7-Amidocoumarins as Multitarget Agents against Neurodegenerative Diseases: Substitution Pattern Modulation
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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 synthesized via 7-amino-4-methylcoumarin acylation, and in vitro evaluation of the molecules against hMAO-A, hMAO-B, hAChE, hBuChE and hBACE1 was performed. Five compounds turned out to be potent and selective hMAO-B inhibitors in the nanomolar range, six displayed inhibitory activity of hMAO-A in the low micromolar range, one showed hAChE inhibitory activity and another one hBACE1 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 H2O2 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. © 2020 Wiley-VCH GmbH
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