Promising Non-cytotoxic Monosubstituted Chalcones to Target Monoamine Oxidase-B

Luca G. Iacovino, Luca Pinzi, Giorgio Facchetti, Beatrice Bortolini, Michael S. Christodoulou,*

Letter

Promising Non-cytotoxic Monosubstituted Chalcones to Target

Monoamine Oxidase‑B

∇

Claudia Binda, Giulio Rastelli, Isabella Rimoldi, Daniele Passarella, Maria Luisa Di Paolo,

and Lisa Dalla Via*

Cite This: ACS Med. Chem. Lett. 2021, 12, 1151 −1158

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sı Supporting Information

ABSTRACT: A library of monosubstituted chalcones (1−17) bearing electron-

donating and electron-withdrawing groups on both aromatic rings were selected.

The cell viability on human tumor cell lines was evaluated ﬁrst. The compounds

unable to induce detectable cytotoxicity (1, 13, and 14) were tested using the

monoamine oxidase (MAO) activity assay. Interestingly, they inhibit MAO-B,

acting as competitive inhibitors, with 13 and 14 showing the best proﬁles. In

particular, 13 exhibited a potency higher than that of saﬁnamide, taken as a

reference. Docking studies and crystallographic analysis showed that in human

MAO-B 13 binds with the halogen-substituted aromatic ring in the entrance cavity,

similar to saﬁnamide, whereas 14 is accommodated in the opposite way. The main conclusion of this cell biology, biochemistry, and

structural study is to highlights 13 as a chalcone derivative that is worth consideration for the development of novel MAO-B-

selective inhibitors for the treatment of neurodegenerative diseases.

KEYWORDS: Chalcones, cytotoxicity, monoamine oxidase, molecular modeling, crystallographic analysis

halcones are a key structure motif within the kingdom

Plantae and are widely found in many edible plants.

of interest and encourages studies aimed at developing novel

types of inhibitors.

They are open-chain ﬂavonoids in which a three-carbon α,β-

unsaturated carbonyl moiety joins the two aromatic rings and

are considered as open-chain intermediates in the synthesis of

The chalcone structure has been considered an interesting

7−20

non-nitrogen-containing scaﬀold.

In a recent paper,

detailed structure−activity relationships (SAR) were discussed

for the inhibitory activity and selectivity toward MAOs, with

regard to the inﬂuence of diﬀerent substituents on both

aromatic rings of chalcone derivatives and compounds

ﬂavones. This peculiar chemical structure endows chalcones

with the capability to hit diﬀerent targets (enzymes and

receptors) and to exert a variety of biological activities. The

chalcone skeleton is therefore widely used in medicinal

containing the chalcone motif. In particular, the introduction

of heterocycles, the presence of nitro groups or lipophilic

electron-donating groups, and halogen substitution on phenyl

ring A and/or B are some of the modiﬁcations that were

designed for the chalcone scaﬀold, and frequently, more than

one modiﬁcation/substitution was introduced on the same

chemistry and drug discovery to obtain derivatives with

anticancer, antioxidant, antiviral, and anti-inﬂammatory

activities and for the treatment of neurodegenerative

−9

disorders.

Chalcone derivatives exert their anticancer activity through

,10

multiple mechanisms involving diﬀerent targets, and various

targets are also responsible for the eﬀect of chalcone analogues

compound. On the basis of literature data, among the

simplest, less substituted chalcone derivatives, the most active

compounds against the MAO-B isoform are characterized by

the presence of hydroxyl and methoxy substituents at ortho and

para positions, respectively, of the A aromatic ring and a

1−13

on neurodegenerative diseases.

In this latter ﬁeld,

monoamine oxidases (MAOs) play an important role, being

mitochondrial and ﬂavin adenine dinucleotide (FAD) cofactor-

dependent enzymes, which catalyze the oxidative deamination

of monoamine neurotransmitters. In particular, the MAO-B

isoform is mainly investigated for treatments of neuro-

degenerative disorders (including Parkinson’s and Alzheimer’s

diseases), while the MAO-A isoform mostly deals with

Received: April 22, 2021

Accepted: June 9, 2021

Published: June 14, 2021

14−16

neurological and psychiatric disorders.

