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Review
. 2024 Jul 26;29(15):3514.
doi: 10.3390/molecules29153514.

Naturally Inspired Coumarin Derivatives in Alzheimer's Disease Drug Discovery: Latest Advances and Current Challenges

Rebecca Orioli  1 , Federica Belluti  1 , Silvia Gobbi  1 , Angela Rampa  1 , Alessandra Bisi  1
Affiliations
Review

Naturally Inspired Coumarin Derivatives in Alzheimer's Disease Drug Discovery: Latest Advances and Current Challenges

Rebecca Orioli et al. Molecules. .

Abstract

The main feature of neurodegenerative diseases, including Alzheimer's disease, is the network of complex and not fully recognized neuronal pathways and targets involved in their onset and progression. The therapeutic treatment, at present mainly symptomatic, could benefit from a polypharmacological approach based on the development of a single molecular entity designed to simultaneously modulate different validated biological targets. This strategy is principally based on molecular hybridization, obtained by linking or merging different chemical moieties acting with synergistic and/or complementary mechanisms. The coumarin core, widely found in nature, endowed with a recognized broad spectrum of pharmacological activities, large synthetic accessibility and favourable pharmacokinetic properties, appears as a valuable, privileged scaffold to be properly modified in order to obtain compounds able to engage different selected targets. The scientific literature has long been interested in the multifaceted profiles of coumarin derivatives, and in this review, a survey of the most important results of the last four years, on both natural and synthetic coumarin-based compounds, regarding the development of anti-Alzheimer's compounds is reported.

Keywords: Alzheimer’s disease; cholinesterases; coumarin; polypharmacology.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The main classes of coumarins.
Figure 2
Figure 2
Targets involved in the pathogenesis of AD engaged by coumarin-based compounds.
Figure 3
Figure 3
Natural coumarins endowed with anti-AD properties.
Figure 4
Figure 4
Natural coumarins as dual BChE/AChE inhibitors.
Figure 5
Figure 5
Natural coumarins from Murraya paniculata (Orange Jasmin).
Figure 6
Figure 6
Natural coumarins emerged from a virtual screening on MAO-B and AChE.
Figure 7
Figure 7
Structure of pteryxin.
Figure 8
Figure 8
Most common synthetic approach to coumarin derivatives.
Figure 9
Figure 9
Design of hybrids based on 7-benzyloxycoumarin and various heterocycles, connected by nitrogen-bearing linkers.
Figure 10
Figure 10
Hybrids coumarin-pyrazole, coumarin-carbazole and coumarin-aromatic/heterocycles.
Figure 11
Figure 11
Design strategy for coumarin-1,3,5-triazine derivatives.
Figure 12
Figure 12
Synthetic derivatives inspired by natural compounds.
Figure 13
Figure 13
3-arylcoumarin-based pyridinium salt 33.
Figure 14
Figure 14
Design of chalcone-coumarin merged derivatives acting as TRKB pathway activators.
Figure 15
Figure 15
Coumarin-chalcone hybrids as ChEs inhibitors.
Figure 16
Figure 16
Coumarin-Schiff base hybrid as AChEI.
Figure 17
Figure 17
Coumarin-propargylamine derivatives.
Figure 18
Figure 18
Design of hybrid 41.
Figure 19
Figure 19
Design strategy for the naturally inspired derivative 42.
Figure 20
Figure 20
N-benzyltriazole derivatives with dual BChE and 15-LOX activity and neuroprotective and anti-aggregating properties.
Figure 21
Figure 21
Design of metal-chelating coumarin-based compounds.
Figure 22
Figure 22
Development of ChEs-FAAH inhibitors.
Figure 23
Figure 23
Merged coumarin-dihydropyridines as ChEs/hCA inhibitors.
Figure 24
Figure 24
Coumarins acting on MAO-B and CA VII, IX and XII.
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