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 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 H₂ O₂ 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.