Monoamine oxidase (MAO) inhibitory activity: 3-phenylcoumarins versus 4-hydroxy-3-phenylcoumarins

Article abstract of DOI:10.1002/cmdc.201402010

Monoamine oxidase (MAO) is a useful target in the treatment of neurodegenerative diseases and depressive disorders. Both isoforms, MAO-A and MAO-B, are known to play critical roles in disease progression, and as such, the identification of novel, potent a

Full text of DOI:10.1002/cmdc.201402010

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DOI: 10.1002/cmdc.201402010
Monoamine Oxidase (MAO) Inhibitory Activity: 3-
Phenylcoumarins versus 4-Hydroxy-3-phenylcoumarins
Giovanna L. Delogu,*[a] Silvia Serra,*[a] Elias Quezada,[b] Eugenio Uriarte,[b] Santiago Vilar,[b, c]
Nicholas P. Tatonetti,[c] and Dolores ViÇa[d]
Monoamine oxidase (MAO) is a useful target in the treatment
of neurodegenerative diseases and depressive disorders. Both
isoforms, MAO-A and MAO-B, are known to play critical roles in
disease progression, and as such, the identification of novel,
potent and selective inhibitors is an important research goal.
Here, two series of 3-phenylcoumarin derivatives were synthe-
sized and evaluated against MAO-A and MAO-B. Most of the
compounds tested acted preferentially on MAO-B, with IC50
values in the micromolar to nanomolar range. Only 6-chloro-4-
an important place in the realm of natural products and syn-
thetic organic chemistry.[1] They are widely distributed through-
out the plant kingdom, but they also occur as secondary me-
tabolites in the seeds, roots, and leaves of many plant spe-
cies.[2] Other more synthetic coumarins are commonly used as
aroma chemicals because of their potent odour, tenacity, sta-
bility to alkali, and relatively inexpensive price.[3] Their interest-
ing pharmacological properties make them attractive targets in
organic and medicinal chemistry. Coumarins are present in
a broad range of therapeutic agent classes, such as anticoagu-
lants, antimicrobials, antibacterials, anticancers, and antivirals.[4]
Furthermore, recent several studies have paid special attention
to their antioxidative and enzyme inhibitory properties.[5,6]
In particular, some natural coumarins have shown weak
monoamine oxidase (MAO) inhibitory potency,[7] while properly
modified natural coumarins have been characterized as potent
and selective MAO inhibitors.[8] MAO is a flavin adenine dinu-
cleotide (FAD)-dependent enzyme found in the outer mito-
chondrial membrane of neuronal, glial, and other mammalian
cells.[9] This enzyme is responsible for catalyzing the oxidative
deamination of dietary amines and neurotransmitters, regulat-
ing intracellular levels of biogenic amines in the brain and the
peripheral tissues.[10] Two isoforms, namely MAO-A and MAO-B,
have been identified basis on their amino acid sequences,
three-dimensional structures, substrate preferences, and inhibi-
tor selectivity.[11] MAO-A has a higher affinity for serotonin and
noradrenaline, while MAO-B preferentially deaminates phenyle-
thylamine and benzylamine.[12] It is well-known that both MAO
isoforms play a critical role in the regulation of the central
nervous system (CNS) and contribute to the pathogenesis of
human neurodegenerative and depressive disorders. Recent
findings revealed that affinity and selectivity for MAO-A and
MAO-B can be efficiently modulated by appropriate substitu-
tions of the coumarin moiety; the 3/4 and 6/7 positions are
particularly amenable to modification.[8,13,14] Our research
group has also reported compounds with high MAO-B selectiv-
ity containing 6- or 8-substituted-3-arylcoumarin scaffolds. A
variety of functional groups of diverse size, lipophilic and elec-
tronic properties were introduced in both aromatic rings, and
the results showed that a small substituent at C6 or C8 of the
coumarin nucleus is important when a phenyl group is located
at C3. Substituents on the 3-phenyl ring also play a crucial role
in activity and selectivity—meta and para substitutions are the
most favorable for desired activity.[5,15]
hydroxy-3-(2’-hydroxyphenyl)coumarin
exhibited
activity
against the MAO-A isoform, while still retaining good selectivi-
ty for MAO-B. 6-Chloro-3-phenylcoumarins unsubstituted at
the 4 position were found to be more active as MAO-B inhibi-
tors than the corresponding 4-hydroxylated coumarins. For 4-
unsubstituted coumarins, meta and para positions on the 3-
phenyl ring seem to be the most favorable for substitution.
