Novel reversible monoamine oxidase A inhibitors: Highly potent and selective 3-(1 H-pyrrol-3-yl)-2-oxazolidinones

Article abstract of DOI:10.1021/jm201011x

Monoamine oxidases (MAOs) are involved in various psychiatric and neurodegenerative disorders; hence, MAO inhibitors are useful agents in the therapy of Parkinson's disease, Alzheimer's dementia, and depression syndrome. Herein we report a novel series of 3-(1H-pyrrol-3-yl)-2-oxazolidinones 3-7 as reversible, highly potent and selective anti-MAO-A agents. In particular, 4b, 5b, and 4c showed a K_i-MAO-A of 0.6, 0.8, and 1 nM, respectively, 4c being 200000-fold selective for MAO-A with respect to MAO-B.

Full text of DOI:10.1021/jm201011x

Brief Article
pubs.acs.org/jmc
Novel Reversible Monoamine Oxidase A Inhibitors: Highly Potent
and Selective 3-(1H-Pyrrol-3-yl)-2-oxazolidinones
Sergio Valente,† Stefano Tomassi,† Giampiero Tempera,‡ Stefania Saccoccio,‡ Enzo Agostinelli,*,‡
and Antonello Mai*,†
†Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur, Fondazione Cenci Bolognetti, Sapienza Universita
Piazzale Aldo Moro 5, 00185 Roma, Italy
̀
di Roma,
‡Dipartimento di Scienze Biochimiche Rossi-Fanelli and Istituto di Biologia e Patologia Molecolare del CNR, Istituto Pasteur,
̀
Fondazione Cenci Bolognetti, Sapienza Universita di Roma, Piazzale Aldo Moro 5, 00185 Roma, Italy
S
* Supporting Information
ABSTRACT: Monoamine oxidases (MAOs) are involved in various psychiatric and neurodegenerative disorders; hence, MAO
inhibitors are useful agents in the therapy of Parkinson’s disease, Alzheimer’s dementia, and depression syndrome. Herein we
report a novel series of 3-(1H-pyrrol-3-yl)-2-oxazolidinones 3−7 as reversible, highly potent and selective anti-MAO-A agents. In
particular, 4b, 5b, and 4c showed a Ki‑MAO‑A of 0.6, 0.8, and 1 nM, respectively, 4c being 200000-fold selective for MAO-A with
respect to MAO-B.
safinamide, Chart S1). Recent reversible MAO-A inhibitors
include amifuraline,14 a selective peripheral inhibitor, and
CX157,15 specific for inhibition of MAO-A in human brain.
Against MAO-B PF9601N,16 endowed with antioxidant/neuro-
protective properties in an experimental model of PD, and
M-30,17 a brain selective agent with antioxidant and neuro-
protective properties for Alzheimer’s disease, have been reported.
In addition to neurological disorders, MAO-A seems to play a
role in cardiac cellular degeneration18 and high expression of
MAO-A in normal basal prostatic epithelium, and high-grade
primary prostate cancer (PCa) has been identified. Moreover,
clorgyline has been shown to inhibit several oncogenic pathways
in PCa cells, suggesting MAO-A inhibitors as prodifferentiation
and antioncogenic agents for high-risk PCa.19 Phenelzine directly
and potently inhibits adipocyte lipid storage and differentiation,20
while selegiline was a potent inducer for bone marrow stromal
cell differentiation into neuronal phenotype.21 Finally, MAO-A
and -B are the major enzyme systems involved in vivo in the
oxidative metabolism of xenobiotic amines, drugs in particular.22
Toloxatone (Humoryl), characterized by the presence of the
oxazolidin-2-one as a core structure, was the first reversible and
selective MAO-A inhibitor introduced in the clinical practice as
antidepressant agent. Between 2002 and 2005, we reported a
new series of 3-(1H-pyrrol-1-yl)-2-oxazolidinones (1) active as
reversible, potent, and MAO-A selective inhibitors23,24 (Figure 1)
and the 3-(1H-pyrrol-2-yl)-2-oxazolidinone derivatives (2),25 in
which the 2-oxazolidinone nucleus was inserted at the C2 posi-
tion of the pyrrole.
