Molecules (Aug 2023)

Investigation on Novel <i>E/Z</i> 2-Benzylideneindan-1-One-Based Photoswitches with AChE and MAO-B Dual Inhibitory Activity

  • Marco Paolino,
  • Modesto de Candia,
  • Rosa Purgatorio,
  • Marco Catto,
  • Mario Saletti,
  • Anna Rita Tondo,
  • Orazio Nicolotti,
  • Andrea Cappelli,
  • Antonella Brizzi,
  • Claudia Mugnaini,
  • Federico Corelli,
  • Cosimo D. Altomare

DOI
https://doi.org/10.3390/molecules28155857
Journal volume & issue
Vol. 28, no. 15
p. 5857

Abstract

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The multitarget therapeutic strategy, as opposed to the more traditional ‘one disease-one target-one drug’, may hold promise in treating multifactorial neurodegenerative syndromes, such as Alzheimer’s disease (AD) and related dementias. Recently, combining a photopharmacology approach with the multitarget-directed ligand (MTDL) design strategy, we disclosed a novel donepezil-like compound, namely 2-(4-((diethylamino)methyl)benzylidene)-5-methoxy-2,3-dihydro-1H-inden-1-one (1a), which in the E isomeric form (and about tenfold less in the UV-B photo-induced isomer Z) showed the best activity as dual inhibitor of the AD-related targets acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). Herein, we investigated further photoisomerizable 2-benzylideneindan-1-one analogs 1b–h with the unconjugated tertiary amino moiety bearing alkyls of different bulkiness and lipophilicity. For each compound, the thermal stable E geometric isomer, along with the E/Z mixture as produced by UV-B light irradiation in the photostationary state (PSS, 75% Z), was investigated for the inhibition of human ChEs and MAOs. The pure E-isomer of the N-benzyl(ethyl)amino analog 1h achieved low nanomolar AChE and high nanomolar MAO-B inhibition potencies (IC50s 39 and 355 nM, respectively), whereas photoisomerization to the Z isomer (75% Z in the PSS mixture) resulted in a decrease (about 30%) of AChE inhibitory potency, and not in the MAO-B one. Molecular docking studies were performed to rationalize the different E/Z selectivity of 1h toward the two target enzymes.

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