期刊
BIOORGANIC CHEMISTRY
卷 104, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2020.104203
关键词
Coumarin-pyridazine hybrids; MAO-B; Parkinson's disease; In vivo study; SAR study
资金
- Universidade de Vigo
- Conselleria de Cultura, Educacion e Ordenacion Universitaria [CN2012/184, EM2014/016]
- Conselleria de Cultura, Educacion e Ordenacion Universitaria (Centro singular de investigacion de Galicia acreditacion 2016-2019) [ED431G/05]
- European Regional Development Fund (ERDF)
- Xunta de Galicia
The 3-pyridazinylcoumarin scaffold was previously reported as an efficient core for the discovery of reversible and selective inhibitors of MAO-B, a validated drug target for PD therapy which also plays an important role in the AD progress. Looking for its structural optimization, novel compounds of hybrid structure coumarin-pyridazine, differing in polarizability and lipophilicity properties, were synthesized and tested against the two MAO isoforms, MAO-A and MAO-B (compounds 17a-f and 18a-f). All the designed compounds selectively inhibited the MAO-B isoenzyme, exhibiting many of them IC50 values ranging from sub-micromolar to nanomolar grade and lacking neuronal toxicity. The 7-bromo-3-(6-bromopyridazin-3-yl)coumarin (18c), the most potent compound of these series (IC50 = 60 nM), was subjected to further in vivo studies in a reserpine-induced mouse PD model. The obtained results suggest a promising potential for 18c as antiparkinsonian agent. Molecular modeling studies also provided valuable information about the enzyme-drug interactions and the potential pharmacokinetic profile of the novel compounds.
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