INTRODUCTION
■
Mitochondrial monoamine oxidases (MAOs, EC 1.4.3.4) are
primarily involved in the metabolism of the biogenic mono-
amines. They catalyze the oxidative deamination of structurally
different amines including the neurotransmitters dopamine,
norepinephrine, serotonin (5-HT), tyramine, 2-phenethylamine
(PEA), and exogenous arylalkylamines.1,2 The electron acceptor
of the reaction is O2, which is converted to H2O2 by the
enzymes. MAOs are flavin adenine dinucleotide (FAD)
containing enzymes located in the outer mitochondrial
membrane of neuronal, glial, and other cells. Two different
isoenzymatic forms have been identified, MAO-A and MAO-B,
and are distinguishable by their differences in their amino acids
sequences,3 three-dimensional structures,4−8 substrate specific-
ity, and sensitivity to inhibitors.9 MAO-A preferentially
catalyzes the oxidation of 5-HT and norepinephrine, and it is
selectively inhibited by clorgyline, whereas MAO-B catalyzes
the oxidation of PEA and benzylamine, and it is selectively
inhibited by selegiline (l-deprenyl) and rasagiline.10 Tyramine
and tryptamine appear to be substrates for both isoforms. Most
human tissues express both isoenzyme, nevertheless blood
platelets and myocardium are particularly rich in MAO-B, while
high levels of MAO-A are detected in the human placenta, lung,
and small intestine.11
Isoenzyme A occurs in catecholaminergic neurons, whereas
isoenzyme B is mainly present in neurons and glial cells of the
human brain and also in other different cell types. The different
localization suggests that the two subtypes have different
physiological functions. In fact, MAO-A and -B are probably
related to psychiatric and neurological disorders such as
depression and Parkinson’s disease (PD), respectively.12 Several
selective and reversible MAO-A inhibitors13 have been described
as antidepressants (i.e., moclobemide, brofaromine, toloxatone,
Chart S1 in Supporting Information), and selective and
reversible/irreversible MAO-B inhibitors have been shown as
useful in the treatment of PD (i.e., rasagiline, lazabemide,
As a logical succession, we have now investigated the C3
position of the pyrrole, and we planned the synthesis of the
3-(1H-pyrrol-3-yl)-2-oxazolidinone derivatives 3−7, shifting
the 2-oxazolidinone nucleus at the pyrrole C3 position and
introducing at the pyrrole N1 position three different alkyl
Received: September 11, 2011
Published: October 21, 2011
© 2011 American Chemical Society
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Journal of Medicinal Chemistry
Brief Article
a
groups (Figure 1), obtaining compounds active up to sub-
nanomolar concentration.
Scheme 1
Figure 1. 1H-Pyrrolyl-2-oxazolidinones series.
a
(a) (1) KOH, DMSO, room temp, 30 min; (2) X3-I or X3-Br, room
temp, 1 h; (b) AgNO3, NaOH, methanol, 70 °C or KMnO4,
2-propanone/H2O, room temp, overnight; (c) (1) (PhO)2PON3,
Et3N, benzene, 80 °C; (2) PhCH2OH, benzene, 80 °C, overnight; (d)
(1) n-BuLi, THF, N2, −78 °C, 30 min; (2) (R)-glycidyl butyrate, N2, 1
h, −78 °C, overnight at room temp; (e) CH3SO2Cl, Et3N, CH2Cl2,
15 min; (f) NaN3, DMF, N2, 65 °C, overnight; (g) H2, Pd/C, 1 h,
room temp; (h) CH3ONa, MeOH, N2, room temp, overnight; (i)
CH3NH2, THF, 80 °C, sealed tube, overnight.
