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Acta Pharm Sin B. 2019 Mar;9(2):335-350. doi: 10.1016/j.apsb.2019.01.003. Epub 2019 Jan 7.

Design, synthesis and biological evaluation of chalcone analogues with novel dual antioxidant mechanisms as potential anti-ischemic stroke agents.

Author information

1
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
2
Municipal Hospital Affiliated to Medical School of Taizhou University, Taizhou 318000, China.
3
Ningbo Medical Centre Li Huili Hospital, Ningbo 315041, China.
4
College of Information Science and Computer Engineering, Wenzhou Medical University, Wenzhou 325035, China.

Abstract

Scavenging reactive oxygen species (ROS) by antioxidants is the important therapy to cerebral ischemia-reperfusion injury (CIRI) in stroke. The antioxidant with novel dual-antioxidant mechanism of directly scavenging ROS and indirectly through antioxidant pathway activation may be a promising CIRI therapeutic strategy. In our study, a series of chalcone analogues were designed and synthesized, and multiple potential chalcone analogues with dual antioxidant mechanisms were screened. Among these compounds, the most active 33 not only conferred cytoprotection of H2O2-induced oxidative damage in PC12 cells through scavenging free radicals directly and activating NRF2/ARE antioxidant pathway at the same time, but also played an important role against ischemia/reperfusion-related brain injury in animals. More importantly, in comparison with mono-antioxidant mechanism compounds, 33 exhibited higher cytoprotective and neuroprotective potential in vitro and in vivo. Overall, our findings showed compound 33 could emerge as a promising anti-ischemic stroke drug candidate and provided novel dual-antioxidant mechanism strategies and concepts for oxidative stress-related diseases treatment.

KEYWORDS:

Antioxidants; Cerebral ischemia-reperfusion injury; Chalcones; Dual-antioxidant mechanism; NRF2/ARE; Oxidative stress; Reactive oxygen species; Stroke

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