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

Dong Lu; Jianan Liu; Yunzhe Zhang; Feifei Liu; Limin Zeng; Runze Peng; Li Yang; Huazhou Ying; Wei Tang; Wuhong Chen; Jianping Zuo; Xiankun Tong; Tao Liu; Youhong Hu

doi:10.1016/j.ejmech.2018.01.008

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

Eur J Med Chem. 2018 Feb 10:145:328-337. doi: 10.1016/j.ejmech.2018.01.008. Epub 2018 Jan 5.

Authors

Dong Lu¹, Jianan Liu¹, Yunzhe Zhang², Feifei Liu¹, Limin Zeng³, Runze Peng¹, Li Yang³, Huazhou Ying², Wei Tang³, Wuhong Chen³, Jianping Zuo³, Xiankun Tong⁴, Tao Liu⁵, Youhong Hu⁶

Affiliations

¹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
² Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
⁴ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China. Electronic address: [email protected].
⁵ Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: [email protected].
⁶ Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China. Electronic address: [email protected].

PMID: 29335200
DOI: 10.1016/j.ejmech.2018.01.008

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.

Keywords: Dengue virus; Inhibitor; Optimization; Phthalazinone; SAR.

MeSH terms

Aedes / cytology
Aedes / virology
Animals
Antiviral Agents / chemical synthesis
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Cell Line
Dengue Virus / drug effects*
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Male
Mice
Microbial Sensitivity Tests
Molecular Docking Simulation
Molecular Structure
Phthalazines / chemical synthesis
Phthalazines / chemistry
Phthalazines / pharmacology*
Structure-Activity Relationship
Virus Replication / drug effects

Substances

Antiviral Agents
Phthalazines