Structure-Based Design and Optimization of Multitarget-Directed 2<i>H</i>‑Chromen-2-one Derivatives as Potent Inhibitors of Monoamine Oxidase B and Cholinesterases

Abstract

The multifactorial nature of Alzheimer’s disease calls for the development of multitarget agents addressing key pathogenic processes. To this end, by following a docking-assisted hybridization strategy, a number of aminocoumarins were designed, prepared, and tested as monoamine oxidases (MAOs) and acetyl- and butyryl-cholinesterase (AChE and BChE) inhibitors. Highly flexible <i>N</i>-benzyl-<i>N</i>-alkyloxy coumarins <b>2</b>–<b>12</b> showed good inhibitory activities at MAO-B, AChE, and BChE but low selectivity. More rigid inhibitors, bearing <i>meta</i>- and <i>para</i>-xylyl linkers, displayed good inhibitory activities and high MAO-B selectivity. Compounds <b>21</b>, <b>24</b>, <b>37</b>, and <b>39</b>, the last two featuring an improved hydrophilic/lipophilic balance, exhibited excellent activity profiles with nanomolar inhibitory potency toward hMAO-B, high hMAO-B over hMAO-A selectivity and submicromolar potency at hAChE. Cell-based assays of BBB permeation, neurotoxicity, and neuroprotection supported the potential of compound <b>37</b> as a BBB-permeant neuroprotective agent against H₂O₂-induced oxidative stress with poor interaction as P-gp substrate and very low cytotoxicity