Combined 3D-QSAR and docking analysis for the design and synthesis of chalcones as potent and selective monoamine oxidase B inhibitors

Article abstract of DOI:10.1016/j.bioorg.2021.104689

Monoamine oxidases (MAOs) are important targets in medicinal chemistry, as their inhibition may change the levels of different neurotransmitters in the brain, and also the production of oxidative stress species. New chemical entities able to interact selectively with one of the MAO isoforms are being extensively studied, and chalcones proved to be promising molecules. In the current work, we focused our attention on the understanding of theoretical models that may predict the MAO-B activity and selectivity of new chalcones. 3D-QSAR models, in particular CoMFA and CoMSIA, and docking simulations analysis have been carried out, and their successful implementation was corroborated by studying twenty-three synthetized chalcones (151–173) based on the generated information. All the synthetized molecules proved to inhibit MAO-B, being ten out of them MAO-B potent and selective inhibitors, with IC₅₀ against this isoform in the nanomolar range, being (E)-3-(4-hydroxyphenyl)-1-(2,2-dimethylchroman-6-yl)prop-2-en-1-one (152) the best MAO-B inhibitor (IC₅₀ of 170 nM). Docking simulations on both MAO-A and MAO-B binding pockets, using compound 152, were carried out. Calculated affinity energy for the MAO-A was +2.3 Kcal/mol, and for the MAO-B was ?10.3 Kcal/mol, justifying the MAO-B high selectivity of these compounds. Both theoretical and experimental structure–activity relationship studies were performed, and substitution patterns were established to increase MAO-B selectivity and inhibitory efficacy. Therefore, we proved that both 3D-QSAR models and molecular docking approaches enhance the probability of finding new potent and selective MAO-B inhibitors, avoiding time-consuming and costly synthesis and biological evaluations.

Full text of DOI:10.1016/j.bioorg.2021.104689

Bioorganic Chemistry 108 (2021) 104689
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Combined 3D-QSAR and docking analysis for the design and synthesis of
chalcones as potent and selective monoamine oxidase B inhibitors
a
,
*
b
c
a
d,e
Marco Mellado , C ´e sar Gonz a´ lez , Jaime Mella , Luis F. Aguilar , Dolores Vi n˜ a
,
f
,
g
h
f,i,*
Eugenio Uriarte , Mauricio Cuellar , Maria J. Matos
a
Facultad de Ciencias, Instituto de Química, Pontificia Universidad Cat ´o lica de Valparaíso, Av. Universidad #330, Curauma, Valparaíso, Chile
Departamento de Química, Universidad T ´e cnico Federico Santa María, Av. Espa n˜ a, 1680 Valparaíso, Chile
Instituto de Química y Bioquímica, Facultad de Ciencias, Universidad de Valparaíso, Av. Gran Breta n˜ a, 1111 Valparaíso, Chile
b
c
d
Chronic Diseases Pharmacology Group, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela, 15782
Santiago de Compostela, Spain
e
Departamento de Farmacología, Farmacia y Tecnología Farmac ´e utica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Departamento de Química Org a´ nica, Facultade de Farmacia, Universidade Santiago de Compostela, 15782 Santiago de Compostela, Spain
Instituto de Ciencias Químicas Aplicadas, Universidad Aut o´ noma de Chile, 7500912 Santiago, Chile
Centro de Investigaci ´o n Farmacopea Chilena, Escuela de Química y Farmacia, Facultad de Farmacia, Universidad de Valparaíso, Av. Gran Breta n˜ a, 1093 Valparaíso,
f
g
h
Chile
i
CIQUP/Departamento de Química e Bioquímica, Faculdade de Ci ˆe ncias, Universidade do Porto, 4169-007 Porto, Portugal
A R T I C L E I N F O
A B S T R A C T
Keywords:
Monoamine oxidases (MAOs) are important targets in medicinal chemistry, as their inhibition may change the
levels of different neurotransmitters in the brain, and also the production of oxidative stress species. New
chemical entities able to interact selectively with one of the MAO isoforms are being extensively studied, and
chalcones proved to be promising molecules. In the current work, we focused our attention on the understanding
of theoretical models that may predict the MAO-B activity and selectivity of new chalcones. 3D-QSAR models, in
particular CoMFA and CoMSIA, and docking simulations analysis have been carried out, and their successful
implementation was corroborated by studying twenty-three synthetized chalcones (151–173) based on the
generated information. All the synthetized molecules proved to inhibit MAO-B, being ten out of them MAO-B
potent and selective inhibitors, with IC50 against this isoform in the nanomolar range, being (E)-3-(4-hydrox-
yphenyl)-1-(2,2-dimethylchroman-6-yl)prop-2-en-1-one (152) the best MAO-B inhibitor (IC50 of 170 nM).
Docking simulations on both MAO-A and MAO-B binding pockets, using compound 152, were carried out.
Calculated affinity energy for the MAO-A was +2.3 Kcal/mol, and for the MAO-B was ꢀ 10.3 Kcal/mol, justifying
the MAO-B high selectivity of these compounds. Both theoretical and experimental structure–activity relation-
ship studies were performed, and substitution patterns were established to increase MAO-B selectivity and
inhibitory efficacy. Therefore, we proved that both 3D-QSAR models and molecular docking approaches enhance
the probability of finding new potent and selective MAO-B inhibitors, avoiding time-consuming and costly
synthesis and biological evaluations.
Chalcone derivatives
Monoamine oxidase B inhibitors
3
D-QSAR models
Molecular docking
Drug design
1
. Introduction
Chalcones (Fig. 1) belong to a family of privileged structures that has
been widely prepared, based on the easiness and efficiency of the syn-
thetic methodologies [2]. Both naturally occurring and synthetic chal-
cones have been studied for their interesting biological activities, with
great potential in medicinal chemistry [3]. Antimicrobial, antituber-
cular, anti-inflammatory, anticancer, antioxidant, antileishmanial,
been widely explored as an effective scaffold in drug discovery [1].
Pharmacophores based on this double aromatic ring system have also
*
Corresponding authors at: Facultad de Ciencias, Instituto de Química, Pontificia Universidad Cat o´ lica de Valparaíso, Av. Universidad #330, Curauma, Valparaíso,
Chile (M. Mellado), Departamento de Química Org ´a nica, Facultade de Farmacia, Universidade Santiago de Compostela, 15782 Santiago de Compostela, Spain (M.J.
Matos).
E-mail addresses: marco.mellado@pucv.cl (M. Mellado), mariajoao.correiapinto@usc.es, maria.matos@fc.up.pt (M.J. Matos).
https://doi.org/10.1016/j.bioorg.2021.104689
Received 6 November 2020; Received in revised form 14 December 2020; Accepted 22 January 2021
Available online 2 February 2021
0
045-2068/© 2021 Elsevier Inc. All rights reserved.

M. Mellado et al.
Bioorganic Chemistry 108 (2021) 104689
R2
A
O
R ’
2
R3
R4
R ’
3
B
R6 ’R6
R ’
4
R5
R ’
5
Fig. 1. Structure of the trans-chalcone, with the numbering used throughout
the manuscript, and rings A and B highlighted in grey.
amongst other significant biological activities, have been attributed to
chalcones derivatives and analogues [4–11].
In the last decade, huge efforts from the academic community are
focused on the understanding and treatment of age-related disorders,
especially neurodegenerative diseases. The development of novel and
effective inhibitors of human monoamine oxidases (hMAOs) is still on
the top of the list, due to their role in neurotransmitters’ degradation and
reactive oxygen species generation [12]. New chemical entities able to
interact selectively with one of the MAO isoforms –MAO-A or MAO-B–
binding pockets, are being extensively studied [13]. The chalcone is one
of the scaffolds with great interest as hMAOs inhibitors [14,15].
Knowledge on the selective interaction with both isoforms has generated
potent molecules in the design of new leads [16].
Based on previous results from our research group [17], in the pre-
sent work, we focused our attention on the understanding of the targets,
on their selectivity, and on the selection of substitution patterns that
may amplify the potential of chalcones within this field. Structure-
activity relationship (SAR) studies were performed based on 3D-QSAR
models and docking simulations analysis of a database of one hundred
and fifty molecules. Based on the theoretical approaches, the synthesis
and biological evaluation of twenty-three (151–173) potent and selec-
tive MAO-B inhibitors was successfully carried out.
Fig. 2. Plots of experimental versus predicted pIC50 values for the training (on
the left, in black) and test (on the right, in red) sets. For the test set, the
2
regression line for r is shown in bold. (For interpretation of the references to
color in this figure legend, the reader is referred to the web version of
this article.)
CoMSIA models presented the best statistical values (Table S2), the
contour maps were based on their analysis. For the visualization of the
contour maps, (E)-1-(benzo[d[1,3]dioxol-5-yl)-3-(4-fluorophenyl)prop-
2-en-1-one (51), the best MAO-B inhibitor of the training set, and (E)-1-
(4-bromophenyl)-3-(2,3-diethoxyphenyl)prop-2-en-1-one (139), the
less active compound of the database, were selected.
