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

Abstract 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 IC 50 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 IC 50 value against DENV-2 RNA replication of 0.13 μM and high selectivity (SI = 89.2) with acceptable pharmacokinetics profiles.