Design, Synthesis, and Neuroprotective Effects of Novel Cinnamamide-Piperidine and Piperazine Derivatives

Abstract

In our previous studies, Fenazinel has shown good neuroprotective effects; however, when Fenazinel entered phase 1 clinical trials, it was associated with certain side effects. This study aimed to explore novel neuroprotective agents with higher potency and lower toxicity. Evidence suggested that cinnamic acid and its analogs may serve as promising lead compounds for stroke treatment. In this study, a series of Fenazinel derivatives were first synthesized with potential neuroprotective effects with fragments including cinnamic acid and its analogs as key functional groups. The methyl thiazolyl tetrazolium assay was performed to assess the neuroprotective effects of the compounds in glutamate-induced neurotoxicity in SH-SY5Y cells. The hERG binding assay was conducted to assess drug-induced QT prolongation or other cardiotoxicity. The neuroprotective activity of the most potent compound in vivo was tested through the survival time of mice under the hypoxic condition and a middle cerebral artery occlusion model. Our data suggested that among those derivatives, compound 9d exhibited potent neuroprotective activity in vitro comparable to Fenazinel at the test concentrations. Significantly, 9d exhibited weak hERG inhibitory activity, showing moderate activities in both hypoxia-tolerant and MCAO models in vivo. Given the above, 9d has the potential for the treatment of stroke and could be considered a lead neuroprotective agent for further development.