Potent, selective and reversible hMAO-B inhibition by benzalphthalides: Synthesis, enzymatic and cellular evaluations and virtual docking and predictive studies
Monoaminooxidases (MAOs) are important targets for drugs used in the treatment of neurological and psychiatric
disorders and particularly on Parkinson’s Disease (PD). Compounds containing a trans-stilbenoid skeleton
have demonstrated good selective and reversible MAO-B inhibition. Here, twenty-two (Z)-3-benzylidenephthalides
(benzalphthalides, BPHs) displaying a trans-stilbenoid skeleton have been synthesised and evaluated as
inhibitors of the MAO-A and MAO-B isoforms. Some BPHs have selectively inhibited MAO-B, with IC50 values
ranging from sub-nM to μM. The most potent compound with IC50 = 0.6 nM was the 3′,4′-dichloro-BPH 16, which
showed highly selective and reversible MAO-B inhibitory activity. Furthermore, the most selective BPHs displayed
a significant protection against the apoptosis, and mitochondrial toxic effects induced by 6-hydroxydopamine
(6OHDA) on SH-SY5Y cells, used as a cellular model of PD. The results of virtual binding studies on the
most potent compounds docked in MAO-B and MAO-A were in agreement with the potencies and selectivity
indexes found experimentally. Additionally, related to toxicity risks, drug-likeness and ADME properties, the
predictions found for the most relevant BPHs in this research were within those ranges established for drug
candidates.
