Design, synthesis, and biological activities of pyrrolylethanoneamine derivatives, a novel class of monoamine oxidases inhibitors

Article abstract of DOI:10.1021/jm050172c

Pyrrolylethanoneamines 1-12, 18-23 and related amino alcohols 13-15, 24-27 were synthesized and tested against monoamine oxidases A and B (MAO-A and MAO-B) enzymes. In general, aminoketones 1-12, 18-23 were found to be potent and selective MAO-A inhibitor

Full text of DOI:10.1021/jm050172c

4220
J. Med. Chem. 2005, 48, 4220-4223
Chart 1. Irreversible and Reversible MAO-A (A) and
MAO-B (B) Selective Inhibitors Used in Clinical Practice
or in Clinical Trials
Design, Synthesis, and Biological
Activities of Pyrrolylethanoneamine
Derivatives, a Novel Class of Monoamine
Oxidases Inhibitors
Roberto Di Santo,*,§ Roberta Costi,§
Alessandra Roux,§ Marino Artico,§ Olivia Befani,#
Tiziana Meninno,# Enzo Agostinelli,#
Paola Palmegiani,# Paola Turini,# Roberto Cirilli,†
Rosella Ferretti,† Bruno Gallinella,† and
Francesco La Torre†
Istituto PasteursFondazione Cenci Bolognetti, Dipartimento
di Studi Farmaceutici (Dip. 63), Universita` di Roma
“La Sapienza”, Piazzale A. Moro 5, I-00185 Roma, Italy,
Dipartimento di Scienze Biochimiche, “A. Rossi-Fanelli” and
Istituto di Biologia e Patologia Molecolari del CNR,
Universita` degli Studi di Roma “La Sapienza”,
P.le Aldo Moro 5, I-00185 Roma, Italy, and Dipartimento
del Farmaco, Istituto Superiore di Sanita`,
Viale Regina Elena 299, I-00161 Roma, Italy
Received February 22, 2005
Abstract: Pyrrolylethanoneamines 1-12, 18-23 and related
amino alcohols 13-15, 24-27 were synthesized and tested
against monoamine oxidases A and B (MAO-A and MAO-B)
enzymes. In general, aminoketones 1-12, 18-23 were found
to be potent and selective MAO-A inhibitors. In particular, 18
was more potent and selective against the MAO-A isoenzyme
than reference drugs. Interestingly, amino alcohol 25 selec-
tively inhibited MAO-B enzyme and could be a lead compound
for designing more potent and selective MAO-B inhibitors.
foods (cheese effect).6 The rational design of new agents
targeted to MAOs could be based on the crystal struc-
ture of human MAO-B7 and rat MAO-A8 and aided with
theoretical calculations.9 The above studies have eluci-
dated some factors responsible for selectivity against the
A and B isoforms, such as the lipophilicity of the
inhibitor that is important for achieving effective bind-
ing to MAO-B,9 the presence of electron-rich aromatic
moieties, typical of selective MAO-A inhibitors,10 and
the role played by some amino acid residues in the
active sites, such as Tyr326 for MAO-B and Ile335 for
MAO-A.8
The aim of the present study was the identification
of novel potent, reversible, and selective MAO inhibitors
that could serve as potential lead molecules for drug
discovery. An examination of the chemical structures
of new MAOIs of clinical interest or in clinical trials led
us to identify some structural features that characterize
these compounds: (i) a basic nitrogen atom sometimes
incorporated in an alicyclic ring such as piperidine or
morpholine (brofaromine,11 moclobemide,12 and bazi-
naprine13); (ii) an electron-rich aromatic moiety that
plays a pivotal role in the interaction with the biological
target, as shown in recent QSAR studies by Vallejos et
al.10 (brofaromine, Ro 41-1049,14 and pirlindole deriva-
tives15); (iii) a carbonyl or alcohol group (moclobemide,
Ro 41-1049, Ro 19-6327,14 and toloxatone16) (Chart 1).
