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Design, synthesis and biological evaluation of new coumarin-dithiocarbamate hybrids as multifunctional agents for the treatment of Alzheimer's disease.
Eur J Med Chem. 2018 Feb 25; 146:287-298.EJ

Abstract

A series of new coumarin-dithiocarbamate hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's Disease (AD). The biological assays indicated that most of them showed potent inhibition and excellent selectivity towards acetylcholinesterase (AChE), and could inhibit self-induced β-amyloid (Aβ) aggregation. Especially, compound 4n presented the highest ability to inhibit AChE (IC50, 0.027 μM for hAChE) and good inhibition of Aβ aggregation (40.19% at 25 μM). Kinetic and molecular modeling studies revealed that 4n was a mixed-type inhibitor, which could interact simultaneously with the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. In addition, it also possessed specific metal-chelating ability, good BBB permeability and low toxicity on SH-SY5Y neuroblastoma cells. Moreover, compound 4n did not exhibit any acute toxicity in mice at doses up to 1000 mg/kg, and could reverse the cognitive dysfunction of scopolamine-induced AD mice. As far as we know, 4n was the first reported dithiocarbamate derivative with multifunctional activity. Its excellent profiles in vitro and effectivity in vivo highlight this structurally distinct compound as a potential lead compound in the research of innovative multifunctional drugs for AD.

Authors+Show Affiliations

National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, PR China; Department of Pharmacy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi, PR China.Department of Pharmacy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi, PR China.School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, PR China.Department of Pharmacy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi, PR China. Electronic address: Liangn01@163.com.Pharmaceutical College, Guangxi Medical University, Shuangyong Road, Nanning 530021, Guangxi, PR China.Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, 109 North 2nd Huan Cheng Road, Guilin 541004, PR China.National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, PR China. Electronic address: xiesaisainanchang@hotmail.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29407958

Citation

Jiang, Neng, et al. "Design, Synthesis and Biological Evaluation of New Coumarin-dithiocarbamate Hybrids as Multifunctional Agents for the Treatment of Alzheimer's Disease." European Journal of Medicinal Chemistry, vol. 146, 2018, pp. 287-298.
Jiang N, Huang Q, Liu J, et al. Design, synthesis and biological evaluation of new coumarin-dithiocarbamate hybrids as multifunctional agents for the treatment of Alzheimer's disease. Eur J Med Chem. 2018;146:287-298.
Jiang, N., Huang, Q., Liu, J., Liang, N., Li, Q., Li, Q., & Xie, S. S. (2018). Design, synthesis and biological evaluation of new coumarin-dithiocarbamate hybrids as multifunctional agents for the treatment of Alzheimer's disease. European Journal of Medicinal Chemistry, 146, 287-298. https://doi.org/10.1016/j.ejmech.2018.01.055
Jiang N, et al. Design, Synthesis and Biological Evaluation of New Coumarin-dithiocarbamate Hybrids as Multifunctional Agents for the Treatment of Alzheimer's Disease. Eur J Med Chem. 2018 Feb 25;146:287-298. PubMed PMID: 29407958.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design, synthesis and biological evaluation of new coumarin-dithiocarbamate hybrids as multifunctional agents for the treatment of Alzheimer's disease. AU - Jiang,Neng, AU - Huang,Qichun, AU - Liu,Jing, AU - Liang,Ningsheng, AU - Li,Qing, AU - Li,Qinghua, AU - Xie,Sai-Sai, Y1 - 2018/02/04/ PY - 2017/11/24/received PY - 2017/12/29/revised PY - 2018/01/17/accepted PY - 2018/2/7/pubmed PY - 2018/3/22/medline PY - 2018/2/7/entrez KW - Alzheimer's disease KW - Cholinesterase KW - Coumarin KW - Dithiocarbamate KW - Multifunctional agents SP - 287 EP - 298 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 146 N2 - A series of new coumarin-dithiocarbamate hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's Disease (AD). The biological assays indicated that most of them showed potent inhibition and excellent selectivity towards acetylcholinesterase (AChE), and could inhibit self-induced β-amyloid (Aβ) aggregation. Especially, compound 4n presented the highest ability to inhibit AChE (IC50, 0.027 μM for hAChE) and good inhibition of Aβ aggregation (40.19% at 25 μM). Kinetic and molecular modeling studies revealed that 4n was a mixed-type inhibitor, which could interact simultaneously with the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. In addition, it also possessed specific metal-chelating ability, good BBB permeability and low toxicity on SH-SY5Y neuroblastoma cells. Moreover, compound 4n did not exhibit any acute toxicity in mice at doses up to 1000 mg/kg, and could reverse the cognitive dysfunction of scopolamine-induced AD mice. As far as we know, 4n was the first reported dithiocarbamate derivative with multifunctional activity. Its excellent profiles in vitro and effectivity in vivo highlight this structurally distinct compound as a potential lead compound in the research of innovative multifunctional drugs for AD. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/29407958/Design_synthesis_and_biological_evaluation_of_new_coumarin_dithiocarbamate_hybrids_as_multifunctional_agents_for_the_treatment_of_Alzheimer's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(18)30068-0 DB - PRIME DP - Unbound Medicine ER -