CHEMISTRY
■
1-Alkyl-1H-pyrrole-3-carboxaldehydes 8a−c, key intermediates
for the synthesis of title compounds, were obtained by
alkylation of 1H-pyrrole-3-carboxaldehyde26 with the proper
alkyl halide using potassium hydroxide as a base in
dimethylsulfoxide. Afterward, 1-alkyl-1H-pyrrole-3-carboxylic
acids 9a−c were prepared by oxidation of the aldehydes
8a−c with silver nitrate and 6 N sodium hydroxide in methanol
or with potassium permanganate in water/2-propanone. After
treatment with diphenylphosphorylazide, triethylamine, and
benzyl alcohol in benzene at 80 °C, the carboxylic acids 9a−c
afforded the 1-alkyl-3-benzyloxycarbonylamino-1H-pyrroles
10a−c through Curtius rearrangement of the intermediate
acylazides. Further reaction of 10a−c with n-butyllithium in
hexane at −78 °C followed by addition of (R)-glycidyl butyrate
to the lithiated species furnished directly, after spontaneous
hydrolysis of the butyrate function, the (R)-5-hydroxymethyl-3-
(1-alkyl-1H-pyrrol-3-yl)-2-oxazolidinones 3a−c.
the enzyme source and were isolated according to Basford.28
Activities of MAO-A and MAO-B have been determined by a
fluorimetric method with kynuramine as a substrate at several
different concentrations.29 The Ki values against the two MAO
isozymes and the A-selectivity (expressed as Ki‑MAO‑B/Ki‑MAO‑A
)
are reported in Table 1. All tested compounds showed higher
Table 1. Monoamine Oxidase Inhibitory Activity of Com-
a
pounds 3−7
The alcohols 3a−c were then converted into the
corresponding (R)-5-methanesulfonyloxymethyl derivatives
11a−c with methanesulfonyl chloride and triethylamine, and
the mesylates 11a−c were subjected to nucleophilic displace-
ment with sodium methoxide in methanol (room temperature)
or with sodium azide in N,N-dimethylformamide (65 °C) or
methylamine in tetrahydrofuran (65 °C) to afford the (R)-5-
methoxymethyl-, the (R)-5-azidomethyl-, or the (S)-5-methyl-
aminomethyl-3-(1-alkyl-1H-pyrrol-3-yl)-2-oxazolidinones
4a−c, 5a−c, or 7a−c, respectively. From the (R)-5-azidomethyl
derivatives 5a−c, the corresponding aminomethyl compounds
6a−c have been obtained by catalytic reduction (Scheme 1).
Chemical and physical data for 3−7 and 8−11 are listed in
Tables S1 and S2 of Supporting Information. Synthetic
procedures for the synthesis of 3, 4, and 6 are reported
below. Synthetic procedures for the synthesis of 5 and 7−11
are reported in Supporting Information.
Ki, μM
c
compd
X3
R3
OH
MAO-A MAO-B
SI
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
7a
7b
7c
methyl
ethyl
allyl
1
>10
0.3
625
170
1.3
200
360
20
>10
OH
0.003
0.35
0.3
100
OH
1786
567
methyl
ethyl
allyl
OCH3
OCH3
OCH3
N3
0.0006
0.001
0.2
2167
200000
1800
25000
25000
18000
192
methyl
ethyl
allyl
N3
0.0008
0.004
0.01
0.13
0.7
N3
100
180
25
methyl
ethyl
allyl
NH2
NH2
NH2
8
11
methyl
ethyl
allyl
NHCH3
NHCH3
NHCH3
0.007
0.08
0.1
>100
18
>14286
225
2
20
toloxatone
befloxatone
0.38
0.0025
15
40
b
RESULTS AND DISCUSSION
0.22
88
■
a
3-(1H-Pyrrol-3-yl)-2-oxazolidinones 3−7 have been tested
against MAO-A and MAO-B enzymes, in comparison with
toloxatone as a reference drug. Inhibitory data of befloxatone,27
a more recent oxazolidinone anti-MAO, have been also added
for comparison. Bovine brain mitochondria have been used as
Data represent mean values of at least three separate experiments.
Reference 27. Selectivity index SI = Ki(MAO-B)/Ki(MAO-A).
b
c
anti-MAO-A than -MAO-B activity. Moreover, all derivatives
displayed a reversible mode of action, since dialysis for 24 h in a
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Journal of Medicinal Chemistry
Brief Article
to determine purity of the described compounds, that is >95%.
Analytical results are within ±0.40% of the theoretical values (see
Table S3 in Supporting Information). All chemicals were purchased
from Aldrich Chimica, Milan (Italy), or from Alfa Aesar, Milan (Italy),
and were of the highest purity.
cold room against 0.1 M potassium phosphate buffer (pH 7.2)
was able to restore 90−100% of the enzyme activity.
