Investigation on Novel 2-Benzylideneindan-1-One-Based Photoswitches with AChE and MAO-B Dual Inhibitory Activity.

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-1-inden-1-one (), which in the isomeric form (and about tenfold less in the UV-B photo-induced isomer ) 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 - with the unconjugated tertiary amino moiety bearing alkyls of different bulkiness and lipophilicity. For each compound, the thermal stable geometric isomer, along with the mixture as produced by UV-B light irradiation in the photostationary state (PSS, 75% ), was investigated for the inhibition of human ChEs and MAOs. The pure -isomer of the N-benzyl(ethyl)amino analog achieved low nanomolar AChE and high nanomolar MAO-B inhibition potencies (ICs 39 and 355 nM, respectively), whereas photoisomerization to the isomer (75% 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 / selectivity of toward the two target enzymes.