2
. Results and discussion
For the formulation of the theoretical models, a database of one
hundred and fifty chalcones was used (structures reported in Table S1).
The molecules present a wide structural variability on both sides of the
unsaturated system (rings A and B, Fig. 1). All the compounds span a
biological activity range of more than three logarithmic units. To obtain
the best CoMFA and CoMSIA models, to support the design of new
molecules, a systematic sequential search was carried out (Table S2).
The results of the combination of steric, electrostatic, hydrophobic, and
hydrogen bond donor and acceptor fields, were evaluated. The standard
The steric contour maps analysis of CoMFA (Fig. 3A and B) and
CoMSIA (Fig. 4A and B) are very similar. A green polyhedron is pro-
jected between positions 3 and 4. This means that bulky substituents at
these positions of ring A favor the MAO-B inhibitory activity. As
example, compounds 15–16, 19, 34, 42–67, 72, 109, 115–117, 120,
124, 126, 127, 131–133, 138, 140 and 146 have substituents like
chlorine, bromine, methoxy, ethoxy, trifluoromethyl, N-morpholine,
benzo[d[1,3]dioxol-5-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, and
exhibit pIC50 ≥ 6.5 (Table S3). Indeed, the last two types of substituents
which have a fused ring such as benzo[d[1,3]dioxol-5-yl (compounds
42–54) and 2,3-dihydrobenzo[b][1,4]dioxin-6-yl (compounds 55–67),
show potent inhibitory activity on MAO-B (pIC50 > 7.0, Table S3). In
these compounds, the bulky substituent projects into the green poly-
2
criterion for the discrimination of the models was the value of q higher
than 0.5 [18,19]. Besides, a thorough external validation was carried
out. Several parameters like r2 of test set, and r2
were calculated
Table S4). In addition, a Y-random test was performed (Table S5),
obtaining better values than the established criteria.
m
(
The MAO-B inhibition values, with the predictions made by the
selected CoMFA and CoMSIA models, are presented in Table S3. The
experimental versus predictive activity graphs for the best CoMFA and
CoMSIA models were created to visualize whether there is an adequate
linear distribution of the predictive results for both models (Fig. 2). A
good data distribution along the line y = x for both CoMFA and CoMSIA
in the training and test sets, was observed.
′
hedron (Figs. 3A and 4A). In contrast, close to position 4 of the ring B
(Figs. 3A and 4A), a yellow polyhedron is observed, indicating that a
bulky substituent decreases the MAO-B inhibitory activity (i.e. com-
pounds 5–9, 13, 22–23, 36, 38–41, 101, 103, 105, 110, 111, 113–114,
119, 121–123, 137 and 141–150, pIC50 ≤ 6.5, Table S3). In this sense,
compounds that present 2-furyl (i.e. 4–13 and 22–25), 2-thiophenyl (i.e.
2
9
6, 32 and 33), flurbiprofen (i.e. 35–41) and 1H-imidazol-1-yl (i.e.
8–105) substituents as ring A, project at least one fragment on this
2
.1. Contour map analysis
yellow polyhedron, causing a decrease in the MAO-B inhibitory activity
The information obtained from the SAR studies allows the design and
(
pIC50 ≤ 6.5, Table S3).
synthesis of new promising molecules. One of the advantages of the
employed 3D-QSAR technique is obtaining contour maps around the
studied molecules. The analysis of the different color-polyhedra around
a molecule allows understanding the main characteristics that are
favorable/unfavorable for the biological activity. Since the CoMFA and
′
′
′
Positions 2 , 3 and 4 are oriented within the large green polyhedron
Fig. 3A, on the right), which indicates that bulky substituents at these
(
positions favor the MAO-B inhibitory activity (i.e. compounds 10–12,
4–26, 32–34, 43–72, 115–117, 124–127 and 130–136, pIC50 ≥ 6.5,
2
2

M. Mellado et al.
Bioorganic Chemistry 108 (2021) 104689
Fig. 3. CoMFA steric (A and B) and
electrostatic (C and D) contour maps
around the most active [(E)-1-(benzo[d
[
1,3]dioxol-5-yl)-3-(4-fluorophenyl)
prop-2-en-1-one (51), on the left] and
the less active [(E)-1-(4-bromophenyl)-
3
-(2,3-diethoxyphenyl)prop-2-en-1-one
(
139), on the right] compounds ob-
tained from the training set. Color code:
green, bulky groups are favorable for
activity; yellow, small groups are favor-
able for activity; red, negative charge is
favorable for activity; blue, positive
charge is favorable for activity. (For
interpretation of the references to color
in this figure legend, the reader is
referred to the web version of this
article.)
Fig. 4. CoMSIA steric (A and B), elec-
trostatic (C and D), hydrophobic (E and
F) and hydrogen bonding donor (G and
H) contour maps around the most active
[
(E)-1-(benzo[d[1,3]dioxol-5-yl)-3-(4-
fluorophenyl)prop-2-en-1-one (51), on
the left] and the less active [(E)-1-(4-
bromophenyl)-3-(2,3-diethoxyphenyl)
prop-2-en-1-one (139), on the right]
compounds obtained from the training
set. Color code: green, bulky groups are
favorable for activity; yellow, small
groups are favorable for activity; red,
negative charge is favorable for activity;
blue, positive charge is favorable for
activity. For the hydrophobic contour
map: yellow, hydrophobic groups are
favorable for the activity; grey, hydro-
philic groups are favorable for the ac-
tivity. For the hydrogen bonding donor
contour map: cyan, hydrogen bonding
donor groups are favorable for the ac-
tivity; purple, hydrogen bonding donor
groups are not favorable for the activity.
(
For interpretation of the references to
color in this figure legend, the reader is
referred to the web version of this
article.)
′
′
Table S3). Additionally, positions 5 and 6 are projected into a yellow
polyhedron, indicating that bulky substituents at these positions may
decrease the MAO-B inhibitory activity (i.e. compounds 2–3, 7–9, 13,
The electrostatic contour maps analysis of CoMFA (Fig. 3C and D)
and CoMSIA (Fig. 4C and D) are very similar. A blue polyhedron
extending over position 4 and its surroundings can be observed. This
indicates that a deficiency of electrons favors the MAO-B inhibitory
7
8–95, 137 and 139, pIC50 ≤ 6.5, Table S3).
3

M. Mellado et al.
Bioorganic Chemistry 108 (2021) 104689
activity of chalcones. Indeed, the introduction of heteroatoms at posi-
tion 4 produces the decrease of electron density at that position. As
examples, compounds with benzo[d[1,3]dioxol-5-yl (42–54) and 2,3-
dihydrobenzo[b][1,4]dioxin-6-yl (55–67) as ring A, show potent MAO-B
inhibitory activity (pIC50 > 7.0, Table S3). In the case of 1H-imidazole-1-
yl (i.e. compounds 98–105) and carbamates (i.e. compounds 107–114),
where the electron density of the heteroatom is in resonance with the
imidazole ring and with the carbamate fragment, respectively, there is a
decrease in the MAO-B inhibitory activity (pIC50 ≤ 6.5, Table S3). In this
same ring, in the vicinity of the substituent linked at position 3, a red
polyhedron is projected, which means that an electron-rich substituent
favors the MAO-B inhibitory activity. This is consistent with the pres-
ence of oxygen atoms in benzo[d[1,3]dioxol-5-yl and 2,3-dihydrobenzo
program and the crystal structure of hMAO-B (PDB ID: 1GOS). The re-
sults showed that (E)-1-(benzo[d[1,3]dioxol-5-yl)-3-(4-fluorophenyl)
prop-2-en-1-one (51) has an affinity energy for this isoform of ꢀ 8.8
Kcal/mol. The visualization of the result was carried out with the
PyMOL and Ligplot + programs (Fig. 5).
Fig. 5 shows the general visualization of MAO-B with the best pose of
compound 51 within the active site. This result is consistent with the
best pose previously reported by our group [17,20]. Fig. 5B highlights
the cofactor FAD600 and the Tyr435 and Tyr398 residues, both related
to the inhibition of this enzyme. Indeed, the Tyr435 residue forms a
hydrogen bond with the carbonyl group of the chalcone scaffold. In
addition, the nitrogen atom of FAD600 shows a polar interaction with
the dioxomethylene fragment of compound 51, which stabilizes the li-
gands within the MAO-B active site. These interactions are key for the
inhibition of this enzyme since prior oxidation of FAD600, Tyr435 and
[
b][1,4]dioxin-6-yl derivatives (pIC50 > 7.0, Table S3).
′
′
A blue polyhedron extending over positions 3 and 4 is observed,
indicating that a deficiency of electrons in these carbons increases the
MAO-B inhibitory activity. Therefore, electronegative substituents
attached to these carbons such as halogens, trifluoromethyl, alkyl, hy-
droxy, amongst others, would be favorable (i.e. compounds 10–12,
3
1
2–33, 43–51, 56–57, 62–66, 69–70, 72, 117, 120, 124–127, 130,
33–136 and 146, pIC50 > 6.5, Table S3). Additionally, the blue poly-
′
′
hedron extends over the substituents at positions 2 and 3 . Therefore,
electron-deficient substituents, such as trifluoromethyl and dioxo-
methylene groups, where the carbon atom is projected into the blue
polyhedron, favor the MAO-B inhibitory activity (compounds 11 and
1
24–127, pIC50 > 6.5, Table S3). In this same ring, a red polyhedron is
projected on carbon 3 of the
α
,β-unsaturated carbonyl fragment, indi-
cating that the increase in electron density on this carbon favors the
MAO-B inhibitory activity, which is consistent with the structure of the
heterocyclic derivatives containing the 2-furan (14–16 and 18–20) and
2
-thiophene (34) moieties.
