7-Amidocoumarins as Multitarget Agents against Neurodegenerative Diseases: Substitution Pattern Modulation

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.

Automated summary

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.