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Review
, 23 (2)

Coumarin: A Natural, Privileged and Versatile Scaffold for Bioactive Compounds

Affiliations
Review

Coumarin: A Natural, Privileged and Versatile Scaffold for Bioactive Compounds

Angela Stefanachi et al. Molecules.

Abstract

Many naturally occurring substances, traditionally used in popular medicines around the world, contain the coumarin moiety. Coumarin represents a privileged scaffold for medicinal chemists, because of its peculiar physicochemical features, and the versatile and easy synthetic transformation into a large variety of functionalized coumarins. As a consequence, a huge number of coumarin derivatives have been designed, synthesized, and tested to address many pharmacological targets in a selective way, e.g., selective enzyme inhibitors, and more recently, a number of selected targets (multitarget ligands) involved in multifactorial diseases, such as Alzheimer's and Parkinson's diseases. In this review an overview of the most recent synthetic pathways leading to mono- and polyfunctionalized coumarins will be presented, along with the main biological pathways of their biosynthesis and metabolic transformations. The many existing and recent reviews in the field prompted us to make some drastic selections, and therefore, the review is focused on monoamine oxidase, cholinesterase, and aromatase inhibitors, and on multitarget coumarins acting on selected targets of neurodegenerative diseases.

Keywords: aromatase inhibitors; cholinesterase inhibitors; coumarin; monoamine oxidase inhibitors; multitarget ligands.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structure and numbering scheme of coumarin 1.
Figure 2
Figure 2
Structures of some coumarin drugs: the anticoagulants warfarin 2, acenocoumarin 3, and phenprocoumon 4, the choleretics armillarisin A 5 and hymechromone 6, and the antibiotic novobiocin 7.
Figure 3
Figure 3
General biosynthetic pathway leading to phenylpropanoids (adapted from Vogt, 2010) [23].
Figure 4
Figure 4
Proposed radical mechanism of 7-hydroxycoumarin biosynthesis from 4′-coumaroyl-S-CoA (adapted from Kai et al., 2008) [24]. (a): 2-oxoglutarate-dependent dioxygenase F6′H1.
Figure 5
Figure 5
Representative pathways of coumarin metabolism (adapted from Lake, 1999) [25].
Figure 6
Figure 6
Mechanism of inhibition of serine proteases by 6-halomethyl-3,4-dihydrocoumarins (suicide substrate/inhibitor). Adapted from Pochet et al., 2004 [56].
Scheme 1
Scheme 1
Synthesis of 3-aroylcoumarins from alkynoates.
Scheme 2
Scheme 2
Synthesis of 3-aroylcoumarins from coumarin or coumarin-3-carboxylic acid.
Scheme 3
Scheme 3
Synthesis of 3-substituted coumarins from alkynoates.
Scheme 4
Scheme 4
Synthesis of 3-difluoroacetylated coumarins from alkynoates.
Scheme 5
Scheme 5
Synthesis of 3-substituted coumarins from salicylaldehyde.
Scheme 6
Scheme 6
Synthesis of 3-trifluoromethyl coumarins and carbostyryls from cinnamic esters.
Scheme 7
Scheme 7
Synthesis of 3-azidoacyl coumarins from 3-bromoacyl precursors.
Scheme 8
Scheme 8
Four-component synthesis of 3-sulphonylamidine coumarins.
Scheme 9
Scheme 9
Multicomponent synthesis of 3-aroylamido coumarins.
Figure 7
Figure 7
7-Benzyloxy and 7-arylsulfonyloxycoumarins as monoamine oxidase (MAO) inhibitors.
Figure 8
Figure 8
Ester derivatives of 7-hydroxy-3,4-dimethylcoumarin as rMAO inhibitors.
Figure 9
Figure 9
Left, chemical structure of geiparvarins 19 [98]. Right, molecular overlay of 7-benzyloxy-3,4-dimethylcoumarin (grey) onto 3,4-dimethylgeiparvarin (white). The van der Waals surface of the 3′-methyl group impacts the region of the ortho-substituents in the phenyl ring of 7-benzyloxycoumarins. Reproduced with permission of Elsevier.
Figure 10
Figure 10
3-Carboxamidocoumarins 20 and 3-acylcoumarin derivatives 21 as hMAO inhibitors.
Figure 11
Figure 11
3-Carbamylcoumarins 22 as MAO inhibitors.
Figure 12
Figure 12
3-Phenyl- 23 and 3-pyridazinylcoumarins 24 as hMAO inhibitors.
Figure 13
Figure 13
Benzofuran derivatives 25, obtained from the opening and rearrangement of coumarin lactone ring, as detailed in Ref. 106.
Figure 14
Figure 14
Structure and rMAO inhibitory activity of NW-1772.
Figure 15
Figure 15
General structure of safinamide analogues with rMAO B inhibitory activity.
Figure 16
Figure 16
Overlay of safinamide (black) and 7-(3-chlorobenzyloxy)-4-carboxaldehyde-coumarin (gray), a strict analogue of NW-1772, onto the hMAO B active site [112]. The active site residues and the FAD cofactor are also shown. Reproduced with permission of ACS.
Figure 17
Figure 17
Computer-assisted design of coumarin derivatives as potent hMAO B inhibitors.
Figure 18
Figure 18
Computer-assisted design of selective hMAO A/B inhibitors.
Figure 19
Figure 19
General formulae of DBS bAChE inhibitors.
Figure 20
Figure 20
bAChE-selective coumarin inhibitors.
Figure 21
Figure 21
Coumarin–pyridinium derivatives as ChEs inhibitors.
Figure 22
Figure 22
Donepezil-like coumarin 34 as bAChE selective inhibitor.
Figure 23
Figure 23
Chemical structure of hAChE selective inhibitor AP2238.
Figure 24
Figure 24
3-Carboxamidocoumarins 35 as eeAChE selective inhibitors.
Figure 25
Figure 25
Example of tacrine–coumarin hybrids 36 as potent hChEs inhibitors.
Figure 26
Figure 26
Multitarget drug design strategies.
Figure 27
Figure 27
7-Substituted coumarins bearing protonatable groups for dual ChE–MAO inhibition.
Figure 28
Figure 28
7-Substituted coumarins as dual ChE/MAO inhibitors.
Figure 29
Figure 29
Coumarin–tacrine conjugates as multitarget-directed ligands.
Figure 30
Figure 30
3-Propargylamine derivatives of coumarin as dual ChE–MAO inhibitors.
Figure 31
Figure 31
3-Phenylcoumarins as multitarget-directed ligands.
Figure 32
Figure 32
8-Aminomethylcoumarins as multitarget-directed ligands.
Figure 33
Figure 33
7-Hydroxycoumarin–tacrine conjugates as multitarget-directed ligands.
Figure 34
Figure 34
3-Carboxamidocoumarins as multitarget-directed ligands.
Figure 35
Figure 35
Chen’s coumarin derivatives as aromatase (AR) inhibitors.
Figure 36
Figure 36
4-Methylimidazolyl coumarins with good inhibitory activity towards AR.
Figure 37
Figure 37
Open analogues of 4-imidazolylmethyl coumarin as selective inhibitors of CYP11B1.
Figure 38
Figure 38
Luqman’s neoflavonoid AR inhibitors.
Figure 39
Figure 39
Yamaguchi’s coumarins with AR inhibitory activity.

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