The hydrophobic contour map of the CoMSIA model is shown in
Fig. 4E-F. A gray polyhedron appears in the proximity of positions 3 and
, which means that hydrophilic substituents favor the MAO-B inhibi-
4
tory activity. This is consistent with derivatives that possess pyridine
and hydroxy groups (i.e. 28, 74 and 106, pIC50 ~ 6.5). Furthermore, in
this same ring, a yellow polyhedron extends over the vicinity of the
substituent at position 4, indicating that hydrophobic substituents may
favor the MAO-B inhibitory activity. This is consistent with the potent
activity shown by the benzo[d[1,3]dioxol-5-yl (42–54) and the 2,3-
dihydrobenzo[b][1,4]dioxin-6-yl derivatives (i.e. 55–67, pIC50 > 7.0,
Table S3).
′
In contrast, a gray polyhedron extends in the vicinity of position 3 ,
which means that a hydrophobic substituent at that position does not
favor the MAO-B inhibitory activity. This is consistent with the presence
of chlorine, methoxy, carbamate and alkylamine substituents, as com-
pounds 2–4, 6, 8, 13, 21–22, 27, 79–90, 92–97 and 139 (pIC50 < 6.5,
′
′
′
Table S3). Likewise, close to the substituents at positions 2 , 4 and 5 , a
yellow polyhedron is shown, which implies that substituents with hy-
drophobic characteristics may favor the MAO-B inhibitory activity.
Substituents such as halogens, alkyl, methoxy, dioxomethylene and
bulky NR
2
would be favorable (i.e. compounds 10–12, 24–26, 32–34,
4
4–47, 49–51, 53–54, 57–60, 62, 66–70, 100, 115–117, 120, 123–127
and 146, pIC50 > 6.5, Table S2).
The hydrogen bond donor map obtained from the CoMSIA analysis is
shown in Fig. 4G and H. A cyan polyhedron is projected under the
carbonyl group of the chalcone scaffold, which means that a hydrogen
bond donor promotes the MAO-B inhibitory activity. This trend is
corroborated by pyrrole-chalcone derivatives (i.e. 27 and 29–31), which
have pIC50 that vary between 5.5 and 6.1. In these cases, the hydrogen
atom corresponding to the NH fragment of the pyrrole is orientated
towards this polyhedron.
Fig. 5. Molecular docking performed with (E)-1-(benzo[d[1,3]dioxol-5-yl)-3-
(
4-fluorophenyl)prop-2-en-1-one (51). A. 3D overview within the active site of
MAO-B. B. MAO-B inhibition site and key amino acid residues. C. Details of
polar and van der Waals interactions established with the residues on the MAO-
B active site. Hydrogen bonds are represented in yellow segmented lines. Polar
interactions are. represented in red segmented lines. (For interpretation of the
references to color in this figure legend, the reader is referred to the web
version of this article.)
2
.2. Molecular docking
The docking analysis was performed using the Autodock Vina
4

M. Mellado et al.
Bioorganic Chemistry 108 (2021) 104689
Tyr398 residues polarize the ligand [21]. Finally, as observed in Fig. 4C,
ring A is oriented towards the FAD cofactor, while ring B is oriented
towards Phe168 and Ile199 residues, favoring the stabilization of com-
pound 51 within the MAO-B active site.
models, the synthesis of twenty-three derivatives (Scheme 1, compounds
151–173) was carried out. The compounds were synthesized based on
the information obtained from the contour maps (Figs. 3 and 4), which
suggested that bulky and hydrophobic groups linked to positions 3 and 4
of the chalcone scaffold, and hydrophobic and/or electron withdrawing
Comparing the molecular docking results with those obtained by 3D-
QSAR, it is corroborated that a bulky element in the vicinity of positions
′
′
or donating substituents at positions 2 to 5 , would provide compounds
with good activity and selectivity. Methyl, hydroxy, methoxy, fluorine,
bromine and 3,4-dioxomethylene groups were selected, and strategi-
cally placed on the pharmacophoric core, based on the Craig diagram, in
order to explore the chemical space as much as possible, and optimize
the synthetic strategies. To obtain compounds 151–158, the precursor
[1-(4-hydroxy-3-(3-methylbut-2-en-1-yl)phenyl)ethan-1-one (A)] was
previously isolated from S. graveolens [17,22]. Compound A was then
stirred with formic acid to cyclize the prenyl group, obtaining compound
1-(2,2-dimethylchroman-6-yl)ethan-1-one (B) in very good yield (96%).
This allowed obtaining a key voluminous substitution pattern that may
improve the MAO-B inhibition. This compound was characterized by IR
and NMR spectroscopic techniques, following previous reports from our
research group [22]. To obtain compounds 159–165 and 166–173, the
commercial acetophenones, 4-methoxyacetophenone (C) and aceto-
phenone (D) were reacted, respectively, with the appropriate benzal-
dehydes, in alkaline medium [23,24].
3
and 4 favors the MAO-B inhibition, since the Phe343 residue may
improve the stabilization of the ligand within the MAO-B active site.
Additionally, substituents with hydrophilic characteristics favor the
MAO-B inhibition, result consistent with the potential interaction with
the Tyr60 residue through polar interactions or hydrogen bonding. The
results of 3D-QSAR show that an electron-rich group may establish
hydrogen bonds with both Tyr60 and Gln206 residues, interactions
corroborated by the docking simulations. Another important charac-
teristic of the ring A is the presence of an electron-deficient substituent
at position 4, which is consistent with the polar interaction between the
cofactor FAD600 and compound 51.
Ring B is orientated towards Leu171, Ile199, Phe168 and Cys172
residues. According to the 3D-QSAR, bulky substituents in the vicinity of
′
′
′
positions 2 , 3 and 4 favor the MAO-B inhibition. This is consistent with
the vicinity of Leu171, Ile199 and Phe168 residues. This could improve
the stabilization of compound 51 within the MAO-B active site by van
′
der Waals interactions. Near position 2 , it was determined that hydro-
After the synthesis of the proposed compounds, their MAO-A and
MAO-B inhibitory activities were evaluated by measuring the produc-
philic and electron-deficient substituents favor the MAO-B inhibitory
activity. This is consistent with the projection of the Cys172 residue in
the vicinity of this position, and the potential formation of hydrogen
bonds with this residue. Another important characteristic of this ring is
the closeness to Ile199 and Leu171 residues, consistent with the pres-
ence of hydrophobic substituents found in the hydrophobic contour
map.
2 2
tion of hydrogen peroxide (H O ) from p-tyramine, using the Amplex®
red MAO assay kit, according to previous protocols [17,25]. The
experimental and predicted inhibitory MAO-B values (IC50 and pIC50),
using both CoMFA and CoMSIA models, are shown in Table 1.
All the evaluated compounds exhibited MAO-B inhibitory activity in
the micro- and nanomolar ranges, being seventeen compounds selective
against the MAO-B isoform. Ten compounds from this series were active
against MAO-B in the nanomolar range, being the best MAO-B inhibitor
the (E)-3-(4-hydroxyphenyl)-1-(2,2-dimethylchroman-6-yl)prop-2-en-1-
one (152, pIC50 = 6.770), confirming the structural information ob-
tained from both CoMFA and CoMSIA models, pIC50 = 6.621 and 6.886,
respectively). In the same range of activity appear (E)-3-(4-methox-
yphenyl)-1-(2,2-dimethylchroman-6-yl)prop-2-en-1-one (153), (E)-3-
(4-hydroxy-3-methoxyphenyl)-1-(2,2-dimethylchroman-6-yl)prop-2-
en-1-one (155), (E)-1-(4-methoxyphenyl)-3-(p-tolyl)prop-2-en-1-one
(161), (E)-3-(4-hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one
(162), (E)-1-phenyl-3-(p-tolyl)prop-2-en-1-one (168), (E)-3-(4-hydrox-
yphenyl)-1-phenylprop-2-en-1-one (169) and (E)-3-(4-methoxyphenyl)-
1-phenylprop-2-en-1-one (170), proving that the presence of electron
Finally, the carbonyl group is found close to the Tyr326 and Tyr398
residues. These residues could generate polar interactions and/or
hydrogen bonds with the molecule. According to the 3D-QSAR, the
presence of hydrogen bond donor groups under the carbonyl group fa-
vors the MAO-B inhibitory activity of compound 51, which is consistent
with the docking calculations.
