Discovery and optimization of phthalazinone derivatives as a new class of potent dengue virus inhibitors

Using a dengue replicon cell line-based screening, we identified 3-(dimethylamino)propyl(3-((4-(4-fluorophenyl)-1-oxophthalazin-2(1H)-yl)methypphenyl)carbamate (10a) as a potent DENV-2 inhibitor, with an IC50 value of 0.64 mu M. 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 141, which displayed potent anti-DENV-2 activity, with low IC50 value against DENV-2 RNA replication of 0.13 mu M and high selectivity (SI = 89.2) with acceptable pharmacokinetics profiles. (C) 2018 Elsevier Masson SAS. All rights reserved.