In this connection,

although a number of MAO-A and MAO-B inhibitors are

already available in clinical practice, the need to reduce their

side eﬀects and/or to improve their selectivity is still deﬁnitely

2021 The Authors. Published by

American Chemical Society

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ACS Medicinal Chemistry Letters

Letter

Table 1. Cell Growth Inhibition after 72 h of Incubation in the Presence of the Examined Chalcones and Saﬁnamide

Values are reported as mean ± SD of at least three independent experiments in duplicate.

chlorine atom at the para position of the B ring. Nevertheless,

a role for each speciﬁc substituent did not emerge.

In this frame, we focused our attention on a small library of

monosubstituted chalcone derivatives bearing an electron-

2,13,17,18,21

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ACS Med. Chem. Lett. 2021, 12, 1151−1158

Letter

Figure 1. Competitive inhibition of chalcone derivatives on human MAO-B activity. Lineweaver−Burk double-reciprocal plots of MAO-B initial

velocity vs substrate concentration (1/v vs 1/[kynuramine]) in the absence and presence of various concentrations of compounds. Continuous

lines are the results of linear regression analysis of plotted data (r > 0.98). (a) Reciprocal plots at diﬀerent concentrations of 13 (5−40 nM)

showing that increasing the concentration of the compound increases the eﬀect on K (from the x-intercept), while no eﬀect on V (from the y-

max

intercept) is observed. (b) Examples of reciprocal plots in the presence of 1, 14, and chalcone (the lead compound) that demonstrate their

competitive behavior (eﬀect on K only). Saﬁnamide is shown as a standard competitive inhibitor. As these compounds have diﬀerent inhibitory

potencies, diﬀerent concentrations were used to show the eﬀect on MAO-B.

donating or electron-withdrawing substituent in the A or B

ring, with the aim to further clarify the function of the single

substituent in the biological properties. Such derivatives were

previously reported and studied as antiproliferative agents on

MSTO-211H (biphasic mesothelioma). Data are expressed in

terms of the GI₅₀value, i.e., the concentration of compound

able to inhibit 50% cell growth with respect to the control

culture. Unsubstituted chalcone and saﬁnamide were reported

as reference.

Interestingly, these results show that derivatives 1, 13, and

14 were unable to induce any cytotoxicity in any of the tested

cell lines. Otherwise, the majority of the chalcones belonging

to the selected library, as for the unsubstituted chalcone

scaﬀold, induced a signiﬁcant antiproliferative eﬀect, with GI₅₀

values ranging from 2.8 to 16.7 μM. In particular, in the series

leukemia cells, and for them few or no data on MAO activity

9,23

were reported.

All of the compounds were synthesized

using a classical Claisen−Schmidt condensation of the

appropriate acetophenone with the corresponding aldehyde

in a methanolic solution of sodium hydroxide. The products

were obtained after being recrystallized twice from ethanol

with a good grade of purity (see the Supporting Information).

As the absence of cytotoxicity is a mandatory requirement for

compounds to be used to treat neurodegenerative diseases, the

potential antiproliferative eﬀects of the compounds belonging

to the library were evaluated on a wider number of human

tumor cell lines. The chalcone derivatives that were unable to

induce any signiﬁcant antiproliferative eﬀect were selected and

further studied as potential inhibitors for human recombinant

MAO-A and MAO-B. In detail, we evaluated the inhibition

constant values, the selectivity indices, and the mechanism of

inhibition. The kinetic characterization of the most interesting

derivatives, 13 and 14, integrated with docking studies and

crystallographic experiments uncovered their binding mode

inside the MAO-B active site. Overall, our ﬁndings expand the

knowledge in terms of possible molecular interactions between

the chalcone scaﬀold and MAO-B and highlight 13 as a

scaﬀold worth further study in view of the development of new

promising drugs for neurodegenerative diseases.

1−9 bearing an electron-donating or electron-withdrawing R

substituent, derivative 2, characterized by the m-NO group,

showed the highest cytotoxic eﬀect in all of the considered cell

lines (GI₅₀values ranging from 2.8 to 5.1 μM), while the o-

NO analogue 1 was completely ineﬀective on cells. For all of

the other derivatives (3−9), an intermediate eﬀect was

observed.

