biostudies-literatureHerrera-Arozamena CAgencia Estatal de Investigación, Ministerio de Ciencia, Innovación y UniversidadesSociedad Española de Química TerapéuticaConsejo Superior de Investigaciones CientíficasInstituto de Salud Carlos IIIFundación Teófilo HernandoEuropean Structural FundsGeneral Council for Research and Innovation of the Community of MadridMinisterio de Educación - Gobierno de EspañaEuropean Regional Development Fund4727-4751https://www.ebi.ac.uk/biostudies/studies/S-EPMC8958504biostudies-literatureUnknown65(6)By replacing a phenolic ring of (<i>E</i>)-resveratrol with an 1,3,4-oxadiazol-2(3<i>H</i>)-one heterocycle, new resveratrol-based multitarget-directed ligands (MTDLs) were obtained. They were evaluated in several assays related to oxidative stress and inflammation (monoamine oxidases, nuclear erythroid 2-related factor, quinone reductase-2, and oxygen radical trapping) and then in experiments of increasing complexity (neurogenic properties and neuroprotection <i>vs</i> okadaic acid). 5-[(<i>E</i>)-2-(4-Methoxyphenyl)ethenyl]-3-(prop-2-yn-1-yl)-1,3,4-oxadiazol-2(3<i>H</i>)-one (<b>4e</b>) showed a well-balanced MTDL profile: cellular activation of the NRF2-ARE pathway (CD = 9.83 μM), selective inhibition of both hMAO-B and QR2 (IC₅₀s = 8.05 and 0.57 μM), and the best ability to Journal of medicinal chemistryResveratrol-Based MTDLs to Stimulate Defensive and Regenerative Pathways and Block Early Events in Neurodegenerative Cascades.PMC8958504RTI2018-095793-B-I00PIE-202080I026FPU13/03737FPU18/00630PIE-202080E118PI17/01700SAF2015-64948-C2-1-RFPU16/01704RTI2018-093955-B-C21B2017/BMD-3827 - NRF24ADCMFPU15/03269PID2021-122650OB-I00FPUEST17/00233Michalska PEstrada-Valencia MSastre EDDuarte PPerez-Castillo ALopez MGLopez-Caballero PFernandez-Mendivil CHerrera-Arozamena CPerez CLombardia JLeon RSenar SRodriguez-Franco MIMorales-Garcia JAfalseResveratrol-Based MTDLs to Stimulate Defensive and Regenerative Pathways and Block Early Events in Neurodegenerative Cascades.By replacing a phenolic ring of (<i>E</i>)-resveratrol with an 1,3,4-oxadiazol-2(3<i>H</i>)-one heterocycle, new resveratrol-based multitarget-directed ligands (MTDLs) were obtained. They were evaluated in several assays related to oxidative stress and inflammation (monoamine oxidases, nuclear erythroid 2-related factor, quinone reductase-2, and oxygen radical trapping) and then in experiments of increasing complexity (neurogenic properties and neuroprotection <i>vs</i> okadaic acid). 5-[(<i>E</i>)-2-(4-Methoxyphenyl)ethenyl]-3-(prop-2-yn-1-yl)-1,3,4-oxadiazol-2(3<i>H</i>)-one (<b>4e</b>) showed a well-balanced MTDL profile: cellular activation of the NRF2-ARE pathway (CD = 9.83 μM), selective inhibition of both hMAO-B and QR2 (IC₅₀s = 8.05 and 0.57 μM), and the best ability to 2022-01-01T00:00:00Z2022 Mar2026-05-31T06:03:48.81Z2025-04-20T00:20:38.193ZS-EPMC89585043524505110.1021/acs.jmedchem.1c01883