In the alcoholic series (3a−c), the MAO-A inhibitory activity
depends on the substituent at the pyrrole N1 position. In fact,
when we changed the methyl or allyl group with the ethyl one,
General Procedure for the Synthesis of (R)-5-Hydroxymeth-
yl-3-(1-alkyl-1H-pyrrol-3-yl)-2-oxazolidinones (3a−c). Example:
Synthesis of (R)-5-Hydroxymethyl-3-(1-ethyl-1H-pyrrol-3-yl)-2-
oxazolidinone (3b). n-Butyllithium (2.5 M in hexane, 3.3 mmol,
1.32 mL) was added dropwise, over a period of 5 min, under nitrogen
atmosphere at −78 °C to a solution of 1-ethyl-1H-2-benzyloxycarbo-
nylaminopyrrole 10b (3.24 mmol, 0.79 g) in dry THF (10 mL). The
mixture was stirred at −78 °C for 1 h. Then it was followed by
addition of (R)-glycidyl butyrate (3.3 mmol, 0.47 mL). The resulting
mixture was stirred initially at −78 °C for 1 h, and then it was kept at
room temperature overnight. Afterward, the reaction was quenched by
addition of saturated ammonium chloride solution (100 mL) and
extracted with ethyl acetate (3 × 50 mL). The combined organic
extracts were washed with water (100 mL) and brine (100 mL) and
dried. The residue obtained upon evaporation of solvent was
chromatographed over silica gel by eluting with ethyl acetate to give
the inhibiting activity shifted from micromolar (3a, Ki‑MAO‑A
1 μM; 3c, Ki‑MAO‑A = 0.35 μM) to nanomolar level (3b, Ki‑MAO‑A
= 3 nM).
=
The 5-methoxymethyl derivatives 4a−c showed an anti-
MAO-A activity increasing from low micromolar to sub-
nanomolar range (4a, Ki‑MAO‑A = 0.3 μM; 4c, Ki‑MAO‑A = 1 nM;
4b, 0.6 nM). Even in this series the ethyl group at the pyrrole
N1 position was the most efficient substituent, despite the fact
that the pyrrole N1-allyl derivative 4c showed the highest
MAO-A selectivity ratio (200000).
Among the azides 5a−c, the 5-azidomethyl-3-(1-ethyl-1H-
pyrrol-3-yl)-2-oxazolidinone (5b, Ki‑MAO‑A = 0.8 nM) was
almost as active as 4b against MAO-A, while its MAO-B
inhibitory concentration is 25000-fold higher than MAO-B.
This series showed an activity trend similar to that of the
5-hydroxymethyl and 5-methoxymethyl series (N1-substituents
potency degree: ethyl > allyl > methyl). In the 5-aminomethyl
series 6a−c, the compounds were endowed with a moderate
inhibitory activity and MAO-A selectivity, they being active in
the low micromolar range, with the exception of the pyrrole
N1-methyl derivative 6a that showed Ki‑MAO‑A = 10 nM and
SI = 18000.
Finally, the 5-methylaminomethyl compounds 7a−c showed
an inversion of the reported structure−activity relationship: an
increase in the size of the pyrrole N1-substituent produced less
active and selective derivatives (7a, Ki‑MAOA = 7 nM, Ki‑MAOB
100 μM, SI ≥ 14286; 7c, Ki‑MAOA = 0.1 μM, Ki‑MAOB = 2 μM,
SI = 20).
In conclusion, we have reported a novel series of 5-sub-
stituted 3-(1-alkyl-1H-pyrrol-3-yl)-2-oxazolidinones 3−7 as
reversible, highly potent, and selective anti-MAO-A agents.
Compared to the related 3-(1H-pyrrol-1-yl)- and 3-(1H-pyrrol-
2-yl)-2-oxazolidinones 1 and 2,23,25 3−7 were in general more
efficient in inhibiting MAO-A: the most potent derivatives 4b
and 5b are about 5-fold more effective than the best-scoring
compounds of the 1 and 2 series, and the unique SI shown by
4c (200000) is about 20-fold higher than those displayed by the
best compounds of 1 and 2. With respect to toloxatone, 4b, 4c,
and 5b show 633-, 380-, and 475-fold higher MAO-A inhibitory
activity, respectively. In comparison with befloxatone, 4b, 4c,
and 5b present similar anti-MAO-A activity but increased
A-selectivity ratio. Such results suggest that these compounds
could be useful as novel promising antidepressant agents.