With regard to 10−17, interesting diﬀerences in anti-

proliferative activity were observed for the derivatives bearing

CF as the R substituent (12−14). In detail, while the o-CF -

substituted chalcone 12 was able to induce signiﬁcant

cytotoxicity, the insertion of the same group at the meta

(13) or para (14) position abolished the eﬀect on cells. For

10−11 and 15−17, the position of the NO or OCH

substituent, respectively, did not signiﬁcantly aﬀect the

cytotoxicity. Finally, as expected, saﬁnamide was completely

ineﬀective on human cancer cells.

The absence of any cytotoxicity and the enzyme inhibition

mechanism are fundamental elements in the development of

novel MAO-B inhibitors to target neurodegenerative diseases.

With this aim, cell biology, biochemical, and structural studies

were combined to explore the activity proﬁles of a small library

of monosubstituted chalcones as potential MAO-B inhibitors.

Table 1 reports the chalcone series and the results on

antiproliferative activity, which was evaluated through an in

vitro assay performed on three tumor cell lines, i.e., A2780

(

ovarian carcinoma), HT-29 (colorectal adenocarcinoma), and

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ACS Medicinal Chemistry Letters

Standard MAO-A and MAO-B inhibitor.

Letter

All of the tested chalcones were found to inhibit both MAO-

inhibitors saﬁnamide and isatin. From the data in Table 2, it

clearly appears that the presence of the −CF group as the R

A and MAO-B. In particular, the Lineweaver−Burk double-

reciprocal plots (1/v vs 1/[S]) of the kinetic data for MAO-B

substituent (at the meta (13) or para (14) position of the

phenyl ring) signiﬁcantly improves both the potency of the

inhibition and the selectivity toward the MAO-B isoform with

respect to unsubstituted chalcone. Otherwise, the insertion of

the −NO group as the R substituent at the meta position (1)

in the presence of various concentrations (5−40 nM) of 13

Figure 1A) clearly demonstrate a competitive mode of

(

inhibition, as only the x-intercept (−1/K ) is aﬀected by the

presence of the compound, in contrast to the y-intercept (1/

^Vmax), which is not signiﬁcantly diﬀerent at all tested

concentrations. The reversibility of the inhibition was

evaluated by incubating MAOs with 13 (at a concentration

is detrimental to both MAO-B inhibition and the selectivity

index (S.I.).

In particular, compound 13 emerges as the most potent and

selective inhibitor for MAO-B. Indeed, its inhibition constant

equal to 4 times the K value) for 20 min before starting

dialysis cycles. After dialysis, the MAO activity was fully

recovered, supporting the reversibility of the mode of

inhibition of this compound. The same behavior was found

for 1 and 14, as can be clearly seen in Figure 1B, where results

for the lead compound (chalcone) and saﬁnamide are also

shown. This competitive behavior has been reported previously

value (K = 5.0 nM) is lower than that obtained for saﬁnamide

(

K_i= 17 nM), and it shows very good selectivity (S.I. = 920 vs

820 of saﬁnamide). Finally, derivative 17 is less potent (K =

2 nM) and less selective (S.I. = 594) than 13 under our

experimental conditions. It is worth mentioning that the K_i

value reported in Table 2 for 17 is lower than that previously

20,23

for other chalcone derivatives.

19,23

reported in the literature

because it was determined under

The values of the inhibition constant (K ) for 1, 2, 13, 14,

diﬀerent experimental buﬀer and temperature conditions. In

this regard, the 15−17 subseries was also tested previously on

MAO-B, and for both 15 and 16 a lower inhibitory potency

and 17 were determined for both MAO-A and MAO-B and are

reported in Table 2 in a comparative analysis with the standard

19,23

than for 17 was found.

