Estrada-Valencia_2019_J.Enzyme.Inhib.Med.Chem_34_712

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), beta-secretase (hBACE-1), monoamine oxidases (hMAO-A/B), lipoxygenase-5 (hLOX-5) and sigma receptors (sigma1R/sigma2R). 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 sigma1R. Molecular dynamic simulations showed the most relevant drug-protein interactions of hybrid 6, which could synergistically contribute to neuronal regeneration and block neurodegeneration.