Therefore, we decided to test the activity against
MAO-A and MAO-B enzymes of a series of phenylpyr-
rolylethanoneamines 1-10 (PEAs) previously reported
by us, of which some showed antiphobic-anxiolitic
activity.17 In fact, 1-10 (Table 1, Chart 1) are charac-
terized by (i) an amino group linked at the 2-position of
the ethanone chain, (ii) a pyrrole ring as an electron-
Mitochondrial monoamine oxidases (MAOs, EC 1.4.3.4)
are flavin-containing enzymes (FAD or FMN) that
catalyze the oxidative deamination of neurotransmitters
and exogenous arylalkylamines. In mammals, two dif-
ferent types of MAOs are present in most tissues,
namely, MAO-A and MAO-B.1 MAO-A preferentially
deaminates aromatic monoamines such as the neu-
rotransmitters serotonin (5-HT), noradrenaline (NA),
and adrenaline (A), while MAO-B mainly oxidizes
â-phenylethylamines (PEA) and benzylamines. Both
isoforms act on dopamine (D) and tryptamine.1 Selective
MAO-A inhibitors are currently used for treating neu-
rological disorders such as anxiety and depression,2
while selective inhibitors of the B isoform (e.g., sel-
egiline) are administered alone or together with L-DOPA
for the treatment of Parkinson’s syndrome3 and Alz-
heimer’s disease.4 Chart 1 shows the structures of some
MAO inhibitors (MAOIs) used in clinical practice or in
clinical trials.1,5
More recent studies on MAOIs have been focused on
reversible and selective agents. In fact, irreversible and/
or nonselective inhibitors showed shortcomings includ-
ing cumulative effects, loss of selectivity after chronic
treatment, and interaction with tyramine-containing
* To whom correspondence should be addressed. Phone and fax:
+39-06-49913150. E-mail: roberto.disanto@uniroma1.it.
§ Dipartimento di Studi Farmaceutici, Universita` di Roma “La
Sapienza”.
# Dipartimento di Scienze Biochimiche, Universita` di Roma “La
Sapienza”.
† Istituto Superiore di Sanita`.
10.1021/jm050172c CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/03/2005

Letters
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 13 4221
Table 1. Anti-MAO Activities of Pyrrolylethanonamines 1-12, 18-23, and Pyrrolylethanolamines 13-15, 24-27a
compd
R
X
stereochemistry
MAO-A Ki (µM)
MAO-B Ki (µM)
A-selectivityb
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
CH3
Ph
Ph
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
NH2
racemic
racemic
racemic
racemic
racemic
racemic
racemic
racemic
racemic
racemic
0.095 ( 0.0005
1.75 ( 0.045
0.0075 ( 0.0015
0.096 ( 0.005
0.347 ( 0.006
0.93 ( 0.001
0.35 ( 0.005
0.1 ( 0.015
0.81 ( 0.002
0.83 ( 0.01
0.007 ( 0.0009
0.038 ( 0.001
31 ( 1.5
42 ( 0.14
875 ( 1
442
2
N(CH3)2
500
3
1-pyrrolidinyl
1-piperidinyl
4-methyl-1-piperazinyl
4-benzyl-1-piperazinyl
4-morpholinyl
4-thiomorpholinyl
1-phthalimido
4-etoxyphenylamino
1-piperidinyl
1-piperidinyl
600 ( 5
80000
5208
>288
11
>286
>1000
>123
>121
947
4
500 ( 0.01
>100 ( 0.02
10 ( 4
>100 ( 1
>100 ( 2
>100 ( 2.1
>100 ( 3
15 ( 0.01
36 ( 0.9
9.22 ( 0.15
140 ( 1
23.9 ( 1.1
700 ( 1
500 ( 4
520 ( 4.3
410 ( 2
5
6
7
8
9
10
11
12
13
14
15
18
19
20
21
22
23
24
25
26
27
MCLc
TOLd
SELe
racemic
racemic
racemic
2143
0.29
140
1 ( 0.5
0.51 ( 0.02
0.0035 ( 0.0005
0.0095 ( 0.001
0.01 ( 0.002
0.1 ( 0.04
0.076 ( 0.002
0.082 ( 0.001
55 ( 1
7 ( 0.1
0.6 ( 0.03
0.52 ( 0.06
11.5 ( 0.1
0.38 ( 0.023
38 ( 1
47
1-pyrrolidinyl
1-pyrrolidinyl
1-piperidinyl
1-piperidinyl
4-thiomorpholinyl
4-thiomorpholinyl
(-)-(R)
200000
52632
5200
4100
5263
1220
0.31
0.18
77
(+)-(S)
(-)-(R)
(+)-(S)
(-)-(R)
400 ( 2.6
100 ( 0.9
17.2 ( 1.5
1.24 ( 0.06
46 ( 3
(+)-(S)
(-)-threo
(+)-threo
(-)-erythro
(+)-erythro
>10 ( 2
>19
>100 ( 2
15 ( 0.96
0.97 ( 0.01
>8.7
39.5
0.025
a Data represent mean values of at least three separate experiments. b Expressed as Ki(MAO-B)/Ki(MAO-A). c MCL: moclobemide.
