Abstract
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.
Highlights
Despite the great advances achieved in the understanding of the Alzheimer’s disease (AD) pathophysiology, our current knowledge about this illness is still an incomplete puzzle
All 4-chromenone – and 4-quinolone – DBMA hybrids 1–13 were purified in silica gel cartridges using an automatic chromatographic equip (IsoleraOne, Biotage) and were characterised by their analytical (HPLC, High resolution mass spectrometry (HRMS)) and spectroscopic data (1H NMR, 13 C NMR)
Complete NMR assignment of their hydrogen and carbon atoms were made by 1H – 13 C two-dimensional diagrams, mainly
Summary
Despite the great advances achieved in the understanding of the Alzheimer’s disease (AD) pathophysiology, our current knowledge about this illness is still an incomplete puzzle. Up to date, all of them are just loose pieces of the puzzle, and none of them is able to account for the complexity of AD1 This brings us to the main fact that is clear today, the multifactorial nature of this disease, in which different factors contribute to its onset and progression. The current approved drugs are mainly active at a single target, acetylcholinesterase (AChE) or N-methyl-D-aspartate receptor (NMDA), that have barely been able to modify the disease progression[2]. This failure lies in the complex network of pathophysiological processes underlying the origin of the AD-related neurodegeneration, and in our lack of knowledge about the primordial event that triggers the others, if there is only one. We understand that genetic, epigenetic and environmental factors are involved in neurodegeneration
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