2
.3. Summary of the main results obtained from the theoretical models
In Fig. 6, the information on the SAR obtained from the 3D-QSAR and
molecular docking models is summarized. Fulfilling the requirements of
a bulky, hydrophobic group in the vicinity of positions 3 and 4 (in
particular a fused ring), an electron donating atom at position 4, and
hydrophobic and/or electron withdrawing/donating groups at positions
′
donating groups at position 4 of the chalcone scaffold is indeed inter-
′
′
′
′
2
, 3 , 4 and 5 , new potent MAO-B compounds may be obtained. Finally,
esting for the studied activity. The only exception within the series are
(E)-1-(4-methoxyphenyl)-3-phenylprop-2-en-1-one (159), without sub-
stitutions in the ring B, and (E)-3-(5-bromo-2-fluorophenyl)-1-(2,2-
dimethylchroman-6-yl)prop-2-en-1-one (154), presenting two halogens
′
the presence of hydrogen bonding donors at positions 2 and/or 2 may
contribute to increase the desired activity.
′
′
3
. Synthesis, biological evaluation and docking calculations
at positions 2 and 5 . Despite being important structural differences,
these results are also aligned with the theoretical prediction.
In the specific case of compounds 152, 153 and 154, the three have a
To perform an experimental validation of the obtained theoretical
Hydrogen bonding donors
R2
A
O
R ’
2
R3
R4
R ’
3
Bulky and
hydrophobic groups
Hydrophobic and/or electron
withdrawing/donating groups
B
R ’
4
R ’
5
electron donating atom
Fig. 6. Summary of the main theoretical structure–activity relationships for the MAO-B inhibition found in the present study.
5

M. Mellado et al.
Bioorganic Chemistry 108 (2021) 104689
O
O
i.
HO
O
(
A)
(B)
(
(
(
(
151) R = H
1
152) R = 4-OH
1
153) R = 4-OMe
1
154) R = 2-F, 5-Br
1
O
(155) R = 3-OMe, 4-OH
1
(
156) R = 3,4-(OMe)2
1
R1
(157) R = 3-OCH O-4
1
2
O
O
(
158) R = 3-OMe, 4-OC H
151-160
1 6 13
(
(
(
(
159) R = H
O
1
(
B)
160) R = 2-OH
1
O
O
161) R = 4-Me
1
or
ii.
+
H
162) R = 4-OH
O
R1
R1
1
MeO
(163) R1= 4-OMe
164) R = 4-NMe2
1
61-167
(
1
R
(165) R = 3-OMe, 4-OH
1
(
(
C) R= OMe
D) R= H
O
(
(
(
(
(
(
(
(
166) R = H
1
167) R = 2-OH
1
R1
168) R = 4-Me
1
169) R = 4-OH
168-175
1
170) R = 4-OMe
1
171) R = 2-OH, 3-OMe
1
172) R = 2-OH, 3-NO2
1
173) R = 3-NO , 4-OH
1
2
Scheme 1. Synthetic route to obtain compounds 151–173. Reagents and conditions: (i) HCO
2
H, overnight, rt. (ii) NaOH/EtOH (20% m/v), 48 h, rt.
hydrophobic and bulky group at both positions 3 and 4, having an
electronegative substituent attached directly to the carbon 4. Com-
pounds 159, 161 and 162 present only an electron donating group at
position 4, being the substituent a methoxy group. Compounds 161 and
Tyr407 and Tyr444 residues, perpendicular to the FAD (Fig. 7A and 7B).
Calculated affinity energy for the MAO-A isoform was + 2.3 Kcal/mol.
This is consistent with a non-spontaneous process and non-inhibition of
this isoform. This result may be due to repulsions of the dihydrochroman
fragment with the Tyr407, Tyr444 and Asn181 residues (Fig. S3). In the
MAO-B study, the calculated affinity energy for compound 152 was
ꢀ 10.3 Kcal/mol. This is consistent with a spontaneous process and the
potent MAO-B inhibitory activity of this compound.
1
62 present additionally a hydrophobic and electron donating group at
′
position 4 of the chalcone scaffold. These are two of the most active
compounds within the series, proving that the combination of sub-
stituents in para position at both rings may be ideal to increase the MAO-
B inhibitory activity. Comparing compounds 152 and 162, the only
structural difference is the presence of a pyran ring attached to the ring
A. This voluminous substituent makes compound 152 exhibit a two-fold
higher MAO-B inhibitory activity comparing to compound 162. Even if
the pyran ring seems to play an important role for the activity, these are
the two best compounds of the studied series. Finally, compounds 168,
Fig. 8 presents the graph of the experimental versus predicted activity
for the synthesized compounds 151–173. All the compounds are within
one logarithmic unit of residual value. The best predictions are for the
most active compounds, with pIC50 > 6.0. For compounds presenting
pIC50 < 6.0, both models tended to overestimate the predicted activity
values.
1
69 and 170 do not present any substituent in the ring A, proving that
Finally, analyzing the experimental data obtained, the presence of
electron donating and bulky substituents at positions 3 and 4 of the
chalcone scaffold seems to be important for the studied activity. In
substituents in the ring B, specially at para position, may play themselves
an important role for the activity.
′
As said before, the evaluated compounds showed experimental
selectivity towards hMAO-B. The high selectivity against this isoform is a
subject of high interest for the future design of MAO-B inhibitors.
Therefore, a molecular docking analysis was performed simulating the
interaction of compound 152 with the active site of both MAO isoforms.
According to Abad and co-workers, the ligand was positioned between
Tyr435 and Tyr398 residues, and perpendicular to the FAD cofactor in
the MAO-B binding pocket (Fig. 7D and 7E) [21]. Then, applying the
same criteria for the MAO-A isoform, the ligand was located between
addition, the presence of an electron donating group at position 4 , in
this case non-bulky groups, may be very important to enhance the
inhibitory activity. Finally, the presence of a hydrogen bond donor at
′
′
′
position 2 and a halogen at positions 2 and/or 5 may contribute to
increase the desired activity. A summary of the best substitution patterns
is shown in Fig. 9.
6

M. Mellado et al.
Bioorganic Chemistry 108 (2021) 104689
Table 1
in the current study, and a MAO-A versus MAO-B comparative study,
using compound 152, was performed. Calculated affinity energy for the
MAO-A isoform was + 2.3 Kcal/mol, and for the MAO-B was ꢀ 10.3
Kcal/mol. Together with the residues’ interactions nature, these may
explain the high MAO-B selectivity of this family of compounds. Some
important structural features that may be conditioning the biological
activity can be highlighted analyzing all the theoretical data together.
Hydrophobic groups, like ethers, may be present at both 3 and 4 posi-
tions of the chalcone scaffold. In addition, hydrophobic and electron
donating substituents, like halogens, hydroxyl, methyl or methoxy
Experimental MAO-A and MAO-B inhibition values (IC50 and pIC50) and pre-
dicted activity on MAO-B (pIC50 CoMFA and pIC50 CoMSIA) for compounds
1
51–173.
Compounds
IC50
(
μ
M)
MAO-B pIC50
MAO-A
MAO-B
Experimental
CoMFA
CoMSIA
1
1
51
52
>100
>100
2.0 ± 0.10
0.17 ±
5.699
6.770
5.669
6.621
5.653
6.886
0
.01
1
1
1
1
1
1
1
1
1
1
1
1
1
1
53
54
55
56
57
58
59
60
61
62
63
64
65
66
>100
>100
8.20 ±
0.93 ±
.07
0.39 ±
.02
6.032
6.409
6.155
5.747
5.836
5.747
6.367
5.198
6.678
6.456
5.467
5.640
5.654
5.485
5.908
6.405
6.188
5.680
5.905
5.900
6.328
5.907
6.613
6.528
5.988
6.129
6.499
6.141
6.029
6.494
6.121
5.823
6.116
5.664
6.391
6.048
6.621
6.459
5.975
6.240
6.320
6.361
0
′
′
′
groups, at positions 2 , 4 or 5 , may be important in the design of new
lead compounds. Based on all these data, it can be concluded that 3D-
QSAR models, together with docking simulations, constitute robust
tools for the design of new MAO-B inhibitors based on the chalcone
scaffold.
0
0.70 ±
0.08
1
.53
11.92 ±
.69
49.80 ±
.87
11.92 ±
.69
1.79 ±
0.03
2
1.46 ±
0.08
5
. Experimental section
5
1.79 ±
0.04
2
5.1. Theoretical calculations
>100
>100
>100
>100
>100
>100
4.18 ±
0.43 ±
0
.04
The 3D-QSAR study (CoMFA and CoMSIA models) was carried out
using a dataset of 150 compounds, according to the previously reported
procedure [26,27]. The molecular docking analysis was carried out
using the compounds 51 and 152 and MAO crystal structure (PDB code
6.34 ±
.33
0.21 ±
.03
0.35 ±
.03
3.41 ±
.12
2.29 ±
.21
0
0
2
Z5Y for MAO-A and PDB code 1GOS for MAO-B) [28,29], with the
0
AutoDock vina program [30], and the results were processed using
Pymol [31] and LigPlot + software [32,33]. All details for 3D-QSAR
study, as well as the molecular docking, are included in the supple-
mentary material.