d TOL: toloxatone. e SEL: selegiline.
Scheme 1a
rich aromatic moiety, and (iii) a carbonyl group linked
at the R-carbon of pyrrole ring. Moreover, as a prelimi-
nary study of the structure-activity relationships in
this class of inhibitors, amines 11-15 related to 1-10
were designed, synthesized, and tested on both MAO
isoforms.
The newly synthesized derivatives 11-15 were ob-
tained as depicted in Scheme 1. 1-Methylpyrrole un-
derwent a Friedel-Crafts reaction with 2-chloroacetyl
chloride or 2-chloropropionyl chloride to give ketones
1618 or 17,19 respectively. These compounds were treated
with piperidine in the presence of K2CO3 to afford amino
derivatives 11 and 12. Reaction of ketones 4 and 11 with
lithium aluminum hydride in anhydrous ethyl ether
gave the corresponding carbinols 13-15. In particular,
the reduction of 4 gave a mixture of threo (13) and
erythro (14) isomers, with predominance of erythro
couple 14, according to Cram’s rule.20 Separation of
diastereoisomers 13 and 14 was performed by prepara-
a Reagents and conditions: (i) RCH(Cl)COCl, AlCl3, CH2Cl2,
tive TLC on silica gel using a mixture of chloroform/
-20 °C, 15 min, 16 26%, 17 47%; (ii) piperidine, K2CO3, acetone,
methanol 20:1 as eluent.
reflux 15 h, 11 86%, 12 67%; (iii) LiAlH4, Et2O, 0 °C, 40 min, 13
Because of the well-known stereoselectivity of en-
13%, 14 75%, 15 87%.
antiomeric chiral MAOIs such as selegiline (SEL)21 and
oxazolidinones,22 we decided to resolve a number of
potent racemates (3, 4, 8) and aminoethanols 13, 14 to
determine the impact of chirality in biological efficacy
within this novel class of MAOIs. Single enantiomers
18-27 were obtained by semipreparative HPLC of the
racemic mixtures on a polysaccharide-based chiral
stationary phase (CSP)23 (Chiralpak AD) (the reader is
referred to the Supporting Information for details of the
separation methods).
As reported in Scheme 2, a synthesis of R isomer 18
was accomplished to determine the absolute configura-
tion of the enantiomers of 3 (and related derivatives 4,
8), separated by chiral HPLC. Reaction of (R)-phenyl-
glycine with ethyl trifluoroacetate afforded the N-
trifluoroacetamide derivative24 (99% ee), which was then
converted to the corresponding acyl chloride with a
procedure that gives high retention of stereochemical
integrity.25 The acyl chloride was immediately used in

4222 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 13
Letters
Scheme 2a
derivatives 13, 24, and 25, respectively. On the basis of
the above remarks, in the present work, preliminary
structure-activity relationships shall only be discussed
for MAO-A inhibitors.
