Using a dengue replicon cell line-based screening, we identified 3-(dimethylamino)propyl(3-((4-(4-fluorophenyl)-1-oxophthalazin-2(1H)-yl)methyl)phenyl)carbamate (10a) as a potent DENV-2 inhibitor, with an IC₅₀ value of 0.64 μM. A series of novel phthalazinone derivatives based on hit 10a were synthesized and evaluated for their in vitro anti-DENV activity and cytotoxicity. The subsequent SAR study and optimization led to the discovery of the most promising compound 14l, which displayed potent anti-DENV-2 activity, with low IC₅₀ value against DENV-2 RNA replication of 0.13 μM and high selectivity (SI = 89.2) with acceptable pharmacokinetics profiles.

使用基于登革热复制子细胞系的筛选，我们确定了3-（二甲基氨基）丙基（3-（（（4-（4-氟苯基）-1-氧酞嗪-2（1H）-基）甲基）苯基）氨基甲酸酯（10a）作为有效的DENV-2抑制剂，IC ₅₀值为0.64μM。合成了一系列基于命中10a的新型酞嗪酮衍生物，并对其体外抗-DENV活性和细胞毒性进行了评估。随后的SAR研究和优化导致发现最有前途的化合物14l，该化合物显示出强大的抗-DENV-2活性，对DENV-2 RNA复制的IC ₅₀值低，为0.13μM，选择性高（SI = 89.2）。可接受的药代动力学资料。