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.

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

Laurini, Erik;Pricl, Sabrina;
2019-01-01

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.
2019
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https://www.tandfonline.com/action/showCopyRight?scroll=top&doi=10.1080%2F14756366.2019.1581184
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11368/2938996
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