Molecular docking simulations were used to explain the ob-
served hMAO-B structure–activity relationships for this type of
compound. 6-Chloro-3-(3’-methoxyphenyl)coumarin was the
most active compound identified (IC50 =0.001 mm) and is sever-
al times more potent and selective than the reference com-
pound, R-(ꢀ)-deprenyl hydrochloride. This compound repre-
sents a novel tool for the further investigation of the therapeu-
tic potential of MAO-B inhibitors.
Coumarins constitute an important class of benzopyrones of
different origins. Due to their structural variability, they occupy
[a] Dr. G. L. Delogu, Dr. S. Serra
Department of Life Sciences & Environment
Section of Pharmaceutical Sciences, University of Cagliari
Palazzo delle Scienze, Via Ospedale, 72, 09124 Cagliari (Italy)
E-mail: delogug@unica.it
silvserra@tiscali.it
[b] Dr. E. Quezada, Prof. E. Uriarte, Dr. S. Vilar
Department of Organic Chemistry, Faculty of Pharmacy
University of Santiago de Compostela
15782 Santiago de Compostela (Spain)
[c] Dr. S. Vilar, Dr. N. P. Tatonetti
Department of Biomedical Informatics
Columbia University Medical Center of New York
622 W. 168th St., Vanderbilt Clinic 5th Floor, 10032 New York, NY (USA)
[d] Dr. D. ViÇa
Department of Pharmacology
Center for Research in Molecular Medicine & Chronic Diseases (CIMUS)
University of Santiago de Compostela
Based on the previous 3-phenylcoumarins experimental re-
sults and with the aim of finding novel and selective MAO in-
hibitors, here, we describe a comparative study between differ-
Avda. Barcelona s/n, Campus Vida, 15782 Santiago de Compostela (Spain)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201402010.
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ently substituted 6-chloro-3-phenylcoumarins and 6-chloro-4-
hydroxy-3-phenylcoumarins. Substituents and their positions
on the 3-phenylcoumarin nucleus were selected following on
from previous results that showed very high MAO inhibitory
activity for some derivatives. We also analyzed some structural
patterns for MAO activity using molecular docking simulations.
3-Phenylcoumarins were prepared by Perkin reaction[16] ac-
cording to the protocol outlined in Scheme 1. Treatment of
the 5-chlorosalicylaldehyde with the appropriate methoxy-sub-
stituted phenylacetic acid in the presence of dehydrating
agent dicyclohexylcarbodiimide (DCC) afforded 6-chloro-3-phe-
nylcoumarins 1–4.[17,18] Hydrolysis of the methoxy groups[19] of
compound 2–4 by treatment with hydrogen iodide in acetic
acid/acetic anhydride gave corresponding hydroxy derivatives
5–7, respectively.[18]
Scheme 2. Synthesis of 6-chloro-4-hydroxy-3-phenylcoumarin derivatives. Re-
agents and conditions: a) PhI(OAc)2, Na2CO3, H2O, RT, 14 h; b) Pd(OAc)2, LiOH,
H2O, P(t-But)3, DME/H2O (4:1), RT, 24–48 h.
The results of the hMAO-A and hMAO-B inhibition studies,
together with the MAO-B selectivity index, are reported in
Table 1. Enzymatic assays revealed that most of the test com-
pounds were moderate-to-potent inhibitors of hMAO at low
micromolar to nanomolar concentrations, showing selectivity
toward hMAO-B. Only 6-chloro-4-hydroxy-3-(2’-hydroxyphenyl)-
coumarin (14) exhibited affinity for the MAO-A receptor, al-
though a high MAO-B selectivity was also retained.
As a rule, 6-chloro-3-phenylcoumarins unsubstituted at posi-
tion 4 were found to be more active as MAO-B inhibitors than
the corresponding 4-hydroxylated coumarins. In addition, the
methoxy derivatives were generally observed to be more
active than the corresponding hydroxy derivatives. As de-
scribed previously, the meta and para positions on the 3-
phenyl ring of 4-unsubstituted coumarins appear to be the
most favorable for substitution. Therefore, compound 1, con-
taining a simple phenyl ring in position 3 of coumarin nucleus,
showed activity in the low micromolar range (IC50 =0.56 mm).