0
0
2.22 ±
0.08
1
.49
6
. General information
>100
3.27 ±
0
.15
1
1
67
68
>100
>100
4.0 ± 0.39
0.43 ±
5.398
6.367
5.980
6.206
6.163
6.412
All reagents were purchased from Sigma-Aldrich or Merck and used
without further purification. All solvents were commercially available
grade. Reaction mixtures were purified by flash column chromatog-
raphy using silica gel high purity grade (Merck grade 9385 pore size 60
Å, 230–400 mesh particle size). Reaction mixtures were analyzed by
analytical thin-layer chromatography (TLC) using plates precoated with
silica gel (Merck 60 F254, 0.25 mm). Visualization was accomplished
0
.06
1
1
1
1
1
69
70
71
72
73
>100
>100
6.92 ±
0.44 ±
.02
0.99 ±
.12
6.357
6.004
5.597
5.535
5.253
7.699
5.123
6.405
6.058
5.860
5.869
6.277
6.290
6.129
6.060
6.413
5.904
0
0
2.53 ±
0.27
0
.73
2 4
with UV light (254 nm) or sulfuric acid (H SO :MeOH, 5:95). The
>100
2.92 ±
ꢀ 1
0
.20
recorded range of the IR spectra was 600–4000 cm , and all samples
1
>100
5.58 ±
.42
were examined using the ATR (attenuated total reflectance) system. H
0
13
NMR (400.13 MHz), C NMR (100.6 MHz), spectra were recorded on a
Selegiline
67.25 ±
0.020 ±
0.009
Bruker Avance 400 Digital NMR spectrometer (Berlin, Germany) using
1
.02
the stated solvents (CDCl
3 6
or Acetone‑d ), using tetramethylsilane
Iproniazide
6.56 ±
.76
7.54 ±
0.36
0
(TMS) as an internal standard. Chemical shifts were reported in parts per
million (ppm) on the δ scale from an internal standard (NMR de-
scriptions: s, singlet; bs, broad singlet; d, doublet; dd, double doublet; t,
triplet; m, multiplet). Mass spectroscopy was performed using a Hewlett-
Packard 5988A spectrometer. This system is an automated service uti-
lizing electron impact (EI) ionization.
4
. Conclusions
In the current study, robust 3D-QSAR models –CoMFA and CoMSIA–
were constructed based on a database of one hundred and fifty com-
pounds previously reported in scientific articles. All the molecules pre-
sent a chalcone scaffold, known for their MAO inhibitory activity. The
best models obtained were, afterwards, internal and externally vali-
dated. The best CoMFA model presented a combination of both steric
6
.1. Chemistry
Plant material and extraction procedure. Senecio graveolens was
collected from an area near Chungara Lake at 4500 m.a.s.l. (Chile). The
dry plant material (180 g) was macerated in 95% ethanol (2 × 500 mL)
for 72 h, according to the procedures described in our previous reports
2
and electrostatic fields, with a q value of 0.851, and the best CoMSIA
2
model presented a q value of 0.813. The reliability of the models was
tested, and both present good external predictive capabilities. To
experimentally validate the models, twenty-three new derivatives
[
17,22].
.2. Synthetic procedures
4‑Hydroxy‑3‑(3‑methylbut‑2‑enyl)phenyl)ethenone(A). This
(
compounds 151–173) have been designed, synthesized and evaluated.
6
Ten new derivates proved to be potent and selective MAO-B inhibitors,
presenting activities in the nanomolar range. The most powerful and
selective compound within this series was (E)-3-(4-hydroxyphenyl)-1-
(
compound was separated from the dry methanol extract (52.8 g) by
column chromatography using hexane/EtOAc (9:1), obtaining a pale
(
2,2-dimethylchroman-6-yl)prop-2-en-1-one (152), presenting a MAO-B
IC50 of 170 nM. Docking simulations have also been taken into account
◦
yellow solid (1.09 g). Mp 95–96 C. The spectroscopic information (IR,
7

M. Mellado et al.
Bioorganic Chemistry 108 (2021) 104689
Fig. 7. Molecular docking of (E)-3-(4-
hydroxyphenyl)-1-(2,2-dimethylchro-
man-6-yl)prop-2-en-1-one (152) on
MAO-A and MAO-B. A. 3D overview
inside the active site of MAO-A. B. MAO-
A inhibition site and key amino acid
residues. C. Details of polar and van der
Waals interactions established with the
MAO-A active site. D. 3D overview in-
side the active site of MAO-B. E. MAO-B
inhibition site and key amino acid resi-
dues. F. Details of polar and van der
Waals interactions established with the
MAO-B active site.
O
OH/X
R
A
B
RO
OH/CH /OCH
3
3
X
Fig. 9. Summary of the main experimental structure–activity relationships for
the MAO-B inhibition found in the present study.
added, and the mixture was stirred overnight at room temperature.
2 3
Finally, the acid was neutralized using Na CO 5%. This mixture was
extracted with EtOAc (3x50 mL), and the organic layer was dried with
Fig. 8. Values of experimental versus predicted MAO-B inhibitory activity for
the synthesized compounds (151–173). Color code: black spheres, CoMFA
predictions; red squares, CoMSIA predictions. (For interpretation of the refer-
ences to color in this figure legend, the reader is referred to the web version of
this article.)
Na
2
SO
4
and separated by column chromatography using hexane/EtOAc
◦
(
8:2) obtaining a colorless solid (0.48 g). Yield: 96%. Mp 91–92 C. The
1
13
spectroscopic information (IR, H NMR and C NMR) analysis results
were consistent with the previous report [22].
General procedure for chalcone synthesis (151–173). To a dry
1
00 mL round-bottomed flask, semisynthetic acetophenone B or com-
1H NMR and 13C NMR) analysis results were consistent with previous
reports [17,22].
mercial acetophenone C or D (250 mg, between 1.22 and 2.08 mmol)
and corresponding benzaldehyde (1.2 equiv.) were added, and then
solubilized in ethanol (5 mL). A NaOH 20% m/v solution (in 10 mL of
ethanol) was added, and the mixture was stirred for 48 h. To stop the
1
‑(2,2‑Dimethylchroman‑6‑yl)ethanone(B). In a 100 mL round-
bottomed flask, compound A (0.5 g) and formic acid (15 mL) were
8

M. Mellado et al.
Bioorganic Chemistry 108 (2021) 104689
reaction, 5% HCl solution was added until pH ~ 7, and the mixture was
extracted with EtOAc (3x30 mL). The organic layer was dried with
prop-2-en-1-one (157). Yield: 72%. Mp 158–159 ◦C. IR: 3052, 2967,
ꢀ
1 1
2941, 1652, 1604, 1576, 1490, 1446, 1360, 1320, 1233 cm . H NMR
Na
2
SO
4
, filtered, and separated by column chromatography using a
(CDCl
(1H, d, J = 15.6 Hz, H
d, J = 8.2 Hz), 6.83 (1H, d, J = 8.0 Hz), 6.02 (2H, s, OCH
J = 6.7 Hz, CH ), 1.85 (2H, t, J = 6.7 Hz, CH ), 1.37 (6H, s, 2xCH
NMR (CDCl ): 188.7, 158.5, 149.6, 148.3, 143.4, 130.7, 130.2, 129.6,
3
): 7.82 (1H, s), 7.80 (1H, s), 7.72 (1H, d, J = 15.6 Hz, Hβ), 7.39
), 7.17 (1H, s), 7.12 (1H, d, J = 8.0 Hz), 6.84 (1H,
O), 2.85 (2H, t,
hexane/EtOAc, obtaining compounds 151–173 in yields between 27
and 99%.
α
2
1
3
(
E)-1-(2,2-Dimethylchroman-6-yl)-3-phenylprop-2-en-1-one
2
2
3
).
