Investigating Amphoteric 3,4’-Biscoumarin-Based ortho-[(dialkylamino)methyl]phenols as Dual MAO and ChE Inhibitors

About twenty previously and newly synthesized amphoteric 8-[(dialkylamino)methyl]-7-hydroxy-4-(2-oxo-2H-chromen-3-yl)-2H-chromen-2-ones were assayed as inhibitors of monoamine oxidases (MAOs A and B) and cholinesterases (AChE and BChE). Five of the tested compounds (2b, 2c, 3c, 5b and 5c), namely those bearing the less bulky alkyls in the Mannich base 8-CH2NR2 (R = Me, Et) and the halogens (Cl, Br) at C6 of the 4-coumarin-3-yl moiety, showed inhibitory potencies towards MAO-A in the single-digit micromolar range (IC50s 1.49÷3.04 µM). Among them, 3c proved to be also the strongest inhibitor of AChE (IC50 = 1.56 µM) in the series. Molecular docking calculations suggested binding modes of the most active compounds to MAO-A and AChE binding sites fairly consistent with the experimental data. Chemoinformatic tools suggest for the most active compounds, including the dual MAO-A/AChE inhibitor 3c, full compliance with Lipinski’s rule-of-five, high probability of gastrointestinal absorption, and no or poor blood-brain barrier (BBB) permeability. While there is room to improve their CNS distribution, herein we identified 4-(2-oxo-2H-chromen-3-yl)-2H-chromen-2-one as a new scaffold of amphoteric MTDLs with potential for neurodegenerative syndromes.