Potent, selective and reversible hMAO-B inhibition by benzalphthalides: Synthesis, enzymatic and cellular evaluations and virtual docking and predictive studies

• Published in: Bioorganic chemistry Vol. 146; p. 107255
• Main Authors: Olmo, Esther del, Barboza, Bianca, Delgado-Esteban, Maria, Escala, Nerea, Jiménez-Blasco, Daniel, Lopez-Pérez, José L., Cillero de la Fuente, Laura, Quezada, Elías, Munín, Javier, Viña, Dolores, Bolaños, Juan P., Feliciano, Arturo San
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2024
• Subjects: Benzalphthalides; Cellular protection; Docking; Monoaminoxidase inhibitors; Reversibility; Selectivity; Reversibility; Docking; Monoaminoxidase inhibitors; Selectivity; Cellular protection; Benzalphthalides
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2024.107255

[Display omitted] •11 BPHs inhibited hMAO-B selectively with a Selectivity Indexes (SI) ≥ 100.•1 BPH inhibited hMAO-B selectively at the sub-nanomolar level.•2 BPHs displayed SI values from 1.5 to 3 times higher than the reference drug Selegiline.•Most potent BPHs reverted the toxicity effects on 6-hydroxydopamine on Parkinson's model SH-SY5Y cells.•Docking studieson BPHs-hMAO-B interactions mainly agree with the experimental results. 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.