1
the alcohol 3b. H NMR (CDCl3) δ 1.42 (t, 3H, CH2CH3), 2.73 (bs,
1H, OH exchangeable with D2O), 3.73−3.82 (m, 2H, NCH2), 3.87−
3.96 (m, 4H, CH2OH and CH2CH3), 4.74 (m, 1H, OCH), 6.07 (m,
1H, pyrrole α proton), 6.56 (m, 1H, pyrrole β proton), 6.92 (m, 1H,
pyrrole α proton) ppm. 13C NMR (CDCl3) δ 15.60, 47.0, 47.80, 62.30,
84.80, 103.60, 117.10, 121.80, 122.80, 153.0 ppm. MS (EI), m/z [M]+:
210.1004.
General Procedure for the Synthesis of (R)-5-Methoxymeth-
yl-3-(1-alkyl-1H-pyrrol-3-yl)-2-oxazolidinones (4a−c). Example:
Synthesis of (R)-5-Methoxymethyl-3-(1-ethyl-1H -pyrrol-3-yl)-
2-oxazolidinone (4b). A solution of sodium metal (3.43 mmol,
0.079 g atom) in methanol (5 mL) was added to (R)-5-
methanesulfonyloxymethyl-3-(1-ethyl-1H-pyrrol-3-yl)-2-oxazolidinone
11b (0.86 mmol, 0.25 g) in methanol (5 mL), and the resulting
mixture was stirred under nitrogen atmosphere at room temperature
overnight. The reaction was quenched with water and extracted with
ethyl acetate (3 × 50 mL). The combined organic extracts were
washed with water (100 mL) and brine (100 mL) and dried. The
residue obtained upon evaporation of solvent was purified by column
chromatography (silica gel, ethyl acetate/chloroform 1:1) to give the
>
1
methoxymethyl derivative 4b as a pure oil. H NMR (CDCl3) δ 1.40
(t, 3H, CH2CH3), 3.42 (s, 1H, OCH3), 3.59−3.61 (m, 2H, NCH2 and
CH2O), 3.72−3.76 (m, 1H, NCH2), 3.85−3.94 (m, 3H, CH2CH3 and
CH2O), 4.69−4.76 (m, 1H, OCH), 6.05 (m, 1H, pyrrole β proton),
6.54 (m, 1H, pyrrole α proton), 6.91 (m, 1H, pyrrole α proton). 13C
NMR (CDCl3) δ 15.60, 47.0, 52.20, 55.10, 103.60, 113.10, 117.10,
121.80, 122.80, 153.0 ppm. MS (EI), m/z [M]+: 210.1004.
General Procedure for the Synthesis of (S)-5-Aminomethyl-
3-(1-alkyl-1H-pyrrol-3-yl)-2-oxazolidinones (6a−c). Example:
Synthesis of (S)-5-Aminomethyl-3-(1-ethyl-1H-pyrrol-3-yl)-2-
oxazolidinone (6b). A suspension of (R)-5-azidomethyl-3-(1-ethyl-
1H-pyrrol-3-yl)-2-oxazolidinone 5b (2.38 mmol, 0.56 g), methanol
(60 mL), and palladium on 10% carbon placed in a Parr apparatus was
hydrogenated at 50 psi and 25 °C for 1 h. At last, palladium was
filtered and methanol was evaporated to afford an oily residue that was
chromatographed over silica gel by eluting with 9:1 chloroform/
EXPERIMENTAL SECTION
■
1
Chemistry. Melting points were determined on a Buchi 530
methanol to provide the amine derivative 6b as a pure oil. H NMR
melting point apparatus and are uncorrected. H NMR and 13C NMR
1
(CDCl3) δ 1.90 (bs, 2H, NH2 exchangeable with D2O), 2.83−2.96 (m,
2H, CH2NH2), 3.61−3.69 (m, 1H, NCH2), 3.85−3.94 (m, 3H, NCH2
and CH2CH3), 4.52−4.67 (m, 1H, OCH), 6.36 (m, 1H, pyrrole β
proton), 6.86 (m, 1H, pyrrole α proton), 7.08−7.30 (m, 1H, pyrrole α
proton) ppm. 13C NMR (CDCl3) δ 15.60, 43.80, 47.0, 48.90, 87.0,
103.60, 117.1, 121.80, 122.80, 153.0 ppm. MS (EI), m/z [M]+:
209.1164.