C
(
151). Yield: 87%. Mp 85–87 ◦C. IR: 3050, 2975, 2938, 1659, 1604,
3
ꢀ 1 1
1
574, 1495, 1448, 1336, 1258, 1230 cm . H NMR (CDCl
3
): 7.83 (1H,
128.3, 124.9, 120.9, 120.0, 117.3, 108.6, 106.2, 101.5, 75.5, 32.5, 26.9,
+
s), 7.82 (1H, d, J = 2.6 Hz), 7.80 (1H, d, J = 15.7 Hz, Hβ), 7.65–7.62 (1H,
m), 7.56 (1H, d, J = 15.7 Hz, H ), 7.41–7.39 (4H, m), 6.86 (1H, d, J =
.2 Hz), 2.85 (2H, t, J = 6.7 Hz, CH ), 1.85 (2H, t, J = 6.7 Hz, CH ), 1.37
): 188.7, 158.5, 143.4, 135.1, 130.8,
22.4. EI-MS m/z (%): 336 (M , 100) [22].
α
(E)-3-(4-Hexyloxy-3-methoxyphenyl)-1-(2,2-dimethylchroman-
6-yl)prop-2-en-1-one (158). Yield: 59%. IR: 3068, 2935, 1654, 1576,
8
2
2
1
3
ꢀ 1
1
(
6H, s, 2xCH
3
). C NMR (CDCl
3
1509, 1424, 1251, 1234 cm . H NMR (CDCl
s), 7.73 (1H, d, J = 15.5 Hz, Hβ), 7.40 (1H, d, J = 15.5 Hz, H
dd, J = 8.3, 1.6 Hz), 7.15 (1H, d, J = 1.6 Hz), 6.87 (1H, d, J = 8.3 Hz),
6.83 (1H, d, J = 8.3 Hz), 4.04 (2H, t, J = 6.8 Hz, CH ), 3.92 (3H, s,
OCH ), 1.85
), 2.84 (2H, t, J = 6.7 Hz, CH
(2H, t, J = 6.8 Hz, CH ), 1.35 (6H, s,
2xCH
), 1.36–1.32 (4H, m, 2xCH
NMR (CDCl
3
): 7.83 (1H, s), 7.80 (1H,
1
2
30.1, 128.9, 128.8, 128.4, 128.3, 121.9, 120.9, 117.3, 75.5, 32.5, 26.9,
α), 7.19 (1H,
+
2.3. EI-MS m/z (%): 292 (M , 100) [22].
(
E)-3-(4-Hydroxyphenyl)-1-(2,2-dimethylchroman-6-yl)prop-2-
2
◦
en-1-one (152). Yield: 27%. Mp 158–160 C. IR: 3226, 2971, 2941,
3
2
), 1.83 (2H, t, J = 6.7 Hz, CH
2
ꢀ 1
1
1
647, 1602, 1574, 1512, 1446, 1343, 1321, 1231 cm
CDCl
): 7.83 (1H, s), 7.81 (4H, s), 7.76 (1H, d, J = 15.5 Hz, Hβ), 7.52
2H, d, J = 8.4 Hz), 7.42 (1H, d, J = 15.5 Hz, H ), 6.92 (2H, d, J = 8.4
), 1.84 (2H, t, J
): 190.0, 158.7,
.
H NMR
2
), 1.45 (2H, t, J = 6.8 Hz, CH
2
1
3
(
(
3
3
2
), 0.88 (3H, t, J = 6.8 Hz, CH
3
). C
α
3
): 188.8, 158.3, 150.8, 149.4, 143.8, 130.7, 130.3, 128.2,
Hz), 6.85 (1H, d, J = 8.5 Hz), 2.84 (2H, t, J = 6.7 Hz, CH
2
127.9, 122.8, 120.9, 119.7, 117.1, 112.4, 110.7, 75.4, 68.9, 56.0, 32.5,
1
3
+
=
6.7 Hz, CH
2
), 1.36 (6H, s, 2xCH
3
). C NMR (CDCl
3
31.5, 28.9, 26.8, 25.5, 22.5, 13.9. EI-MS m/z (%): 422 (M , 100). HR-EI-
1
7
44.5, 132.5, 131.0, 130.4, 128.6, 127.3, 121.0, 119.2, 117.4, 116.1,
MS: 422.2457 calc, found 422.2370 (Δ = 0.0087).
+
5.7, 32.5, 26.9, 22.4. EI-MS m/z (%): 308 (M , 100) [22,34].
(E)-1-(4-Methoxyphenyl)-3-phenylprop-2-en-1-one (159). Yield:
68%. Mp 92–96 ◦C. IR: 3078, 2972, 2954, 1655, 1603, 1558, 1508,
(
E)-3-(4-Methoxyphenyl)-1-(2,2-dimethylchroman-6-yl)prop-2-
◦
ꢀ 1
1
en-1-one (153). Yield: 96%. Mp 79–81 C. IR: 3082, 2975, 1655, 1589,
1448, 1241, 1190 cm . H NMR (CDCl
3
): 8.05 (2H, d, J = 8.7 Hz), 7.81
ꢀ 1 1
1
510, 1492, 1338, 1318, 1227 cm . H NMR (CDCl
1H, s), 7.77 (1H, d, J = 15.6 Hz, Hβ), 7.60 (2H, d, J = 8.7 Hz), 7.43 (1H,
d, J = 15.6 Hz, H ), 6.93 (2H, d, J = 8.7 Hz), 6.84 (1H, d, J = 8.4 Hz),
.85 (3H, s, OCH ), 1.85 (2H, t, J = 6.7 Hz,
), 2.85 (2H, t, J = 6.7 Hz, CH
CH ), 1.37 (6H, s, 2xCH ): 188.9, 161.4, 158.4, 143.4,
3
): 7.83 (1H, s), 7.81
(1H, d, J = 15.6 Hz, Hβ), 7.64 (2H, m), 7.55 (1H, d, J = 15.6 Hz, Hα
),
13
(
7.38–7.43 (3H, m), 6.98 (2H, d, J = 8.7 Hz), 3.88 (3H, s, OCH
3
).
C
α
3
NMR (CDCl
3
): 188.6, 163.4, 143.9, 135.0, 131.0, 130.8, 130.3, 128.9,
+
3
2
128.3, 121.8, 113.8, 55.4. EI-MS m/z (%): 238 (M , 100) [23].
(E)-3-(2-Hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one
1
3
2
3 3
). C NMR (CDCl
◦
1
5
30.7, 130.4, 130.0, 128.3, 127.9, 120.9, 119.7, 117.2, 114.3, 77.5,
(160). Yield: 44%. Mp 149–151 C. IR: 3284, 3074, 2922, 1602, 1555,
1506, 1362, 1230, 1202 cm . H NMR (CDCl
+
ꢀ 1
1
5.4, 32.5, 26.9, 22.3. EI-MS m/z (%): 322 (M , 100) [22].
3
): 8.17 (1H, d, J = 15.9
(
E)-3-(5-Bromo-2-fluorophenyl)-1-(2,2-dimethylchroman-6-yl)
Hz, Hβ), 8.06 (2H, d, J = 8.8 Hz), 7.70 (1H, d, J = 15.9 Hz, Hα
), 7.60
◦
prop-2-en-1-one (154). Yield: 98%. Mp 124–125 C. IR: 3053, 2978,
(1H, d, J = 8.0 Hz), 7.27 (1H, t, J = 8.0 Hz), 6.99 (2H, d, J = 8.8 Hz),
6.96 (1H, t, J = 8.0 Hz), 6.92 (1H, d, J = 8.0 Hz), 6.55 (1H, bs, OH), 3.90
ꢀ 1
1
2
944, 1657, 1609, 1544, 1484, 1453, 1311, 1234 cm
CDCl
): 7.89 (1H, d, J = 2.2 Hz), 7.81 (1H, s), 7.76 (1H, d, J = 15.9 Hz,
Hβ), 7.73 (1H, d, J = 2.4 Hz), 7.60 (1H, d, J = 15.9 Hz, H ), 7.37–7.41
. H NMR
1
3
(
3
3 3
(3H, s, OCH ). C NMR (CDCl ): 190.1, 163.5, 155.8, 140.1, 131.6,
α
131.2, 131.0, 129.2, 122.5, 122.4, 120.8, 116.7, 113.8, 55.5. EI-MS m/z
+
(
1H, m), 6.97 (1H, t, J = 9.4 Hz), 6.82 (1H, d, J = 8.2 Hz), 2.82 (2H, t, J
(%): 254 (M , 100) [23].
1
3
=
6.7 Hz, CH
2
), 1.82 (2H, t, J = 6.7 Hz, CH
2
), 1.34 (6H, s, 2xCH
3
).
C
(E)-1-(4-Methoxyphenyl)-3-(p-tolyl)prop-2-en-1-one
(161).
◦
NMR (CDCl
3
): 187.8, 161.6, 158.7, 134.1, 133.8, 133.7, 131.5, 130.8,
Yield: 99%. Mp 120–124 C. IR: 3078, 2975, 2936, 1654, 1596, 1562,
ꢀ
1 1
1
29.5, 128.4, 125.2, 120.9, 117.8, 117.3, 116.8, 75.5, 32.3, 26.7, 22.2.
1508, 1417, 1246, 1224, 1170 cm . H NMR (CDCl
8.8 Hz), 7.79 (1H, d, J = 15.6 Hz, Hβ), 7.55 (2H, d, J = 8.1 Hz), 7.51 (1H,
d, J = 15.6 Hz, H ), 7.22 (2H, d, J = 8.1 Hz), 6.98 (2H, d, J = 8.8 Hz),
3.89 (3H, s, OCH
3
): 8.04 (2H, d, J =
+
EI-MS m/z (%): 388 (M , 8), 199 (100). HR-EI-MS: 388.0474 calc, found
3
88.0417 (Δ = 0.0057).
