Design, Synthesis and Characterization of a Visible‐Light‐Sensitive Molecular Switch and Its PEGylation Towards a Self‐Assembling Molecule

Paolino, Marco; Reale, Annalisa; Licciardi, Mariano; Varvarà, Paola; Marquette, Arnaud; Léonard, Jérémie; Bonechi, Claudia; Donati, Alessandro; Giorgi, Gianluca; Giuliani, Germano; Carlotti, Benedetta; Ortica, F.; Latterini, Loredana; Gentile, Mariangela; Paccagnini, Eugenio; Olivucci, Massimo; Cappelli, Andrea

doi:10.1002/chem.202201477

Cited by 6 publications

(3 citation statements)

References 83 publications

(141 reference statements)

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“…HBDI-LPs and benzofulvene-based HBDI-LP, Fig. 1) [38][39][40] and of a p-hydroxycinnamate analogue of the photoactive yellow protein (PYP) chromophore structure. 41 The HBDI-LPs perform the E/Z photoisomerization with relatively high isomerization quantum yield in picosecond and subpicosecond timescale under UV/vis light irradiation.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of light-driven on–off multitarget AChE and MAO-B inhibitors

et al. 2022

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Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of light-driven on–off multitarget AChE and MAO-B inhibitors

et al. 2022

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“…1 H NMR (400 MHz, CD3OD): 0.94 (t, J = 7.4, 3H), 1. 35 Compound 7h was obtained as a yellow oil (0.49 g, yield 98%) starting from ester 6h (0.56 g, 1.98 mmol) after purification with a mixture of petroleum ether/ethyl acetate (8:2) as the eluent. 1 H NMR (400 MHz, CD3OD): 1.09 (t, J = 7.1, 3H), 2.50 (q, J = 7.1, 2H), 3.56 (s, 2H), 3.57 (s, 2H), 4.60 (s, 2H), 7.23 (t, J = 7.1, 1H), 7.33 (m, 8H).…”

Section: General Procedures For the Synthesis Of Compounds 6b-hmentioning

confidence: 99%

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

Paolino¹,

Candia²,

Purgatorio³

et al. 2023

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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.

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“…In this context, we have combined the expertise in the synthesis and characterization of biomimetic light-controlled molecular switches and motors [30][31][32][33][34][35][36] and in the design of ChE-Is [37][38][39], which have recently led to a small series of photoisomerizable donepezil-like compounds with on-off inhibitory activity towards AChE and MAO-B [40]. These molecules consist of a diversely decorated indanone moiety linked to an N-benzyl-N-ethylethanamine group via an isomerizable carbon-carbon double bond.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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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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Design, Synthesis and Characterization of a Visible‐Light‐Sensitive Molecular Switch and Its PEGylation Towards a Self‐Assembling Molecule

Cited by 6 publications

References 83 publications

Design, synthesis and biological evaluation of light-driven on–off multitarget AChE and MAO-B inhibitors

Design, synthesis and biological evaluation of light-driven on–off multitarget AChE and MAO-B inhibitors

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

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

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