Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 151, Issue -, Pages 261-271Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.03.081
Keywords
Clovamide analogues; Neuroinflammation; Nitric oxide; iNOS inhibitor; Parkinson's disease
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Funding
- Jiangsu science and technology support program [BE2014710]
- National Natural Science Foundation of China [81573309, 81473160]
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A series of clovamide analogues, namely, 1a-13a and 1b-13b, was synthesized and evaluated for their anti-neuroinflammatory activities using BV-2 microglia cells. Among these compounds, six (1b, 4b-8b) showed NO inhibition with no or weak cytotoxicity (CC50 > 100 mu M), especially 4b, and showed an IC50 value of 2.67 mu M. Enzyme activity and docking assay revealed that the six compounds, especially 4b, target inducible NO synthase (iNOS) and exhibit potent inhibitory effects on iNOS with IC50 values ranging from 1.01 mu M to 29.23 mu M 4b significantly suppressed the expression of pro-inflammatory cytokines in lipopolysaccharide-stimulated cells. Notably, the oral administration of 4b remarkably improved dyskinesia, reduced the expression of glial fibrillary acidic protein (GFAP)-a marker of neuroinflammation, and increased tyrosine hydroxylase-positive cells in 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine-induced Parkinson's disease (PD) mouse models. These observations demonstrated that 4b is an effective and promising candidate for PD therapy. (C) 2018 Elsevier Masson SAS. All rights reserved.
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