Amino derivative 1 showed potent and selective
activity against MAO-A enzyme (Ki(MAO-A) ) 0.095
µM, Ki(MAO-B) ) 42 µM, A-selectivity ) 442). It was
4- and 120-fold more potent than TOL and MCL,
respectively. Methylation of 1 gave the N,N-dimethyl-
amino derivative 2, which was less potent than the
parent compound. The presence of morpholine and
piperidine moieties in certain anti-MAO-A drugs cur-
rently in clinical use (MCL, bazinaprine, and bro-
faromine) induced us to replace the amino group of 1
with some six-membered cyclic amines. Piperazine and
morpholine gave derivatives 5-7 that had decreased
activity. In contrast, the piperidine and thiomorpholine
derivatives 4 and 8 were comparable to the lead
compound 1 and proved to be 3-10 times more potent
than 5-7. Insertion of phthalimide and ethoxyphenyl-
amine moieties at the 2-position of ethane chain led to
9 and 10, endowed with lower potencies if compared to
those of the alicyclic counterparts. Conversely, when the
NH2 group of 1 was replaced by a pyrrolidine ring, a
potent and highly selective MAO-A inhibitor (3) was
obtained.
In general, R isomers (18, 20, 22) were more active
than the parent racemates (3, 4, 8) and 2-10 times more
potent than the S counterparts (19, 21, 23). In particu-
lar, compound 18 showed the highest potency and
selectivity (Ki(MAO-A) ) 0.0035 µM, Ki(MAO-B) ) 700
µM, and A-selectivity ) 200000) among all test deriva-
tives. 18 was 3285 and 108 times more potent and 23000
and 5060 times more A-selective than MCL and TOL.
To determine the role of the ketone group in the
binding to biological target, we synthesized amino
alcohols 13-15, 24-27 related to piperidine derivative
4. Reduction of the ketone group of 4 produced four
diastereoisomers, 24, 25 (threo isomers), and 26 and 27
(erythro isomers), which were 5-570 times less potent
against MAO-A isoenzyme than the parent ketone 4.
Similar results were obtained when the ketone 11 was
reduced to the corresponding alcohol 15. In fact, an
abatement of anti-MAO-A and anti-MAO-B activities
was observed with a shift of A-selectivity from 2143 to
47. This led to conclude that the ketone group seems to
play a pivotal role in the tight binding with the MAO-A
isoenzyme.
a Reagents and conditions: (i) CF3COOC2H5, tetramethylguani-
dine, MeOH, room temp, 24 h, 93%; (ii) Vilsmeier reactive, n-butyl
acetate, -15 °C, 3 h; (iii) 1-methylpyrrole, AlCl3, CH2Cl2, -5 °C,
2 h, 13%; (iv) concentrated HCl, MeOH, 40 °C, 15 h, 80%; (v) 1,4-
dibromobutane, NaI, KHCO3, reflux, 12 h, 67%.
a Friedel-Crafts reaction with 1-methylpyrrole to achieve
protected amino ketone 28 (80% ee), which was then
deprotected in acidic medium to afford 29. Finally, 29
was alkylated with 1,4-dibromobutane in the presence
of NaI to give the required pyrrolidine 18 (the 80% ee
of the starting material 28 was nearly retained in the
last two steps). The designed R isomer 18 and the
related derivatives 20 and 22 were levorotatory, as well
as the intermediates 28 and 29. A similar procedure was
performed starting from (S)-phenylglycine to afford 19
via intermediates (S)-1-(1-methyl-1H-pyrrol-2-yl)-2-
phenyl-2-[N-(trifluoroacetyl)amino]ethanone (30) and
(S)-2-amino-1-(1-methyl-1H-pyrrol-2-yl)-2-phenyletha-
none (31) (for details, see Supporting Information).
Derivatives 1-15, 18-27 were tested on bovine brain
mitochondria isolated according to Basford,26 used as
the source of the two isoforms of MAO, in comparison
with moclobemide (MCL), toloxatone (TOL), and SEL
as reference drugs. MAO-A and MAO-B activities were
determined by a fluorometric assay, using kinuramine
as a substrate,27 in the presence of their specific inhibi-
tor (1 µM SEL to estimate the MAO-A activity, and 1
µM clorgyline to assay the isoform B). The Ki values
against the two isoforms and the A-selectivity (ex-
pressed as Ki(MAO-B)/Ki(MAO-A) ratio) are reported in
Table 1. All compounds act as reversible inhibitors. In
fact, 90-100% of enzyme activity was restored by
dialysis performed in a period of 24 h in a cold room
against 0.1 M potassium phosphate buffer (pH 7.2).