Coumarins 2 and 3 contain a methoxy group in the 3-phenyl
ring at the para and meta position, respectively. The results re-
vealed that these derivatives, with IC50 values of 0.004 and
0.001 mm, respectively, were the most active hMAO-B inhibitor
compounds of our series. Their IC50 values are better than R-
(ꢀ)-deprenyl hydrochloride, a known MAO-B inhibitor used
here as a reference agent (IC50 =0.017 mm). In this study, we
also corroborated a previous finding[15c] that substitution at the
ortho position of the 3-phenyl ring of 6-chloro-3-phenylcou-
marins is unfavorable for activity. Indeed, compound 4, which
has a methoxy substituent at the ortho position, was inactive
at 100 mm—the highest concentration tested.
Scheme 1. Synthesis of 3-phenylcoumarins derivatives via Perkin reaction.
Reagents and conditions: a) DCC, DMSO, 1108C, 12 h; b) 57% HI/AcOH/Ac2O,
08C!RT, 3 h.
The synthesis of 6-chloro-4-hydroxy-3-phenylcoumarins 8–
14[6,14,20] was achieved by preparation of the phenyliodonium
coumarinate species starting from the corresponding commer-
cially available 6-chloro-4-hydroxycoumarin. Palladium-cata-
lyzed Suzuki coupling between the phenyliodonium zwitterion
species and the appropriately substituted phenyl boronic acids
afforded the desired final compounds (Scheme 2).
The potential effects of newly synthesized compounds 1–14
on both isoforms of human MAO were investigated using mi-
crosomal MAO isoforms prepared from insect cells (BTI-TN-
5B1-4) infected with recombinant baculovirus containing cDNA
inserts for hMAO-A or hMAO-B and an Amplex Red MAO assay
kit following a previously described procedure.[21] The activity
of the compounds was determined by monitoring their effects
on hydrogen peroxide production from para-tyramine induced
by MAO. The test compounds did not show any interference
with the reagents used in the biochemical assay indicating the
suitability of this technique for their evaluation. The control ac-
tivity of hMAO-A and hMAO-B was evaluated using para-tyra-
mine as the common substrate; the oxidation of the substrate
to para-hydroxyphenylacetaldehyde proceeded at a rate of
165ꢁ2 pmolminꢀ1 (n=20).
Since some of the synthesized derivatives exhibited good
activity against hMAO-B, we performed molecular docking cal-
culations to predict the most stable poses of the ligands inside
the protein binding site. To perform the modeling, we followed
a
similar protocol recently published by our research
group[22,23] in which we used the crystallized structure of the
hMAO-B bound to 7-(3-chlorobenzyloxy)-4-carboxaldehyde-
coumarin (c17) (PDB: 2V60).[24] A water molecule that estab-
lishes a hydrogen bond with the co-crystallized ligand was re-
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Table 1. Enzyme inhibition and MAO-B selectivity of new compounds
and reference inhibitors.
Compd
IC50 [mm][a]
hMAO-A
SI[b]
hMAO-B
1
2
3
4
5
6
7
8
**
**
**
**
**
**
**
**
**
**
**
**
**
0.56ꢁ0.04
>179[d]
0.004ꢁ0.0003 >25000
0.001ꢁ0.0001 >100000
***
–
>752
>472
>225
>50[d]
–
>16[d]
>159[d]
>4.3[d]
>1.3
154
0.000082
4.043
0.133ꢁ0.020
0.212ꢁ0.022
0.443ꢁ0.055
2.00ꢁ0.13
***
6.20ꢁ0.42
0.63ꢁ0.04
23.42ꢁ1.56
75.74ꢁ3.36
0.36ꢁ0.02
9
10
11
12
13
14
Clorgyline
R-(ꢀ)-deprenyl 68.73ꢁ4.21[c]
hydrochloride
Moclobemide 361.38ꢁ19.37
55.47ꢁ5.00[c]
0.0052ꢁ0.00092[c] 63.41ꢁ1.20
0.017ꢁ0.0019
*
<0.36[d]
[a] IC50 values were determined against human recombinant MAO iso-
forms expressed in baculovirus infected BTI insect cells; data are the
meanꢁSEM of n=5 independent experiments (for details, see Support-
ing Information). Clorgyline, moclobemide and R-(ꢀ)-deprenyl hydrochlo-
ride were used as reference compounds. * Inactive at 1 mm (highest con-
centration tested). ** Inactive at 100 mm (highest concentration tested);
at higher concentrations the compounds precipitate. *** At 100 mm, com-
pound inhibits enzymatic activity by approximately 40–45%. [b] Selectivi-
ty index (SI): [IC50 (MAO-A)]/[IC50 (MAO-B)]. [c] Level of statistical signifi-
cance: P<0.01 versus the corresponding IC50 values obtained against
MAO-B, as determined by ANOVA/Dunnett’s. [d] Values obtained under
the assumption that the corresponding IC50 against MAO-A or MAO-B is
the highest concentration tested (100 mm or 1 mm).