α
1
3
(
E)-3-(4-Hydroxy-3-methoxyphenyl)-1-(2,2-dimethylchroman-
3 3 3
), 2.39 (3H, CH ). C NMR (CDCl ): 188.8, 163.3,
◦
6
-yl)prop-2-en-1-one (155). Yield: 72%. Mp 77–79 C. IR: 3300, 2935,
144.0, 140.8, 132.3, 131.2, 130.7, 129.6, 128.4, 120.8, 113.8, 55.5,
ꢀ 1
1
+
1
654, 1576, 1509, 1455, 1371, 1315, 1251 cm . H NMR (CDCl
3
): 7.83
21.5. EI-MS m/z (%): 252 (M , 100) [23].
(
1H, s), 7.80 (1H, s), 7.73 (1H, d, J = 15.6 Hz, Hβ), 7.39 (1H, d, J = 15.6
Hz, H
), 7.21 (1H, d, J = 8.3 Hz), 7.12 (1H, s), 6.94 (1H, d, J = 8.2 Hz),
.84 (1H, d, J = 8.3 Hz), 6.03 (1H, bs, OH), 3.95 (3H, s, OCH ), 2.85 (2H,
t, J = 6.7 Hz, CH ), 1.85 (2H, t, J = 6.7 Hz, CH ), 1.36 (6H, s, 2xCH ).
): 188.9, 158.4, 148.0, 146.8, 144.0, 130.7, 130.3,
(E)-3-(4-Hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one
◦
α
(162). Yield: 62%. Mp 184–186 C. IR: 3266, 3086, 2949, 1668, 1605,
ꢀ
1 1
6
3
1558, 1531, 1229, 1146 cm
.
H NMR (CDCl
3
): 8.03 (2H, d, J = 8.9
2
2
3
Hz), 7.77 (1H, d, J = 15.6 Hz, Hβ), 7.56 (2H, d, J = 8.4 Hz), 7.42 (1H, d,
1
3
C NMR (CDCl
3
J = 15.6 Hz, Hα), 6.98 (2H, d, J = 8.9 Hz), 6.88 (2H, d, J = 8.4 Hz), 3.89
13
1
2
28.3, 127.7, 123.0, 121.0, 119.7, 117.2, 114.8, 110.1, 75.5, 56.0, 32.5,
(3H, s, OCH
3
). C NMR (CDCl
3
): 188.9, 163.3, 157.7, 143.8, 131.3,
+
+
6.9, 22.4. EI-MS m/z (%): 388 (M , 100). HR-EI-MS: 338.1518 calc,
130.7, 130.3, 128.0, 119.7, 115.9, 113.8, 55.5. EI-MS m/z (%): 254 (M ,
85), 135 (100) [23].
found 388.1426 (Δ = 0.0092).
(
E)-3-(3,4-Dimethoxyphenyl)-1-(2,2-dimethylchroman-6-yl)
(E)-1,3-Bis(4-methoxyphenyl)prop-2-en-1-one (163). Yield: 99%.
Mp 97–101 ◦C. IR: 3062, 2945, 2931, 1654, 1590, 1569, 1509, 1457,
◦
prop-2-en-1-one (156). Yield: 42%. Mp 82–85 C. IR: 3073, 2970,
2
ꢀ 1
1
ꢀ 1
1
937, 1654, 1580, 1514, 1500, 1442, 1316, 1248, 1225 cm . H NMR
CDCl
): 7.83 (1H, s), 7.80 (1H, s), 7.74 (1H, d, J = 15.6 Hz, Hβ), 7.40
), 7.22 (1H, dd, J = 8.3, 1.8 Hz), 7.15 (1H, d, J =
1420, 1246, 1212 cm . H NMR (CDCl
3
): 8.03 (2H, d, J = 8.8 Hz), 7.77
(
(
3
(1H, d, J = 15.6 Hz, Hβ), 7.59 (2H, d, J = 8.7 Hz), 7.42 (1H, d, J = 15.6
Hz, H
), 6.96 (2H, d, J = 8.8 Hz), 6.92 (2H, d, J = 8.7 Hz), 3.87 (3H, s,
OCH
1H, d, J = 15.6 Hz, H
α
α
1
3
1
.8 Hz), 6.89 (1H, d, J = 8.3 Hz), 6.84 (1H, d, J = 8.3 Hz), 3.95 (3H, s,
3 3 3
), 3.83 (3H, s, OCH ). C NMR (CDCl ): 188.6, 163.2, 161.4,
OCH
3
), 3.92 (3H, s, OCH
3
), 2.85 (2H, t, J = 6.7 Hz, CH
2
), 1.85 (2H, t, J =
): 188.8, 158.4,
143.7, 131.2, 130.6, 130.0, 127.7, 119.4, 114.3, 113.7, 55.4, 55.3. EI-
1
3
+
6
1
1
3
.7 Hz, CH
2
), 1,63 (6H, s, 2xCH
3
). C NMR (CDCl
3
MS m/z (%): 268 (M , 100) [23].
51.1, 149.1, 143.7, 130.7, 130.3, 128.3, 128.1, 122.8, 120.9, 119.9,
(E)-1-(4-Methoxyphenyl)-3-(4-(dimethylamino)phenyl)prop-2-
en-1-one (164). Yield: 99%. Mp 122–124 ◦C. IR: 3079, 2979, 2933,
17.2, 111.1, 110.1, 75.5, 55.9, 32.5, 26.9, 26.8, 22.3. EI-MS m/z (%):
+
ꢀ 1
1
52 (M , 100). HR-EI-MS: 352.1675 calc, found 352.1670 (Δ = 0.0005).
1648, 1579, 1546, 1522, 1435, 1252, 1231, 1162 cm . H NMR
(
E)-3-(Benzo[d[1,3]dioxol-5-yl)-1-(2,2-dimethylchroman-6-yl)
(CDCl
3
): 8.03 (2H, d, J = 8.9 Hz), 7.78 (1H, d, J = 15.4 Hz, Hβ), 7.55
9

M. Mellado et al.
Bioorganic Chemistry 108 (2021) 104689
+
MS m/z (%): 269 (M , 100) [24].
(
2H, d, J = 8.6 Hz), 7.36 (1H, d, J = 15.4 Hz, H
α
), 6.97 (2H, d, J = 8.9
).
Hz), 6.69 (2H, d, J = 8.6 Hz), 3.88 (3H, s, OCH
3
), 4.04 (6H, s, N(CH
3
)
2
(E)-3-(4-Hydroxy-3-nitrophenyl)-1-phenylprop-2-en-1-one
1
3
◦
C NMR (CDCl
3
): 188.9, 162.9, 151.9, 144.9, 131.8, 130.5, 130.2,
(173). Yield: 75%. Mp 81–83 C. IR: 3217, 3072, 1659, 1605, 1536,
+
ꢀ 1
1
1
22.8, 116.4, 113.6, 111.8, 55.4, 40.1. EI-MS m/z (%): 281 (M , 100)
1493, 1353 cm . H NMR (CDCl
3
): 10.76 (1H, s, OH), 8.39 (1H, d, J =
[
23].
E)-3-(4-Hydroxy-3-methoxyphenyl)-1-(4-methoxyphenyl)prop-
1.4 Hz), 8.03 (2H, d, J = 7.3 Hz), 7.88 (1H, dd, J = 8.7, 1.4 Hz), 7.74
(
(1H, d, J = 15.7 Hz, Hβ), 7.64–7.53 (3H, m), 7.51 (1H, d, J = 15.7 Hz,
◦
13
2
-en-1-one (165). Yield: 63%. Mp 160–164 C. IR: 3025, 2974, 2922,
H
α
), 7.24 (1H, d, J = 8.7 Hz). C NMR (CDCl
3
): 189.8, 156.3, 141.5,
ꢀ 1 1
1
649, 1599, 1583, 1513, 1466, 1425, 1258, 1245, 1169 cm . H NMR
): 8.03 (2H, d, J = 8.7 Hz), 7.74 (1H, d, J = 15.6 Hz, Hβ), 7.39
1H, d, J = 15.6 Hz, H ), 7.22 (1H, d, J = 8.2 Hz), 7.13 (1H, s), 6.98 (2H,
137.8, 136.5, 133.8, 133.1, 128.8, 128.5, 127.8, 125.0, 122.6, 120.9. EI-
+
(
(
CDCl
3
MS m/z (%): 269 (M , 100) [35].
α
d, J = 8.7 Hz), 6.95 (1H, d, J = 8.2 Hz), 5.95 (1H, bs, OH), 3.96 (3H, s,
6
.3. Determination of in vitro MAO activity
1
3
3 3 3
OCH ), 3.89 (3H, s, OCH ). C NMR (CDCl ): 188.8, 163.3, 148.1,
1
5
46.8, 144.3, 131.3, 130.7, 127.7, 123.1, 119.6, 114.8, 113.8, 110.0,
The effects of the chalcone derivatives on hMAO enzymatic activity
+
6.0, 55.5. EI-MS m/z (%): 284 (M , 100) [23].
were evaluated by a fluorometric method following the experimental
protocol previously described by us. Briefly, 50 µL of sodium phosphate
buffer (0.05 M, pH 7.4) containing the test molecules (compounds or
reference inhibitors) in different concentrations and adequate amounts
of recombinant hMAO-A or hMAO-B [adjusted to obtain in our experi-
◦
(
E)-1,3-Diphenylprop-2-en-1-one (166). Yield: 99%. Mp 65–69 C.