Table 2. Inhibition Constant Values and Selectivity Indices

for Human Recombinant MAO-A and MAO-B by 1, 13, and

The noteworthy inhibitory potency (K value in the

nanomolar range) and the high selectivity exerted by 13

point to this derivative as one of the most promising chalcone

scaﬀolds for the development of agents for neurodegenerative

disease. Indeed, comparable eﬀects on MAO-B have been

4 and Also by Chalcone, 2, and 17 as Reference Chalcone

Compounds and Saﬁnamide and Isatin as Standard MAO

Inhibitors

K (nM)

demonstrated only in a few trisubstituted and disubstituted

chalcone derivatives and in a furan-based chalcone containing a

compound

MAO-A

MAO-B

56 ± 6

400 ± 80

71 ± 11

5.0 ± 0.5

14.6 ± 0.1

21.9 ± 2.3

17 ± 4

S.I.

cinnamyl group. The relevance of 13 is further supported by

the absence of cytotoxicity also on nontumorigenic Met-5A

mesothelial cells, for which a GI value higher than 20 μM was

chalcone

(14.6 ± 1.0) × 10

(2.2 ± 0.2) × 10

(2.5 ± 1.0) × 10

(4.6 ± 0.5) × 10

(9.2 ± 1.8) × 10

(13.0 ± 2.1) × 10

(82 ± 8) × 10

(16 ± 3) × 10

260:1

5.5:1

35:1

920:1

630:1

594:1

4820:1

4:1

obtained, as for saﬁnamide. In contrast, for the chalcone

scaﬀold and 17, cytotoxicity toward Met-5A was also

conﬁrmed, with GI₅₀values of about 7.0 ± 1.5 and 11.8 ±

1.1 μM, respectively.

Overall these results prompted us to perform molecular

modeling studies on the most active compound of the series,

i.e., 13.

saﬁnamide

isatin

(4 ± 1) × 10

Values are reported as mean ± SD of three independent

experiments. Selectivity index, given by S.I. = K (MAO-A)/

First, in silico ADME predictions made with QikProp

predicted that 13 has favorable drug-like properties and good

K (MAO-B). See refs 19 and 23. Standard MAO-B inhibitor.

Figure 2. Predicted docking poses of 13 in the MAO-A and MAO-B crystal structures: (a) binding mode of 13 in the MAO-A protein (PDB ID

Z5X); (b) the more energetically favored binding mode (binding mode b) predicted for 13 in the MAO-B crystal structure (PDB ID 2V5Z).

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Letter

blood−brain barrier permeability (see Table S1). Then,

docking calculations into representative conformations of the

human MAO-A and MAO-B proteins were performed (see the

MAO-B were studied by X-ray crystallography. The three-

dimensional structures of human MAO-B in complex with 13

Figures 3 and 4 a) and 14 (Figure 4 b) were solved at 2.3 and

24,26

Supporting Information for the experimental details).

particular, two diﬀerent binding modes between 13 and MAO-

B were predicted (termed binding modes a and b), while a

single binding mode was observed for MAO-A. Figure 2a

shows the binding mode of 13 in MAO-A, and Figure 2b

depicts the more stable binding mode of 13 in MAO-B (herein

termed binding mode b). The less stable binding mode of 13

in MAO-B (binding mode a) is shown in Figure S1. The two

binding modes in MAO-B are likely due to the peculiar

morphology of this isoform, which is composed of two similar

27,28

subcavities separated by the Ile199 and Tyr326 side chains.

The binding modes are similar to those previously reported for

21,29

other chalcone inhibitors.

The docking scores in MAO-B were −10 kcal·mol for

−

binding mode a and −11 kcal·mol for binding mode b. The

docking score in MAO-A was −7.5 kcal/mol. To better

discriminate between the two binding modes in MAO-B, a

rescoring of the predicted docking poses was performed with a

more rigorous free-energy-based screening methodology (i.e.,

Figure 3. Overall structure of the MAO-B dimer represented as a pink

ribbon diagram (chain A is on the left) with the membrane-spanning

C-terminal helix pointing to the bottom of the ﬁgure. The FAD

cofactor is shown in stick representation with carbon, nitrogen,

oxygen, and phosphorus atoms colored in yellow, blue, red, and

magenta, respectively. The structure in complex with 13 (in green,

with ﬂuorine atoms in light blue and oxygen in red) is shown. The

overall fold is identical to that of the enzyme in complex with 14.

BEAR) to evaluate the binding free energy of the ligand.

