Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 173, Issue -, Pages 203-212Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.04.016
Keywords
Parkinson's disease; Multifunctional compounds; Coumarin Mannich base; MAO-B inhibitors; Anti-inflammatory effect
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Funding
- CAMS Innovation Fund for Medical Sciences (CIFMS) [2016-I2M-3-009]
- National Natural Science Foundation of China [81630097, 81773718]
- National Major Scientific and Technological Special Project [2018ZX09711-001-005, 2018ZX09711-003-020, 2018ZX09711-008-005]
- CAMS Fundamental Research Funds for the Central Universities [2018RC350002]
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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. (C) 2019 Elsevier Masson SAS. All rights reserved.
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