Promising Non-cytotoxic Monosubstituted Chalcones to Target Monoamine Oxidase-B

A library of mono-substituted chalcones (1-17), bearing electron donating and electron withdrawing groups in both aromatic rings, was selected. The cell viability on human tumour cell lines was at first evaluated. The compounds unable to induce detectable cytotoxicity (1, 13 and 14) were tested for monoamine oxidase (MAO) activity assay. Interestingly, they inhibit MAO-B acting as competitive inhibitors, with 13 and 14 showing the best profile. In particular, 13 exhibited a potency higher than safinamide, taken as reference. Docking studies and crystallographic analysis showed that in human MAO-B 13 binds with the halogen-substituted aromatic ring in the entrance cavity, similarly to safinamide, whereas 14 is accommodated in the opposite way. The main conclusion, resulting by this cell biology, biochemistry and structural study, highlights 13 as a chalcone derivative worth to be considered for the development of novel MAO-B selective inhibitors for the treatment of neurodegenerative diseases.