tained in the pocket. The docking protocol was previously vali-
dated through RMSD values of different crystallized ligands
from other hMAO-B structures.[22] As an example, in the current
study, the RMSD value between the calculated and the experi-
mental coordinates for the co-crystallized ligand c17 was
0.81 ꢁ. In addition, we performed docking calculations with
the I199A–Y326A MAO-B mutant (PDB: 3ZYX).[25]
Figure 1. Poses calculated through molecular docking. Hydrogen bonds are
shown in yellow. a) Poses determined for 2 (green), 3 (grey) and 4 (pink). Fa-
vored hydrophobic surface (green mesh) around the 3-aryl fragment was
calculated using the residues in the entrance cavity. Meta and para methoxy
substituents showed better accommodation in the hydrophobic cavity.
b) Pose calculated for 5. Docking showed two possible hydrogen bonds
(Pro102 and Cys172). c) Pose extracted from the docking for 7. The ligand is
predicted to establish hydrogen bonds with Cys172, Tyr326 and Gln206.
Docking calculations carried out in the hMAO-B crystal struc-
ture showed that the favored pose for the studied compounds
orientates the coumarin scaffold towards the FAD cofactor and
the 3-aryl ring towards the hydrophobic entrance cavity. In the
predicted binding mode, the pyrone ring orientates the
oxygen atoms towards the bottom of the binding pocket and
a hydrogen bond can be established between the oxygen of
the carbonyl group and Cys172. The poses determined
through docking calculations are in agreement with previous
results.[22,23]
other hand, the pose of compound 4 is slightly shifted to ac-
commodate the ortho-methoxy group of the 3-aryl ring in the
hydrophobic cavity. This shift could cause the disruption of the
hydrogen bond between the ligand and Cys172.
Docking simulations suggest that methoxy substitutions in
the meta and para positions rather than ortho of the 3-aryl
ring are favored to establish hydrophobic interactions with the
hydrophobic entrance cavity. Figure 1a shows a favored hydro-
phobic area generated by the protein entrance cavity around
the 3-aryl fragment. Meta and para substituents are better ac-
commodated in the hydrophobic cavity (Figure 1a). On the
When a meta or para methoxy group on the 3-phenyl ring is
replaced by a hydroxy substituent (as in 5 and 6), the MAO-B
inhibitory activity of the compounds decreases. These data
suggest that the MAO-B inhibitory activity improves signifi-
cantly when a small lipophilic group is in these positions (meta
and para). Curiously, when the ortho position was substituted
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by a hydroxy group (as in 7), we observed a slight MAO-B in-
hibitor activity (IC50 =0.44 mm).
the ligand stabilization in the pocket. A decrease in the van
der Waals energy contribution of Tyr326 was detected through
the docking simulations for compounds with 4-hydroxy sub-
stituents (Figure 2b).
Molecular docking suggest that hydroxy substituents in the
ring are well accepted in all positions. Compounds 5, 6 and 7
are predicted to establish hydrogen bonds with Pro102,
Ile199, and Gln206 and Tyr326 (Figure 1b,c). However, hydroxy
derivatives exhibited weaker activity than the corresponding
methoxy derivatives, possibly due to decreases in hydrophobic
interactions within the pocket. The exception is the ortho posi-
tion, where the hydroxy substituent is predicted to be better
accommodated than the methoxy group (Figure 1a,c). The
presence of a 4-hydroxy group in the 6-chloro-3-phenylcou-
marin nucleus seems to be unfavorable for activity.
However, compounds 7 and 14 also differentiate at posi-
tion 4, and their IC50 values are similar (0.44 and 0.36 mm, re-
spectively). In this case, 4-hydroxy substituents barely affected
the van der Waals energy for Tyr326. Modeling suggests that
these compounds establish a hydrogen bond between the
ortho hydroxy group in the 3-aryl ring and Tyr326. Their dock-
ing pose is slightly shifted toward the FAD compared with the
other compounds in the series causing a disruption in the van
der Waals Tyr326 energy for both compounds 7 and 14. More-
over, compound 11, a hydroxy derivative substituted at the
ortho position in the phenyl ring with a methoxy group, exhib-
ited better MAO-B inhibitory activity than the corresponding
compound not hydroxylated in the 4 position (4).
