Discovery of coumarin Mannich base derivatives as multifunctional agents against monoamine oxidase B and neuroinflammation for the treatment of Parkinson's disease.

Authors:
Deng Tao
Deng Tao
Wuhan University School of Medicine Wuhan
China
Yue Wang
Yue Wang
State Key Laboratory of Supramolecular Structure and Materials
China
Xiu-Qi Bao
Xiu-Qi Bao
Institute of Materia Medica
Bei-bei Yang
Bei-bei Yang
Institute of Materia Medica
Nanjing | China
Fan Gao
Fan Gao
Baylor College of Medicine
United States
Lin Wang
Lin Wang
Shanghai Chest Hospital
China
Dan Zhang
Dan Zhang
School of Nursing
Richmond | United States
Dr. Li Li, PhD
Dr. Li Li, PhD
Xinjiang Institute of Ecology and Geography
Chinese Academy of Sciences
Microbiology
Urumqi, Xinjiang | China

Eur J Med Chem 2019 Jul 12;173:203-212. Epub 2019 Apr 12.

Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China. Electronic address:

Due to the complexity of the pathogenesis of Parkinson's disease (PD), multimodal treatment may achieve better results. In this study, a series of coumarin Mannich base derivatives were designed and synthesized as multifunctional agents for PD treatment. Among the derivatives, 3-(3-(dimethylamino)propanoyl)-7-hydroxy-5-methyl- 2H-chromen-2-one hydrochloride (24) exhibited the most potent and selective hMAO-B inhibitory activity, and anti-inflammatory and neuroprotective effects in the in vitro studies. It significantly attenuated PD-associated behavioural deficits in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Furthermore, preliminary mechanistic studies indicated that 24 could selectively inhibit MAO-B activity, decrease the neuroinflammatory process, and protect tyrosine hydroxylase-immunopositive dopaminergic neurons. These results suggest that 24 is a promising multifunctional agent for effective therapy for PD.

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http://dx.doi.org/10.1016/j.ejmech.2019.04.016DOI Listing
July 2019
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