According to the binding free energy scores (ΔG_b_i_n_d)

predicted by BEAR, binding mode b of 13 turned out to be 6.8

−

kcal·mol more stable than binding mode a (Table S2). In

binding mode b, the B phenyl ring of 13 establishes

hydrophobic interactions with the aromatic rings of the

Tyr398, Tyr435, and Tyr60 side chains and the ﬂavine ring

of FAD. The α,β-unsaturated ketone binds close to the Ile198

and Leu171 side chains, with the carbonyl moiety forming a

hydrogen bond with the Cys172 side chain, as previously

.1 Å resolution, respectively (statistics are reported in Table

S3). For both structures, the overall fold and, in particular, the

active site and the bound inhibitor display the same

conformation between the two monomers of the dimer

contained in the asymmetric unit (the root-mean-square

deviations for Cα atoms are 0.30 and 0.27 Å between chains

A and B for the structures in complex with compounds 13 and

14, respectively). Hereafter, we will refer to subunit A of each

structure for the following discussion.

observed for other chalcone compounds. The A ring forms

hydrophobic contacts with the Leu164, Leu167, Phe168 and

Trp119 side chains, as previously observed in ref 29. In

particular, the triﬂuoromethyl moiety was predicted to be

accommodated near the Trp119 and Leu164 side chains,

establishing close contacts. The hydrogen bond of the carbonyl

with the Cys172 residue is of special interest because this

residue, which is mutated to Asn181 in MAO-A, has a

Inspection of the electron density in the enzyme active site

revealed that 13 and 14 bind in the hydrophobic cavity of

MAO-B (Figure 4a,b, respectively). In both cases the chalcone

moiety is accommodated with the carbonyl oxygen pointing

toward the bottom of the active site and establishing a

hydrogen bond with Cys172 in one of the two conformations

that this residue adopts. This feature was also found in the

21,29

recognized role in MAO-B/MAO-A selectivity.

Impor-

tantly, docking of 13 into MAO-A did not provide an

orientation similar to that of MAO-B. In MAO-A, the

triﬂuoromethylbenzene moiety (ring A) was predicted to be

accommodated toward the entrance of the MAO-A binding

site near residues Leu97, Ile335, and Leu337 because of steric

clashes with the Phe208 side chain. Moreover, the carbonyl

group of 13 did not establish hydrogen bonds with MAO-A

residues. Interestingly, the lack of a hydrogen bond with

residues in this region of the MAO-A binding pocket, like

those previously observed with Cys172 or Tyr326 into MAO-

B, has been reported to play an important role in isoform

MAO-B structures in complex with chromone inhibitors.

The distances between the cysteine side chain and the

chalcone alkene unit are 4.0 and 4.6 Å for 13 and 14,

respectively, both of which are too long for the formation of a

covalent bond as previously observed for other targets.

Compound 13 binds with the CF substituent in the entrance

cavity space (Figure 4a), which is in agreement with the most

stable orientation predicted by modeling as described above

and is consistent with previous studies highlighting this part of

the active site as a favorable niche for halogen atoms (such as

in the case of saﬁnamide; see Figure 5). Most likely, in the

crystallized MAO-B−13 complex the predicted binding mode

b of 13 is selected. Interestingly, 14 is bound in the opposite

way with respect to the ﬂavin compared with 13, with the CF₃

group positioned within the aromatic cage formed by residues

Tyr398 and Tyr435 in front of the ﬂavin (Figure 4b). This is

unique in MAO-B structures and is probably due to the para

position of the substituent on the aromatic ring, which would

clash with the residues belonging to the gating loop formed by

residues 99−110 (on the left in Figure 4). Similar to the

27,28,31

selectivity for the MAO proteins.

The B phenyl ring is

accommodated close to the Tyr60 and Tyr407 side chains and

FAD, similar to what was observed in MAO-B. Altogether,

these diﬀerences help explain the experimentally observed

selectivity of compound 13 for MAO-B over MAO-A.

