期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 190, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2020.112090
关键词
Indole or naphthalene - oxadiazolones; Melatonin receptors (MT1R and MT2R); Quinone reductase-2 (QR2); Nuclear erythroid 2-related factor (NRF2); Ketch-like ECH associated protein 1 (KEAP1); Monoamine oxidases (MAO-A and MAO-B); Lipoxygenase-5 (LOX-5); Neurogenic activity
资金
- Spanish Ministry of Science, Innovation and Universities
- Spanish Research Agency
- European Regional Development Funds [RTI2018-093955-B-C21, SAF2015-64948-C2-1-R, RTI2018-095793-B-100, SAF2015-64629-C22-R]
- Community of Madrid
- European Structural Funds [B2017/BMD-3827 - NRF24ADCM]
- Health Institute Carlos III (Miguel Servet II Program) [CP16/00014, PI17/01700]
- Spanish Ministry of Education (MEC) [FPU16/01704, FPUEST17/00233, FPU13/03737]
New multi-target indole and naphthalene derivatives containing the oxadiazolone scaffold as a bioisostere of the melatonin acetamido group have been developed. The novel compounds were characterized at melatonin receptors MT1R and MT2R, quinone reductase 2 (QR2), lipoxygenase-5 (LOX-5), and monoamine oxidases (MAO-A and MAO-B), and also as radical scavengers. We found that selectivity within the oxadiazolone series can be modulated by modifying the side chain functionality and coplanarity with the indole or naphthalene ring. In phenotypic assays, several oxadiazolone-based derivatives induced signalling mediated by the transcription factor NRF2 and promoted the maturation of neural stem-cells into a neuronal phenotype. Activation of NRF2 could be due to the binding of indole derivatives to KEAP1, as deduced from surface plasmon resonance (SPR) experiments. Molecular modelling studies using the crystal structures of QR2 and the KEAP1 Kelch-domain, as well as the recently described X-ray free-electron laser (XFEL) structures of chimeric MT1R and MT2R, provided a rationale for the experimental data and afforded valuable insights for future drug design endeavours. (C) 2020 The Authors. Published by Elsevier Masson SAS.
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