Discovery of a potent melatonin-based inhibitor of quinone reductase-2 with neuroprotective and neurogenic properties

Herrera Arozamena, C.Estrada Valencia, MGarcía Díez, G.Pérez, C.León, R.Infantes, L.Morales García, José ÁngelPérez Castillo, AnaSastre, E. delLópez, M.G.Rodríguez Franco, M.I.2024-11-222024-11-222024Herrera-Arozamena C, Estrada-Valencia M, García-Díez G, Pérez C, León R, Infantes L, Morales-García JA, Pérez-Castillo A, Del Sastre E, López MG, Rodríguez-Franco MI. Discovery of a potent melatonin-based inhibitor of quinone reductase-2 with neuroprotective and neurogenic properties. Eur J Med Chem. 2024 Nov 5;277:116763. doi: 10.1016/j.ejmech.2024.116763. Epub 2024 Aug 10. PMID: 39146834.10.1016/J.EJMECH.2024.116763https://hdl.handle.net/20.500.14352/1109345-Methoxy-3-(5-methoxyindolin-2-yl)-1H-indole (3), whose structure was unambiguously elucidated by X-ray analysis, was identified as a multi-target compound with potential application in neurodegenerative diseases. It is a low nanomolar inhibitor of QR2 (IC50 = 7.7 nM), with greater potency than melatonin and comparable efficacy to the most potent QR2 inhibitors described to date. Molecular docking studies revealed the potential binding mode of 3 to QR2, which explains its superior potency compared to melatonin. Furthermore, compound 3 inhibits hMAO-A, hMAO-B and hLOX-5 in the low micromolar range and is an excellent ROS scavenger. In phenotypic assays, compound 3 showed neuroprotective activity in a cellular model of oxidative stress damage, it was non-toxic, and was able to activate neurogenesis from neural stem-cell niches of adult mice. These excellent biological properties, together with its both good in silico and in vitro drug-like profile, highlight compound 3 as a promising drug candidate for neurodegenerative diseases.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/Discovery of a potent melatonin-based inhibitor of quinone reductase-2 with neuroprotective and neurogenic propertiesjournal articlehttps://doi.org/10.1016/j.ejmech.2024.116763https://www.sciencedirect.com/science/article/pii/S0223523424006445?via%3Dihubopen access615Melatonin-based inhibitorQuinone reductase-2NeuroprotectionNeurogenicFarmacología (Medicina)Química orgánica (Farmacia)3209 Farmacología