Considering that docking calculations on 13 suggested two

alternative orientations, one of which was clearly favored over

the other, we sought to investigate whether para (compound

4) instead of meta (compound 13) triﬂuorocarbon

substitution could play a role in discriminating the ligand

orientation. To this aim, the binding modes of 13 and 14 in

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The Supporting Information is available free of charge at

Letter

Figure 4. Architectures of the MAO-B active site in complex with (a) 13 and (b) 14. FAD is depicted as in Figure 3. The residues that line the

cavity are represented as sticks with carbon, nitrogen, oxygen, and sulfur atoms in pink, blue, red, and orange, respectively. The reﬁned 2F − F

electron density map for the inhibitor molecule (contoured at 1.2σ) is shown in blue chicken-wire style. The ﬂuorine atoms of both inhibitors are in

light blue, with carbon atoms in green (13 ) and gray (14 ). Water molecules are depicted as red spheres and hydrogen bonds as dashed lines.

tives (1, 13, and 14) demonstrated a safe proﬁle on diﬀerent

human cell lines and then were considered for further

investigation. In particular, 13 appeared to be good candidate

to target MAO enzymes in the context of neurodegenerative

diseases. Indeed, it behaves as competitive reversible inhibitor

of MAO-B, showing an inhibitory potency of K = 5 nM

(

which is higher than that of the clinically used saﬁnamide)

and a remarkable selectivity toward the MAO-B isoform.

Docking studies of the binding of 13 to MAOs conﬁrmed the

strong aﬃnity and selectivity for MAO-B versus MAO-A by

predicting opposite orientations in the active site of the two

isoforms (with the triﬂuoromethylbenzene moiety pointing

toward the FAD cofactor in MAO-B and toward the active-site

entrance in MAO-A). Crystal structures of MAO-B in complex

with 13 and 14 highlighted the key role played by the position

of the triﬂuoromethyl moiety on the phenyl ring (meta in the

former and para in the latter) in orienting the inhibitor into the

active site.

Overall, our studies pointed to 13 as a very promising

chalcone derivative to be considered for the development of

novel MAO-B-selective inhibitors for the treatment of

neurodegenerative diseases. The evaluation of its eﬀectiveness

and nontoxicity in vivo and the eﬀect on other targets involved

in neurodegenerative disorders warrant further investigation.

Figure 5. Superposition of MAO-B structures in complex with 13, 14,

and saﬁnamide (the latter represented with carbon atoms in magenta;

PDB code 2V5Z). For the sake of clarity, water molecules and

hydrogen bonds shown in Figure 4 have been omitted.

ﬂuorine atom substituent in saﬁnamide, the CF group of 13 is

at the meta position and can easily be accommodated in the

entrance cavity. Superposition of the MAO-B structures in

complex with the two chalcone inhibitors highlights that the

carbonyl−Cys172 hydrogen bond functions as a sort of pivot

point by ﬁxing the molecules in the active site and orienting

them in opposite directions with respect to the ﬂavin (Figure

ASSOCIATED CONTENT

sı Supporting Information

https://pubs.acs.org/doi/10.1021/acsmedchemlett.1c00238.

■

). The chalcone scaﬀold is constrained by the ﬂat and rigid

Chemistry, materials and methods, molecular docking,

crystallographic details, and NMR spectra (PDF)

MAO-B cavity to position the inner aromatic ring

perpendicular to the ﬂavin and the other slightly tilted, similar

to the conformation observed in saﬁnamide (Figure 5).

Retrospective docking calculations predicted only one binding

mode for 14 (docking score of −10 kcal·mol ), consistent

with the orientation observed in the crystal structure and

similar to the predicted binding mode a of 13 (Figure S2).

In conclusion, we report that among a library of

monosubstituted structurally related chalcones, three deriva-

AUTHOR INFORMATION

Corresponding Authors

■

−

Lisa Dalla Via − Dipartimento di Scienze del Farmaco,

Universita degli Studi di Padova, Padova 35131, Italy;

orcid.org/0000-0002-9828-9388; Email: lisa.dallavia@

unipd.it

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ACS Medicinal Chemistry Letters

S.; Perdicchia, D.; Maione, S.; Passarella, D.; Di Marzo, V.; De

Letter

Michael S. Christodoulou − DISFARM, Sezione di Chimica

(6) Schiano Moriello, A.; Luongo, L.; Guida, F.; Christodoulou, M.

Petrocellis, L. Chalcone derivatives activate and desensitize the

transient receptor potential ankyrin 1 cation channel, subfamily A,

member 1 TRPA1 ion channel: structure-activity relationships in vitro

and anti-nociceptive and anti-inflammatory activity in vivo. CNS

Neurol. Disord.: Drug Targets 2016, 15, 987−994.

