Design and Synthesis of Novel Piperidine Urea Derivatives with Neuroprotective Properties

Abstract

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.

Keywords

ischemic stroke - Fenazinel - piperidine urea derivatives - neuroprotection

• References

• 1 Paul S, Candelario-Jalil E. Emerging neuroprotective strategies for the treatment of ischemic stroke: an overview of clinical and preclinical studies. Exp Neurol 2021; 335: 113518
• 2 Han B, Wang M, Li J. et al. Perspectives and new aspects of histone deacetylase inhibitors in the therapy of CNS diseases. Eur J Med Chem 2023; 258: 115613
• 3 Menon BK, Saver JL, Prabhakaran S. et al. Risk score for intracranial hemorrhage in patients with acute ischemic stroke treated with intravenous tissue-type plasminogen activator. Stroke 2012; 43 (09) 2293-2299
• 4 Li X, Wang X, Miao L, Guo Y, Yuan R, Tian H. Design, synthesis, and neuroprotective effects of novel hybrid compounds containing edaravone analogue and 3-N-butylphthalide ring-opened derivatives. Biochem Biophys Res Commun 2021; 556: 99-105
• 5 Abdoulaye IA, Guo YJ. A review of recent advances in neuroprotective potential of 3-N-butylphthalide and its derivatives. BioMed Res Int 2016; 2016: 5012341
• 6 Feng S, Yang Q, Liu M. et al. Edaravone for acute ischaemic stroke. Cochrane Database Syst Rev 2011; 12 (12) CD007230
• 7 Zhao T, Zhang W, Shen F. Protective effects of fenazinel dihydrochloride against stroke in stroke-prone spontaneously hypertensive rats [in Chinese]. Acad J Second Mil Med Univ 2012; 31 (12) 1282-1285
• 8 Li D, Li J, Huang L. Protective effects of fenazinel dihydrochloride on focal cerebral ischemic injury in rats. Chin Pharmacol Bull 2009; 25: 716-720
• 9 Jin L, Sheng Y, Zhong Y, Zhu P, Xia Y. Relation between therapeutic effects and administration time of fenazinel dihydrochloride on focal cerebral ischemia injury in rats. Carol J Pharm 2008; 5: 356-358
• 10 Chen Y, Lu M, Zhang B, Xie B. Preparation of fenazinel dihydrochloride injection. Carol J Pharm 2007; 38 (12) 852-854
• 11 Zhang QW, Jiang L, Wang G. et al. Design, synthesis and neuroprotective effects of fenazinel derivatives. Chin Chem Lett 2017; 28 (07) 1505-1508
• 12 Li JY, Peng XY, Huang YL. et al. Design, synthesis, and neuroprotective effects of novel cinnamamide-piperidine and piperazine derivatives. Pharmaceut Fronts 2023; 05 (03) e132-e40
• 13 Ghosh AK, Brindisi M. Urea derivatives in modern drug discovery and medicinal chemistry. J Med Chem 2020; 63 (06) 2751-2788
• 14 AlNajjar YT, Gabr M, ElHady AK. et al. Discovery of novel 6-hydroxybenzothiazole urea derivatives as dual Dyrk1A/α-synuclein aggregation inhibitors with neuroprotective effects. Eur J Med Chem 2022; 227: 113911
• 15 Azam F, Prasad MV, Thangavel N, Shrivastava AK, Mohan G. Structure-based design, synthesis and molecular modeling studies of thiazolyl urea derivatives as novel anti-parkinsonian agents. Med Chem 2012; 8 (06) 1057-1068
• 16 Cifuentes J, Salazar VA, Cuellar M. et al. Antioxidant and neuroprotective properties of non-centrifugal cane sugar and other sugarcane derivatives in an in vitro induced parkinson's model. Antioxidants 2021; 10 (07) 1040
• 17 Zhang L, Wu Y, Yang G. et al. Design, synthesis and biological evaluation of novel osthole-based derivatives as potential neuroprotective agents. Bioorg Med Chem Lett 2020; 30 (24) 127633
• 18 Lu T, Liu Y, Liu Y. et al. Discovery, biological evaluation and molecular dynamic simulations of butyrylcholinesterase inhibitors through structure-based pharmacophore virtual screening. Future Med Chem 2021; 13 (09) 769-784
• 19 Gu X, Peng XY, Zhang H. et al. Discovery of indole-containing benzamide derivatives as HDAC1 inhibitors with in vitro and in vivo antitumor activities. Pharmaceut Fronts 2022; 04 (02) e61-e70