7‐Amidocoumarins as Multitarget Agents against Neurodegenerative Diseases: Substitution Pattern Modulation. (25th August 2020)

• Record Type: Journal Article
• Authors: Rodríguez‐Enríquez, Fernanda; Viña, Dolores; Uriarte, Eugenio; Laguna, Reyes; Matos, Maria J.
• Is Part Of: ChemMedChem. Volume 16:Number 1(2021)
• Page Start: 179
• Page End: 186
• Publication Date: 2020-08-25
• Subjects: 7-Amidocoumarins -- monoamine oxidase -- cholinesterases -- β-secretase -- neuroprotection; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202000454
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: 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 h MAO‐A, h MAO‐B, h AChE, h BuChE and h BACE1 was performed. Five compounds turned out to be potent and selective h MAO‐B inhibitors in the nanomolar range, six displayed inhibitory activity of h MAO‐A in the low micromolar range, one showed h AChE inhibitory activity and another one h BACE1 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. Abstract : Alzheimer's and Parkinson's diseases are the most prevalent neurodegenerative disorders, and there is no cure for them. Therefore, it is urgent to develop new therapeutic solutions. 7‐Amidocoumarins were synthesized and studied as MAO‐A, MAO‐B, AChE, BuChE and BACE1 inhibitors, and neuroprotective agents. All the studied compounds proved to be non‐neurotoxic on rat motor cortex neurons, five turned out to be potent and selective h MAO‐B inhibitors in the nanomolar range, six displayed h MAO‐A inhibition in the low micromolar range, one showed AChE inhibitory activity, and another showed BACE‐1 inhibitory activity.