%0 Journal Article
%A Herrera Arozamena, C.
%A Estrada Valencia, M
%A García Díez, G.
%A Pérez, C.
%A León, R.
%A Infantes, L.
%A Morales García, José Ángel
%A Pérez Castillo, Ana
%A Sastre, E. del
%A López, M.G.
%A Rodríguez Franco, M.I.
%T Discovery of a potent melatonin-based inhibitor of quinone reductase-2 with neuroprotective and neurogenic properties
%D 2024
%U https://hdl.handle.net/20.500.14352/110934
%X 5-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.
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