Light-mediated activation/deactivation control and in vitro ADME-Tox profiling of a donepezil-like Dual AChE/MAO-B Inhibitor

被引:0
作者
Poggialini, Federica [1 ]
Governa, Paolo [1 ]
Vagaggini, Chiara [1 ]
Maramai, Samuele [1 ]
Lamponi, Stefania [1 ]
Mugnaini, Claudia [1 ]
Brizzi, Antonella [1 ]
Purgatorio, Rosa [2 ]
de Candia, Modesto [2 ]
Catto, Marco [2 ]
Dreassi, Elena [1 ]
Manetti, Fabrizio [1 ]
Corelli, Federico [1 ]
Altomare, Cosimo Damiano [2 ]
Cappelli, Andrea [1 ]
Paolino, Marco [1 ]
机构
[1] Univ Siena, Dept Biotechnol Chem & Pharm, Via A Moro 2, I-53100 Siena, Italy
[2] Univ Bari Aldo Moro, Dept Pharm Pharmaceut Sci, Via E Orabona 4, I-70125 Bari, Italy
关键词
Photopharmacology; Photoswitches; ADME; Dual-target-directed ligand; AChE; MAO-B; DRUG-DELIVERY SYSTEMS; 2-BENZYLIDENE-1-INDANONE DERIVATIVES; ANTICANCER ACTIVITY; DESIGN; PRODRUGS; PHOTOPHARMACOLOGY; PERMEABILITY;
D O I
10.1016/j.ejps.2025.107066
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The possibility to control the effects of drugs in time and space represents an ideal condition for developing safer and more personalized therapies against different disorders. In this context, photopharmacology has paved the way for the use of light in the modulation of drugs activity. Our interest is directed to photo-switchable molecules, capable of interconverting between two different isoforms upon light irradiation. We recently reported 1, a donepezil-like compound based on 2-benzylidenindan-1-one structure, as a dual AChE and MAO-B inhibitor, which can be converted into the E- (active form) and Z- (about tenfold less active form) diastereoisomers by irradiating with UV-vis light. Aiming at identifying compounds with remarkable activity in physiological conditions, we herein report a fine characterization of 1 in PBS solutions. First, we evaluated its ability to act as a photoswitch comparing PBS solution with organic solvents (e.g. methanol), demonstrating that a wavelength in the UV range (330 nm) can convert the E- into the Z-diastereoisomer, while the use of a visible light (400 nm) allows the interconversion from Z to E in both media. Along with its photoinducible behavior, we investigated the passive diffusion across cellular membrane with PAMPA experiments, plasma and microsomal stability, and binding to plasma proteins. Interestingly, the results of such studies suggested that 1 could persist in the blood circulation for a long time, which is desirable for application in photopharmacological therapies. Cytotoxicity studies highlighted the potential of our prototypic compound as a lead photodrug against neurodegenerative disorders, deserving to advance in molecular optimization studies and further in vitro and in vivo characterization.
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页数:12
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