Kounde Cyrille S, Yeo Hui-Quan, Wang Qing-Yin, Wan Kah Fei, Dong Hongping, Karuna Ratna, Dix Ina, Wagner Trixie, Zou Bin, Simon Oliver, Bonamy Ghislain M C, Yeung Bryan K S, Yokokawa Fumiaki
Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, 138670, Singapore.
Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, 138670, Singapore.
Bioorg Med Chem Lett. 2017 Mar 15;27(6):1385-1389. doi: 10.1016/j.bmcl.2017.02.005. Epub 2017 Feb 4.
A series of 2-oxopiperazine derivatives were designed from the pyrrolopiperazinone cell-based screening hit 4 as a dengue virus inhibitor. Systematic investigation of the structure-activity relationship (SAR) around the piperazinone ring led to the identification of compound (S)-29, which exhibited potent anti-dengue activity in the cell-based assay across all four dengue serotypes with EC<0.1μM. Cross-resistant analysis confirmed that the virus NS4B protein remained the target of the new oxopiperazine analogs obtained via scaffold morphing from the HTS hit 4.
基于吡咯并哌嗪酮细胞筛选得到的登革病毒抑制剂命中化合物4，设计了一系列2-氧代哌嗪衍生物。对哌嗪酮环周围的构效关系（SAR）进行系统研究，确定了化合物(S)-29，其在基于细胞的检测中对所有四种登革病毒血清型均表现出强效抗登革热活性，半数有效浓度（EC）<0.1μM。交叉抗性分析证实，病毒NS4B蛋白仍然是通过对高通量筛选命中化合物4进行骨架变形得到的新型氧代哌嗪类似物的作用靶点。