ꢀ 1 1
3
IR: 3134, 1669, 1592, 1548, 1514 cm . H NMR (CDCl ): 8.03 (2H, d, J
=
7.5 Hz), 7.82 (1H, d, J = 15.6 Hz, Hβ), 7.66–7.64 (2H, m), 7.59 (1H, t,
J = 7.5, Hz), 7.54 (1H, d, J = 15.6 Hz, H
α
), 7.52 (2H, d, J = 7.5 Hz),
1
3
7
1
.43–7.40 (3H, m). C NMR (CDCl
30.5, 128.9, 128.6, 128.5, 128.4, 122.1. EI-MS m/z (%): 208 (M , 100)
3
): 190.5, 144.8, 138.2, 134.8, 132.7,
mental conditions the same reaction velocity (hMAO-A: 1.1
specific activity: 150 nmol of p-tyramine oxidized to p-hydrox-
yphenylacetaldehyde/min/mg protein; hMAO-B: 7.5 g protein; specific
μg protein;
+
[
24].
μ
(
E)-3-(2-Hydroxyphenyl)-1-phenylprop-2-en-1-one (167). Yield:
activity: 22 nmol of p-tyramine transformed/ min/mg protein)] were
◦
4
6%. Mp 154–155 C. IR: 3421, 3025, 1650, 1600, 1556, 1505, 1176
◦
incubated for 10 min at 37 C in a flat-black bottom 96-well microtest
ꢀ
1 1
cm . H NMR (CDCl
.5 Hz), 7.70 (1H, d, J = 15.8 Hz, H
d, J = 7.6 Hz), 7.53–7.51 (2H, m), 7.28 (1H, d, J = 6.9 Hz), 6.97 (1H, d,
3
): 8.14 (1H, d, J = 15.8 Hz, Hβ), 8.04 (2H, d, J =
plate, placed in the dark fluorimeter chamber. After this incubation
7
α), 7.59 (1H, t, J = 7.5 Hz), 7.59 (1H,
period, the reaction was started by adding 50 µL of the mixture con-
taining (final concentrations) 200 M of the Amplex® Red reagent, 1 U/
μ
1
3
J = 7.5 Hz), 6.91 (1H, d, J = 8.2 Hz). C NMR (CDCl
3
): 191.8, 156.0,
mL of horseradish peroxidase and 1 mM of p-tyramine. The production
1
1
41.0, 138.3, 132.7, 131.8, 129.5, 128.8, 128.6, 122.7, 122.2, 120.8,
◦
of H
2
O
2
and, consequently, of resorufin, was quantified at 37 C in a
+
16.7. EI-MS m/z (%): 224 (M , 100) [24].
E)-1-Phenyl-3-(p-tolyl)prop-2-en-1-one (168). Yield: 43%. Mp
multidetection microplate fluorescence reader (Fluo-star OptimaTM,
BMG LABTECH, Offenburg, Germany) based on the fluorescence
generated (excitation, 545 nm, emission, 590 nm) over a 10 min period,
in which the fluorescence increased linearly. Control experiments were
carried out simultaneously by replacing the tested molecules with
appropriate dilutions of the vehicles. In addition, the possible capacity
of these molecules to modify the fluorescence generated in the reaction
mixture, due to non-enzymatic inhibition (i.e. for directly reacting with
Amplex® Red reagent), was determined by adding these molecules to
solutions containing only the Amplex® Red reagent in sodium phos-
phate buffer. The specific fluorescence emission (used to obtain the final
results) was calculated after subtraction of the background activity,
which was determined from wells containing all components except the
hMAO isoforms, which were replaced by sodium phosphate buffer
solution.
(
◦
ꢀ 1
1
8
7–91 C. IR: 3000, 2936, 2899, 1662, 1592, 1542, 1512, 1455 cm . H
): 8.02 (2H, d, J = 7.6 Hz), 7.80 (1H, d, J = 15.8 Hz, Hβ),
.60–7.56 (5H, m), 7.50 (1H, d, J = 15.8 Hz, H ), 7.23 (2H, d, J = 7.6
): 190.6, 144.9, 141.0, 138.3,
32.6, 132.1, 129.7, 128.5, 128.4, 128.4, 121.1, 21.5. EI-MS m/z (%):
NMR (CDCl
3
7
α
1
3
3 3
Hz), 2.40 (3H, s, CH ). C NMR (CDCl
1
2
+
22 (M , 100) [24].
(
E)-3-(4-Hydroxyphenyl)-1-phenylprop-2-en-1-one (169). Yield:
◦
8
5%. Mp 183–187 C. IR: 3421, 3024, 1647, 1594, 1566, 1513, 1180
ꢀ
1 1
cm . H NMR (Acetone‑d
6
): 8.11 (2H, d, J = 8.4 Hz), 7.75 (1H, d, J =
1
5.6 Hz, Hβ), 7.71 (2H, d, J = 8.9 Hz), 7.61 (1H, t, J = 8.4 Hz), 7.54 (2H,
d, J = 8.4 Hz), 7.53 (1H, d, J = 15.6 Hz, Hα), 6.92 (2H, d, J = 8.9 Hz).
1
3
C NMR (Acetone‑d
6
): 189.9, 160.8, 145.2, 139.4, 133.3, 131.5, 129.4,
+
1
29.1, 127.5, 119.6, 116.7. EI-MS m/z (%): 224 (M , 100) [24].
(
E)-3-(4-Methoxyphenyl)-1-phenylprop-2-en-1-one (170). Yield:
◦
9
1
9%. Mp 70–72 C. IR: 3066, 2929, 1662, 1596, 1546, 1511, 1466,
ꢀ 1 1
239, 1214 cm . H NMR (CDCl
3
): 8.01 (2H, d, J = 7.5 Hz), 7.89 (1H,
Declaration of Competing Interest
d, J = 15.6 Hz, Hβ), 7.60 (2H, d, J = 8.7 Hz), 7.57 (1H, t, J = 7.5 Hz),
7.49 (2H, d, J = 7.5 Hz), 7.42 (1H, d, J = 15.6 Hz, H
8
1
α
), 6.93 (2H, d, J =
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
1
3
.7 Hz), 3.85 (3H, s, OCH ). C NMR (CDCl ): 190.5, 161.6, 144.7,
3
3
38.4, 132.5, 130.2, 128.5, 128.4, 127.5, 119.7, 114.4, 55.4. EI-MS m/z
+
(
%): 238 (M , 100) [24].
(
E)-3-(2-Hydroxy-3-methoxyphenyl)-1-phenylprop-2-en-1-one
Acknowledgements
◦
(
171). Yield: 68%. Mp 107–109 C. IR: 3383, 2914, 1665, 1598, 1479,
ꢀ 1 1
1
249, 1222 cm . H NMR (CDCl
3
): 8.04 (1H, d, J = 15.7 Hz, Hβ), 8.03
), 7.56 (1H, t, J = 6.9 Hz),
.48 (2H, d, J = 7.5 Hz), 7.18 (1H, t, J = 7.5 Hz), 6.88–6.84 (2H, m),
The authors thanks to Dr. Carlos Echiburu-Chau for the collection
and identification of S. graveolens. MM thanks Agencia Nacional de
Investigaci o´ n y Desarrollo (ANID, Chile, Fondecyt Postdoctoral Grant
3180408). MJM thanks Xunta de Galicia (Galician Plan of Research,
Innovation and Growth 2011–2015, Plan I2C, ED481B 2014/086–0 and
ED481B 2018/007) and Fundaç a˜ o para a Ci ˆe ncia e Tecnologia (FCT,
CEECIND/02423/2018 and UIDB/00081/2020). Authors would like to
thank Prof. Lourdes Santana for her scientific support.
(
2H, d, J = 7.5 Hz), 7.51 (1H, d, J = 15.7, Hα
7
6
1
5
1
3
3 3
.44 (1H, bs, OH), 3.88 (3H, s, OCH ). C NMR (CDCl ): 191.1, 146.8,
45.8, 140.1, 138.3, 132.4, 128.4, 123.2, 121.5, 121.3, 119.6, 111.9,
+
6.1. EI-MS m/z (%): 254 (M , 100) [24].
(
E)-3-(2-Hydroxy-3-nitrophenyl)-1-phenylprop-2-en-1-one
◦
(
172). Yield: 66%. Mp 134–138 C. IR: 3211, 1687, 1607, 1534, 1322,
234 cm . H NMR (Acetone‑d
ꢀ 1 1
1
6
): 8.33 (1H, d, J = 7.9 Hz), 8.22 (1H, d,
J = 7.9 Hz), 8.15 (2H, d, J = 7.2 Hz), 8.14 (1H, d, J = 15.9 Hz, Hβ), 8.00
1H, d, J = 15.9 Hz, H ), 7.65 (1H, t, J = 7.2 Hz), 7.56 (2H, d, J = 7.2
Hz), 7.18 (1H, t, J = 7.9 Hz). C NMR (Acetone‑d
38.8, 136.9, 135.5, 133.8, 12.6, 129.3, 127.6, 127.1, 125.2, 120.8. EI-
Appendix A. Supplementary material
(
α
1
3
6
): 189.8, 154.2,
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bioorg.2021.104689.
1
1
0

M. Mellado et al.
Bioorganic Chemistry 108 (2021) 104689
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