Enzymatic assays revealed that all test compounds
were weak MAO-B inhibitors, while potent activity
against MAO-A was observed at low micromolar or
submicromolar concentrations, with the sole exceptions
of 13, 24, and 25. This behavior could be ascribed to
the presence of a pyrrole ring in the structure of our
inhibitors. In fact, this electron-rich heterocycle could
enhance the affinity for the MAO-A isoenzyme, accord-
ing to literature data.15 Moreover, the inhibitor access
into the catalytic site of bovine MAO-B enzyme is
possibly hindered by Phe208, which replaces Ile208 of
the human enzyme.8 Noteworthy were the A-selectivity
values that ranged from 11 (6) to 200000 (18), with the
exception of 0.29, 0.31, and 0.18 values obtained for
It is worth noting that threo alcohols 13, 24, and 25
were the only selective MAO-B inhibitors reported in
the present work, with B-selectivity (Ki(MAO-A)/Ki-
(MAO-B) ratio) falling in the range 3-6. In particular,
25 (Ki ) 1.24 µM) was as active as SEL (Ki ) 0.97 µM)
but 7-fold less selective in inhibiting the MAO-B isoen-
zyme. The selective activity against MAO-B could be
ascribed to favorable interactions of the ethanolamine
moiety of threo isomers 13, 24, and 25 with the
hydrophilic region located between Tyr398 and Tyr435
or with Tyr326 of the MAO-B catalytic cavity.7,8 On the
other hand, the lower anti-MAO-B potency of erythro
diastereoisomers 14, 26, and 27 is probably due to
different interactions of the aromatic groups with the
biological target. At last, the low potency of 15 against
MAO-B could be reasonably attributed to the lack of a

Letters
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 13 4223
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phenyl group, which causes a decrease of inhibitor
lipophilicity.
In summary, the present work describes the first
report on the identification of PEAs as a novel class of
potent and highly selective MAO-A inhibitors. To our
knowledge, PEAs are the first aminoketone derivatives
described as inhibitors of MAO enzymes. Among the test
derivatives, 18 showed the highest potency against
MAO-A, with the A-selectivity value much higher than
those of MCL and TOL, two clinical agents used as
reference drugs. This result can be regarded as an
important discovery that might be applied as a future
therapeutic application. In addition, this finding lends
support to expanding the chemical and biological search
for novel selective inhibitors of MAO-A enzyme to other
pyrrolylethanoneamines. Furthermore, pyrrolylethanol-
amine 25 was proven to exert significant inhibitory
activity against the MAO-B isoenzyme and can be
considered suitable as a lead compound in the search
for novel potent and selective MAO-B inhibitors. We are
currently expanding our SAR studies on arylethanone-
amines and arylethanoleamines to establish the obser-
vations that the electron-rich aromatic ring and the
ketone function play a role in determining the selectivity
against the MAO-A isozyme. These studies will be
extended to different structural classes of inhibitors
containing electron-rich aromatic moieties and carbonyl
groups, providing useful information for the rational
design of potent MAO-A inhibitors. We will report the
results of our expanded SAR studies in the near future.
Acknowledgment. The authors thank the Italian
MIUR (Ministero dell’Istruzione, dell’Universita` e della
Ricerca), the Ministero della Salute (1% Fondo Sanitario
Nazionale), and the MIUR-PRIN 2003 for partial sup-
port.
Supporting Information Available: Experimental pro-
cedures and characterization data for intermediates 16, 17 and
final compounds 11-15, details on stereoselective syntheses
of 18 and 19 and HPLC separations, and description of
biochemical assays. This material is available free of charge
via the Internet at http://pubs.acs.org.
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