New flavonoid – N,N-dibenzyl(N-methyl)amine hybrids: Multi-target-directed agents for Alzheimer´s disease endowed with neurogenic properties

Journal of Enzyme Inhibition and Medicinal Chemistry

Dolores Viña¹  Alejandro Romero²  Eva Ramos²  Ana Pérez-Castillo³  José A. Morales-García⁴  Martín Estrada-Valencia⁵  Clara Herrera-Arozamena⁵  Concepción Pérez⁵  María Isabel Rodríguez-Franco⁵  Erik Laurini⁶  Sabrina Pricl⁶ 

[1] Centre for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Santiago de Compostela, Spain;Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Complutense University of Madrid, Madrid, Spain;;Institute for Biomedical Research "Alberto Sols", Spanish Council for Scientific Research (IIB-CSIC), Madrid, Spain;Biomedical Research Networking Centre on Neurodegenerative Diseases (CIBERNED), Madrid, Spain;Institute for Biomedical Research "Alberto Sols", Spanish Council for Scientific Research (IIB-CSIC), Madrid, Spain;Biomedical Research Networking Centre on Neurodegenerative Diseases (CIBERNED), Madrid, Spain;Department of Cellular Biology, Medical School, Complutense University of Madrid, Madrid, Spain;Institute of Medicinal Chemistry, Spanish Council for Scientific Research (IQM-CSIC), Madrid, Spain;Molecular Biology and Nanotechnology Laboratory (MolBNL@UniTS), Department of Engineering and Architecture (DEA), Trieste, Ital;

关键词: Multi-target-directed ligands;    neurogenesis;    sigma receptors;    human β-secretase;    human lipoxygenase-5;    human cholinesterases;    Alzheimer’s disease;    neurodegenerative diseases;   

DOI  :  10.1080/14756366.2019.1581184

来源: publisher

【 摘 要 】

The design of multi-target directed ligands (MTDLs) is a valid approach for obtaining effective drugs for complex pathologies. MTDLs that combine neuro-repair properties and block the first steps of neurotoxic cascades could be the so long wanted remedies to treat neurodegenerative diseases (NDs). By linking two privileged scaffolds with well-known activities in ND-targets, the flavonoid and the N,N-dibenzyl(N-methyl)amine (DBMA) fragments, new CNS-permeable flavonoid – DBMA hybrids (1–13) were obtained. They were subjected to biological evaluation in a battery of targets involved in Alzheimer’s disease (AD) and other NDs, namely human cholinesterases (hAChE/hBuChE), β-secretase (hBACE-1), monoamine oxidases (hMAO-A/B), lipoxygenase-5 (hLOX-5) and sigma receptors (σ1R/σ2R). After a funnel-type screening, 6,7-dimethoxychromone – DBMA (6) was highlighted due to its neurogenic properties and an interesting MTD-profile in hAChE, hLOX-5, hBACE-1 and σ1R. Molecular dynamic simulations showed the most relevant drug-protein interactions of hybrid 6, which could synergistically contribute to neuronal regeneration and block neurodegeneration.

【 授权许可】

CC BY