Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Investigation on Novel E/Z 2-Benzylideneindan-1-one-based Photoswitches with AChE and MAO-B Dual Inhibitory Activity

Marco Paolino
,
Modesto De Candia
ORCID logo ,
Rosa Purgatorio
ORCID logo ,
Marco Catto
ORCID logo ,
Mario Saletti
,
Anna Rita Tondo
ORCID logo ,
Orazio Nicolotti
ORCID logo ,
Andrea Cappelli
ORCID logo ,
Antonella Brizzi
ORCID logo ,
Claudia Mugnaini
,
Federico Corelli
ORCID logo ,
Cosimo D. Altomare
* ORCID logo
Version 1 : Received: 27 June 2023 / Approved: 28 June 2023 / Online: 29 June 2023 (02:47:23 CEST)

A peer-reviewed article of this Preprint also exists.

Paolino, M.; de Candia, M.; Purgatorio, R.; Catto, M.; Saletti, M.; Tondo, A.R.; Nicolotti, O.; Cappelli, A.; Brizzi, A.; Mugnaini, C.; Corelli, F.; Altomare, C.D. Investigation on Novel E/Z 2-Benzylideneindan-1-One-Based Photoswitches with AChE and MAO-B Dual Inhibitory Activity. Molecules 2023, 28, 5857. Paolino, M.; de Candia, M.; Purgatorio, R.; Catto, M.; Saletti, M.; Tondo, A.R.; Nicolotti, O.; Cappelli, A.; Brizzi, A.; Mugnaini, C.; Corelli, F.; Altomare, C.D. Investigation on Novel E/Z 2-Benzylideneindan-1-One-Based Photoswitches with AChE and MAO-B Dual Inhibitory Activity. Molecules 2023, 28, 5857.

Abstract

The multitarget therapeutic strategy, as opposed to the more traditional ‘one disease-one tar-get-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 diastereomeric 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 diastereoisomer, along with the E/Z mixture as produced by UV-B light irradia-tion in the photostationary state (PSS, 75% Z), was investigated for the inhibition of human ChEs and MAOs. The pure E-diastereoisomer of the N-benzyl(ethyl)amino analog 1h achieved low nanomolar AChE and high nanomolar MAO-B inhibition potencies (IC50s 39 and 355 nM, re-spectively), 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 diastereoselectivity of 1h toward the two target enzymes.

Keywords

Neurodegenerative diseases; cholinesterase inhibitors; monoaminoxidase inhibitors; photo-pharmacology

Subject

Chemistry and Materials Science, Medicinal Chemistry

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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