Download PDF
CC BY 4.0 · Pharmaceutical Fronts 2025; 07(01): e32-e40
DOI: 10.1055/a-2524-8846
Original Article

Design and Synthesis of Novel Piperidine Urea Derivatives with Neuroprotective Properties

Jiayi Li   #
1   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
2   School of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai, People's Republic of China
,
Mengfei Wang   #
1   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
3   National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co. Ltd., Shanghai, People's Republic of China
,
Ling Jiang
1   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
,
Xinyan Peng
1   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
3   National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co. Ltd., Shanghai, People's Republic of China
,
Bo Han
1   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
3   National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co. Ltd., Shanghai, People's Republic of China
,
Qingwei Zhang
1   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
3   National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co. Ltd., Shanghai, People's Republic of China
› Author Affiliations Funding This work was supported by the National Science and Technology Major Project (Grant No. 2018ZX09711002-002-009), the National Natural Science Foundation of China (Grant No. 81703358), the Science and Technology Commission of Shanghai Municipality (Grant Nos. 17431903900, 18QB1404200, 21S11908000, 22ZR1460300, and 23DZ2292600), and the National Key Laboratory of Lead Druggability Research (Grant No. NKLYT2023007).
› Further Information
Also available at
   Permissions and Reprints


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

Ethical Approval

All animal procedures were conducted according to the Chinese legislation and regulations of Laboratory Animals of the Chinese Animal Welfare Committee. The protocols were approved by the Ethics Committee of the Center for Pharmacological Evaluation and Research (Shanghai 200437, China).


# These authors contributed equally to this work.




Publication History

Received: 30 March 2024

Accepted: 24 January 2025

Article published online:
24 February 2025

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

 

  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 6 Feng S, Yang Q, Liu M. et al. Edaravone for acute ischaemic stroke. Cochrane Database Syst Rev 2011; 12 (12) CD007230
    Search in Google Scholar
  • 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
    CrossrefSearch in Google Scholar
  • 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
    Search in Google Scholar
  • 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
    Search in Google Scholar
  • 10 Chen Y, Lu M, Zhang B, Xie B. Preparation of fenazinel dihydrochloride injection. Carol J Pharm 2007; 38 (12) 852-854
    Search in Google Scholar
  • 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
    CrossrefSearch in Google Scholar
  • 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
    Thieme ConnectSearch in Google Scholar
  • 13 Ghosh AK, Brindisi M. Urea derivatives in modern drug discovery and medicinal chemistry. J Med Chem 2020; 63 (06) 2751-2788
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    Thieme ConnectSearch in Google Scholar