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

Nineteen previously and newly synthesized amphoteric 8-[(dialkylamino)methyl]-7-hydroxy-4-(2-oxo-2<i>H</i>-chromen-3-yl)-2<i>H</i>-chromen-2-ones were assayed as inhibitors of monoamine oxidases (MAO-A and B) and cholinesterases (AChE and BChE). Five of the tested compounds (<b>2b</b>, <b>2c</b>, <b>3c</b>, <b>5b</b>, and <b>5c</b>), 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 moderate inhibitory potencies toward human MAO-A in the single-digit micromolar range (IC₅₀s from 1.49 to 3.04 µM). In particular, the 6'-Cl derivatives <b>2b</b> and <b>5b</b> proved to be reversible competitive inhibitors of human MAO-A with <i>K</i>_i values of 0.272 and 0.326 µM. Among the tested compounds, <b>3c</b> proved to also be a moderate inhibitor of human AChE (IC₅₀ 4.27 µM). Molecular docking calculations suggested binding modes of the most active compounds to MAO-A and AChE binding sites consistent enough with the experimental data. Chemoinformatic tools suggest for the most active compounds, including the dual MAO-A/AChE inhibitor <b>3c</b>, full compliance with Lipinski's rule of five, high probability of gastrointestinal absorption, but low blood-brain barrier (BBB) permeability. While further efforts are required to improve their CNS distribution, herein new phenolic Mannich bases have been identified that may have potential for treating neurodegenerative syndromes.