Design and Synthesis of Novel Piperidine Urea Derivatives with Neuroprotective Properties

Ischemic stroke remains the leading cause of death worldwide, and in experimental studies of ischemic stroke, neuroprotective agents may display good efficacy. In our previous work, Fenazinel showed promising neuroprotective effects and entered phase I clinical trials in China. However, some side effects have limited its further study. To explore novel neuroprotective agents with higher potency and lower cardiotoxicity, in this work, a series of Fenazinel derivatives with piperidine urea groups (A1–A13) were designed and synthesized. The neuroprotective effect of A1–A13 was evaluated in human neuroblastoma cells (SH-SY5Y) by assessing cell survivals, and then in a rat model of middle cerebral artery occlusion (MCAO) by assessing the cerebral infarction area. The hERG (human ether-a-go-go-related gene) inhibitory activity was conducted to predict the cardiotoxicity of compounds. The hypoxia tolerance assay of mice was assessed by determining the survival time of mice in a sealed bottle. Our experimental data suggested that among the compounds, compound A10 demonstrated superior protective activity against SH-SY5Y cells at different concentrations, lower cytotoxicity compared with Fenazinel, and additionally, a weak cardiotoxicity (hERG IC50 > 40 μmol/L). Compound A10 not only effectively prolonged the survival time of mice, but also significantly reduced the percentage of cerebral infarction in MCAO rats with a dose-dependent tendency. In summary, this paper provides a reference for the rational structural medication of Fenazinel to reduce cardiotoxicity and finds compound A10 with better neuroprotective activity.