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

Discovery and optimization of phthalazinone derivatives as a new class of potent dengue virus... 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Medicinal Chemistry Elsevier

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

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Publisher
Elsevier
Copyright
Copyright © 2018 Elsevier Masson SAS
ISSN
0223-5234
eISSN
1768-3254
D.O.I.
10.1016/j.ejmech.2018.01.008
Publisher site
See Article on Publisher Site

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 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.

Journal

European Journal of Medicinal ChemistryElsevier

Published: Feb 10, 2018

References

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