Mitochondria Preparation. See Supporting Information.
Biochemical Assay. All chemicals were commercial reagents of
analytical grade and were used without further purification. In all
experiments, MAO activity of the beef brain mitochondria was
determined by a sensitive fluorimetric method according to
Matsumoto et al.,29 using kynuramine as a substrate at four different
spectra were recorded at 400 MHz on a Bruker AC 400 spectrometer.
Chemical shifts are reported in δ (ppm) units relative to the internal
reference tetramethylsilane (Me4Si). EIMS spectra were recorded with
a Fisons Trio 1000 spectrometer; only molecular ions (M+) and base
peaks are given. All compounds were routinely checked by TLC and
1H NMR. TLC was performed on aluminum-backed silica gel plates
(Merck DC, Alufolien Kieselgel 60 F254) with spots visualized by UV
light. All solvents were reagent grade and, when necessary, were
purified and dried by standard methods. Concentration of solutions
after reactions and extractions involved the use of a rotary evaporator
operating at reduced pressure of ∼20 Torr. Organic solutions were
dried over anhydrous sodium sulfate. Elemental analysis has been used
8230
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Journal of Medicinal Chemistry
Brief Article
final concentrations ranging from 5 μM to 0.1 mM. In all assays, the
incubation mixtures contained 0.1 mL of 0.25 M potassium phosphate
buffer at pH 7.4, 30 μL of mitochondria (from a homogenate solution,
6 mg/mL), and drug solutions. Drug derivatives were dissolved in
dimethylsulfoxide (DMSO), and then added to the reaction mixture,
at final concentrations ranging from 0 to 10−3 μM. The solutions were
preincubated for 30 min at 38 °C before adding the substrate and then
incubated for other 30 min at the same temperature. The inhibitory
activities on MAO-A and -B were separately determined after
incubation of the mitochondrial fractions for 30 min at 38 °C in the
presence of their specific inhibitors (1 μM L-deprenyl to estimate
MAO A activity and 1 μM clorgyline to assay the B isoform). Addition
of perchloric acid ended the reaction. The samples were then
centrifuged at 10000g for 5 min, and the supernatant was added to
2.7 mL of 0.1 N NaOH. Fluorometric measurements were recorded
with a Perkin-Elmer LS 50B spectrofluorimeter, at λexc = 317 nm and
λem = 393 nm. The protein concentration was determined according
to Goa. Dixon plots were used to estimate the inhibition constant (Ki)
of the inhibitors. Data represent the mean of three or more
experiments each performed in duplicate.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Chemical and physical data for 3−11 and general procedures
for the synthesis of 5 and 7−11. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*For E.A.: phone, +3906-4991-0838; fax, +3906-4440062; e-
mail, enzo.agostinelli@uniroma1.it. For A.M.: phone, +3906-
4991-3392; fax, +3906-49693268; e-mail, antonello.mai@
uniroma1.it.
ACKNOWLEDGMENTS
■
This work was partially supported by the Italian MIUR
(Ministero dell’Istruzione, dell’Universita
̀
e della Ricerca), by
“Project Italy-USA”, by Istituto
Istituto Superiore di Sanita
̀
Pasteur-Fondazione Cenci Bolognetti, and by funds from
MIUR-PRIN (Cofin). Thanks are due to Fondazione “Enrico
ed Enrica Sovena” for the scholarship given to S.S. for
supporting her Ph.D.
ABBREVIATIONS USED
■
MAO, monoamine oxidase; 5-HT, 5-hydroxytryptamine; PEA,
2-phenethylamine; FAD, flavin adenine dinucleotide; ROS,
reactive oxygen species; DNA, deoxyribonucleic acid; PCa,
prostate cancer; MAOI, monoamine oxidase inhibitor; PD,
Parkinson’s disease; EDTA, ethylenediaminetetraacetic acid;
PES, polyethersulfone
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