Journal
CHEMMEDCHEM
Volume 16, Issue 1, Pages 179-186Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202000454
Keywords
7-Amidocoumarins; monoamine oxidase; cholinesterases; beta-secretase; neuroprotection
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Funding
- University of Porto
- Conselleria de Cultura, Educacion e Ordenacion Universitaria, Centro Singular de Investigacion de Galicia
- European Regional Development Fund (ERDF) [ED431G/05]
- Xunta de Galicia (Galician Plan of Research, Innovation and Growth 2011-2015, Plan I2C) [ED481B 2014/086-0, ED481B 2018/007]
- Fundacao para a Ciencia e Tecnologia (FCT) [CEECIND/02423/2018, UIDB/00081/2020]
- University of Santiago de Compostela
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The study investigated the potential of 7-amidocoumarins as multitarget agents against Parkinson's and Alzheimer's diseases by modulating substitution patterns within the scaffold. Five compounds were potent and selective hMAO-B inhibitors, while six showed inhibitory activity of hMAO-A. The compounds also demonstrated neurotoxicity and neuroprotection, supporting their safety profile.
This study explores the potential of 7-amidocoumarins as multitarget agents against Parkinson's and Alzheimer's diseases, by modulating the substitution patterns within the scaffold. Sixteen compounds were synthesizedvia7-amino-4-methylcoumarin acylation, andin vitroevaluation of the molecules againsthMAO-A,hMAO-B,hAChE,hBuChE andhBACE1 was performed. Five compounds turned out to be potent and selectivehMAO-B inhibitors in the nanomolar range, six displayed inhibitory activity ofhMAO-A in the low micromolar range, one showedhAChE inhibitory activity and another onehBACE1 inhibitory activity. MAO-B reversibility profile of 7-(4'-chlorobenzamido)-4-methylcoumarin (10) was investigated, with this compound being a reversible inhibitor. Neurotoxicity on motor cortex neurons and neuroprotection against H(2)O(2)were also studied, corroborating the safety profile of these molecules. Finally, theoretical ADME properties were also calculated, showing these molecules as good candidates for the optimization of a lead compound. Results suggest that by modulating the substitution pattern at position 7 of the scaffold, selective or multitarget molecules can be achieved.
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