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Synthesis, pharmacology and molecular docking on multifunctional tacrine-ferulic acid hybrids as cholinesterase inhibitors against Alzheimer's disease.
J Enzyme Inhib Med Chem. 2018 Dec; 33(1):496-506.JE

Abstract

The cholinergic hypothesis has long been a "polar star" in drug discovery for Alzheimer's disease (AD), resulting in many small molecules and biological drug candidates. Most of the drugs marketed for AD are cholinergic. Herein, we report our efforts in the discovery of cholinesterases inhibitors (ChEIs) as multi-target-directed ligands. A series of tacrine-ferulic acid hybrids have been designed and synthesised. All these compounds showed potent acetyl-(AChE) and butyryl cholinesterase(BuChE) inhibition. Among them, the optimal compound 10g, was the most potent inhibitor against AChE (electrophorus electricus (eeAChE) half maximal inhibitory concentration (IC50) = 37.02 nM), it was also a strong inhibitor against BuChE (equine serum (eqBuChE) IC50 = 101.40 nM). Besides, it inhibited amyloid β-protein self-aggregation by 65.49% at 25 μM. In subsequent in vivo scopolamine-induced AD models, compound 10g obviously ameliorated the cognition impairment and showed preliminary safety in hepatotoxicity evaluation. These data suggest compound 10g as a promising multifunctional agent in the drug discovery process against AD.

Authors+Show Affiliations

a Department of Medicinal Chemistry , China Pharmaceutical University , Nanjing , China.a Department of Medicinal Chemistry , China Pharmaceutical University , Nanjing , China.b School of Pharmacy , Nanjing University of Chinese Medicine , Nanjing , China.a Department of Medicinal Chemistry , China Pharmaceutical University , Nanjing , China.a Department of Medicinal Chemistry , China Pharmaceutical University , Nanjing , China.a Department of Medicinal Chemistry , China Pharmaceutical University , Nanjing , China.c School of Nursing , Nanjing University of Chinese Medicine , Nanjing , China.b School of Pharmacy , Nanjing University of Chinese Medicine , Nanjing , China.a Department of Medicinal Chemistry , China Pharmaceutical University , Nanjing , China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29405075

Citation

Zhu, Jie, et al. "Synthesis, Pharmacology and Molecular Docking On Multifunctional Tacrine-ferulic Acid Hybrids as Cholinesterase Inhibitors Against Alzheimer's Disease." Journal of Enzyme Inhibition and Medicinal Chemistry, vol. 33, no. 1, 2018, pp. 496-506.
Zhu J, Yang H, Chen Y, et al. Synthesis, pharmacology and molecular docking on multifunctional tacrine-ferulic acid hybrids as cholinesterase inhibitors against Alzheimer's disease. J Enzyme Inhib Med Chem. 2018;33(1):496-506.
Zhu, J., Yang, H., Chen, Y., Lin, H., Li, Q., Mo, J., Bian, Y., Pei, Y., & Sun, H. (2018). Synthesis, pharmacology and molecular docking on multifunctional tacrine-ferulic acid hybrids as cholinesterase inhibitors against Alzheimer's disease. Journal of Enzyme Inhibition and Medicinal Chemistry, 33(1), 496-506. https://doi.org/10.1080/14756366.2018.1430691
Zhu J, et al. Synthesis, Pharmacology and Molecular Docking On Multifunctional Tacrine-ferulic Acid Hybrids as Cholinesterase Inhibitors Against Alzheimer's Disease. J Enzyme Inhib Med Chem. 2018;33(1):496-506. PubMed PMID: 29405075.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis, pharmacology and molecular docking on multifunctional tacrine-ferulic acid hybrids as cholinesterase inhibitors against Alzheimer's disease. AU - Zhu,Jie, AU - Yang,Hongyu, AU - Chen,Yao, AU - Lin,Hongzhi, AU - Li,Qi, AU - Mo,Jun, AU - Bian,Yaoyao, AU - Pei,Yuqiong, AU - Sun,Haopeng, PY - 2018/2/7/entrez PY - 2018/2/7/pubmed PY - 2018/2/14/medline KW - Alzheimer’s disease KW - cholinesterase inhibitor KW - molecular docking KW - multi-target ligand KW - tacrine-ferulic hybrid SP - 496 EP - 506 JF - Journal of enzyme inhibition and medicinal chemistry JO - J Enzyme Inhib Med Chem VL - 33 IS - 1 N2 - The cholinergic hypothesis has long been a "polar star" in drug discovery for Alzheimer's disease (AD), resulting in many small molecules and biological drug candidates. Most of the drugs marketed for AD are cholinergic. Herein, we report our efforts in the discovery of cholinesterases inhibitors (ChEIs) as multi-target-directed ligands. A series of tacrine-ferulic acid hybrids have been designed and synthesised. All these compounds showed potent acetyl-(AChE) and butyryl cholinesterase(BuChE) inhibition. Among them, the optimal compound 10g, was the most potent inhibitor against AChE (electrophorus electricus (eeAChE) half maximal inhibitory concentration (IC50) = 37.02 nM), it was also a strong inhibitor against BuChE (equine serum (eqBuChE) IC50 = 101.40 nM). Besides, it inhibited amyloid β-protein self-aggregation by 65.49% at 25 μM. In subsequent in vivo scopolamine-induced AD models, compound 10g obviously ameliorated the cognition impairment and showed preliminary safety in hepatotoxicity evaluation. These data suggest compound 10g as a promising multifunctional agent in the drug discovery process against AD. SN - 1475-6374 UR - https://www.unboundmedicine.com/medline/citation/29405075/Synthesis_pharmacology_and_molecular_docking_on_multifunctional_tacrine_ferulic_acid_hybrids_as_cholinesterase_inhibitors_against_Alzheimer's_disease_ L2 - https://www.tandfonline.com/doi/full/10.1080/14756366.2018.1430691 DB - PRIME DP - Unbound Medicine ER -