Wenmin; Liu, Tao; Li, Xiao; Sun, Yueyue; Fu, Lu; Liu, Huiqing; De Clercq, Erik; Pannec 更多 作者机构：[Huang, Boshi; Liang, Xin; Li, Cuicui; Chen, Wenmin; Liu, Tao; Li, Xiao; Sun, Yueyue; Fu, Lu; Zhan, Peng; Liu, Xinyong] Shandong Univ, Sch Pharmaceut 更多
通讯作者地址：[Zhan, P]Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China.
来源：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
关键词：HIV-1 RT; Imidazo[1,2-a]pyrazines; Core-refining; NNRTIs; Biological; activity; Molecular simulation
摘要：Through a structure-guided core-refining approach, a series of novel imidazo[1,2-a]pyrazine derivatives were designed, synthesized and evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Biological results of antiviral assay in MT-4 cell cultures showed that 12 target compounds displayed moderate activities against wild-type (wt) HIV-1 strain (IIIB) with EC50 values ranging from 0.26 mu M to 19 JAM. Among them, 4a and 5a were found to be the two most active analogues possessing EC50 values of 0.26 mu M and 0.32 mu M respectively, comparable to delavirdine (DLV, EC50 = 0.54 mu M) and nevirapine (NVP, EC50 = 0.31 mu M) in a cell-based assay. Additionally, 9 compounds showed RI inhibitory activity superior to that of NVP. Moreover, some predicted drug-like properties of representative compounds 4a and 5a, as well as the structure-activity relationship (SAR) analysis were discussed in detail. The binding mode of compound 4a was investigated by molecular simulation studies. (C) 2015 Elsevier Masson SAS. All rights reserved.