Development of Novel N-hydroxypyridone Derivatives as Potential Anti-Ischemic Stroke Agents

Linghao Hu, Hong-Xuan Feng, Hongguang Zhang, Songda Yu, Qinyuan Zhao, Wei Wang, Fengxia Bao, Xun Ding, Jiajing Hu, Manjiong Wang, Yixiang Xu, Zengrui Wu, Xiaokang Li, Yun Tang, Fei Mao, Xiaoyan Chen, Haiyan Zhang, Jian Li
Journal of Medicinal Chemistry 2020 January 7
Our previous study had identified ciclopirox (CPX) as a promising lead compound for treatment of ischemic stroke. To find better neuroprotective agents, a series of N-hydroxypyridone derivatives based on CPX were designed, synthesized and evaluated in this study. Among these derivatives, compound 11 exhibits significant neuroprotection against oxygen glucose deprivation (OGD) and oxidative stress induced injuries in neuronal cells. Moreover, compound 11 possesses good blood-brain barrier (BBB) permeability and superior antioxidant capability. In addition, complex of compound 11 with olamine-11·Ola possesses good water solubility, negligible hERG inhibition and superior metabolic stability. In vivo experiment demonstrates that 11·Ola significantly reduces brain infarction and alleviate neurological deficits in middle cerebral artery occlusion (MCAO) rats. Hence, compound 11·Ola is identified in our research as a prospective prototype in the innovation of stroke treatment.

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