Although it remains unclear, some poses retrieved by the
docking showed the possibility that compound 11 orients the
ortho-methoxy substituent toward the opposite site of the hy-
drophobic pocket and close to residues Gln206 and Tyr326.
Docking calculations performed with the I199A–Y326A
MAO-B mutant (PDB: 3ZYX) showed that the mutated residue
Ala326 loses van der Waals energy contributions with respect
to the Tyr326 residue in wild-type MAO-B. The average contri-
bution was ꢀ1.18 and ꢀ1.14 kcalmolꢀ1 for compounds 1–7
and compounds 8–14, respectively.
4-Hydroxy derivatives 8–14 all exhibited higher IC50 values
than R-(ꢀ)deprenyl hydrochloride. Modeling results suggest
that compounds without hydroxy substituents at position 4
can establish hydrogen–arene interactions between the hydro-
gen at position 4 and the aromatic ring in Tyr326. Compounds
containing a hydroxy substituent at position 4 are not able to
establish this type of interaction with Tyr326. Moreover, the
docking results suggest that the hydroxy group at position 4 is
close to the phenyl ring in Tyr326 (Figure 2a). This could affect
Compound 14 also exhibits inhibitor activity against MAO-A,
with an IC50 value of 55.47 mm. However, the rest of the studied
compounds showed no activity against human MAO-A. Previ-
ous docking studies suggest a more limited binding inside the
A isoform for similar types of coumarins.[23] Both enzyme iso-
forms showed some different residues in the pocket that can
have an important impact in ligand selectivity. Moreover, water
molecules in the pocket can be important for ligand recogni-
tion, and their displacement could energetically limit the
ligand–protein binding.[23]
In conclusion, we used Perkin and Suzuki reactions as key
steps for the efficient and general synthesis of 6-chloro-3-phe-
nylcoumarins and 6-chloro-4-hydroxy-3-phenylcoumarins. Most
of the synthesized coumarins exhibited a high affinity and se-
lectivity for the MAO-B isoenzyme, with IC50 values in the mi-
cromolar to nanomolar range. As previously described, most
active derivatives contain substituents in the meta or para po-
sition of the 3-phenyl ring. In general, either introduction of
a 4-hydroxy group or ortho-substitution on the 3-phenyl ring
leads to a decrease in the MAO-B activity. However, combina-
tion of both substitutions increased the MAO-B activity of 6-
chloro-4-hydroxy-ortho-substituted-3-phenylcoumarin deriva-
tives compared with 6-chloro-ortho-substituted-3-phenylcou-
marin. Compound 3, with a methoxy group in the in meta po-
sition of the 3-phenyl ring, is the most active compound and is
several times more potent and selective than the reference
compound, R-(ꢀ)-deprenyl hydrochloride. Molecular docking
simulations helped in the explanation of the hMAO-B struc-
ture–activity relationships for this type of compound.
Figure 2. a) Poses determined through docking for 2 (green) and 9 (grey).
Hydrogen bonds between the compounds and Cys 172 are shown in
yellow. b) Calculated van der Waals interaction scores between Tyr326 and
the different compounds in the series observed from the hypothetical bind-
ing modes determined by the docking.
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Supporting Information
Experimental details, including synthesis protocols, characterization
data, biological methods, and docking procedures, can be found in
the Supporting Information available via http://dx.doi.org/10.1002/
cmdc.201402010.
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Acknowledgements
The authors are grateful to the Fondazione Banco di Sardegna
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Keywords: 3-arylcoumarins · molecular docking · monoamine
oxidases · inhibitors
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Received: February 4, 2014
Published online on && &&, 0000
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ChemMedChem 0000, 00, 1 – 5
&
5
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ÞÞ
These are not the final page numbers!

COMMUNICATIONS
G. L. Delogu,* S. Serra,* E. Quezada,
3-Phenylcoumarin-based inhibitors of
monoamine oxidase (MAO), a novel
target in the treatment of neurodege-
nerative diseases and depressive disor-
ders, were synthesized and evaluated
for their inhibition of MAO-A and -B.
Compounds with selectivity for MAO-B
were identified, with activities in the
low micromolar to nanomolar range.
E. Uriarte, S. Vilar, N. P. Tatonetti, D. ViÇa
&& – &&
Monoamine Oxidase (MAO) Inhibitory
Activity: 3-Phenylcoumarins versus 4-
Hydroxy-3-phenylcoumarins
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 0000, 00, 1 – 5
&
6
&
ÞÞ
These are not the final page numbers!