Generale e Organica “A. Marchesini ”, Universita degli Studi

di Milano, Milano 20133, Italy; orcid.org/0000-0002-

098-3143; Email: michail.christodoulou@unimi.it

Authors

Luca G. Iacovino − Dipartimento di Biologia e Biotecnologie,

Universita di Pavia, Pavia 27100, Italy

(7) Quaglio, D.; Zhdanovskaya, N.; Tobajas, G.; Cuartas, V.;

Balducci, S.; Christodoulou, M. S.; Fabrizi, G.; Gargantilla, M.; Priego,

E.-M.; Carmona Pestana, A.; Passarella, D.; Screpanti, I.; Botta, B.;

Luca Pinzi − Dipartimento di Scienze della Vita, Universita

degli Studi di Modena e Reggio Emilia, Modena 41125, Italy

Palermo, R.; Mori, M.; Ghirga, F.; Pérez-Pérez, M.-J. Chalcones and

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acute lymphoblastic leukemia. ACS Med. Chem. Lett. 2019, 10, 639−

Giorgio Facchetti − DISFARM, Sezione di Chimica Generale

e Organica “A. Marchesini ”, Universita degli Studi di Milano,

Milano 20133, Italy; orcid.org/0000-0002-1260-1335

Beatrice Bortolini − Dipartimento di Scienze del Farmaco,

(

43.

8) Karthikeyan, C.; Narayana Moorthy, N. S. H.; Ramasamy, S.;

Universita

degli Studi di Padova, Padova 35131, Italy

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Claudia Binda − Dipartimento di Biologia e Biotecnologie,

Universita di Pavia, Pavia 27100, Italy; orcid.org/0000-

003-2038-9845

Giulio Rastelli − Dipartimento di Scienze della Vita,

Universita degli Studi di Modena e Reggio Emilia, Modena

1125, Italy; orcid.org/0000-0002-2474-0607

Isabella Rimoldi − DISFARM, Sezione di Chimica Generale e

Organica “A. Marchesini ”, Universita degli Studi di Milano,

Milano 20133, Italy; orcid.org/0000-0002-6210-0264

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Daniele Passarella − Dipartimento di Chimica, Universita

degli Studi di Milano, Milano 20133, Italy

Maria Luisa Di Paolo − Dipartimento di Medicina

(12) Mathew, B. Unraveling the structural requirements of chalcone

Molecolare, Universita

Italy

degli Studi di Padova, Padova 35131,

chemistry towards monoamine oxidase inhibition. Cent. Nerv. Syst.

Agents Med. Chem. 2019, 19, 6−7.

(

13) Mathew, B.; Haridas, A.; Suresh, J.; Mathew, G. E.; Uc a ̧ r, G.;

Complete contact information is available at:

https://pubs.acs.org/10.1021/acsmedchemlett.1c00238

Jayaprakash, V. Monoamine oxidase inhibitory action of chalcones: a

mini review. Cent. Nerv. Syst. Agents Med. Chem. 2016, 16, 120−136.

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Author Contributions

L.G.I., L.P., and G.F. contributed equally

Membrane Protein Complexes: Structure and Function; Harris, J. R.,

Boekema, E. J., Eds.; Subcellular Biochemistry, Vol. 87; Springer,

∇

15) Youdim, M.; Edmondson, D.; Tipton, K. The therapeutic

018; pp 117−139.

potential of monoamine oxidase inhibitors. Nat. Rev. Neurosci. 2006,

Notes

The authors declare no competing ﬁnancial interest.

, 295−309.

ACKNOWLEDGMENTS

■

(16) Tripathi, R. K. P.; Ayyannan, S. R. Monoamine oxidase-B

inhibitors as potential neurotherapeutic agents: an overview and

update. Med. Res. Rev. 2019, 39, 1603−1706.

M.L.D.P and L.D.V. are grateful for the ﬁnancial support

provided from DOR (University of Padova). We thank

OpenEye Scientiﬁc Software, Inc., for a free academic license

for the OpenEye Toolkit. This work was supported by the

Italian Ministry of Education, University and Research

MIUR) (Dipartimenti di Eccellenza Program 2018−2022,

Department of Biology and Biotechnology “L. Spallanzani”,

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