Synthesis and biological evaluation of enantiomerically pure pyrrolyloxazolidinones as a new class of potent and selective monoamine oxidase type A inhibitors

Article abstract of DOI:10.1016/S0014-827X(03)00016-8

Due to the key role played by monoamine oxidases (MAOs) in the metabolism of neurotransmitters, MAO inhibitors (MAOIs) represent an useful tool for the treatment of several neurological diseases. Among selective MAOIs, MAO-A inhibitors (e.g. clorgyline) are used as antidepressant and antianxiety drugs and are claimed to protect neuronal cells against apoptosis, and selective MAO-B inhibitors (e.g. L-deprenyl) can be used in the treatment of Parkinson's disease either alone or in combination with L-DOPA. However, they engender covalent bonds with the active site of the enzyme and induce irreversible inhibition; moreover, they tend to lose their initial selectivity at high dosages or with repeated administrations. Phenyloxazolidinones belong to third-generation-MAOIs, characterized by a selective and reversible inhibition of the enzyme. Among these molecules, the most representative are toloxatone and befloxatone, two selective and reversible MAO-A inhibitors used in therapy as antidepressant drugs. Going on our searches on CNS potentially active compounds containing a pyrrole moiety we prepared 3-(1H-pyrrol-1-yl)-2-oxazolidinones (1) and isomeric 3-(1H-pyrrol-2-and -3-yl)-2-oxazolidinones (2 and 3) as anti-MAO agents. Such derivatives resulted selective and reversible MAO-A inhibitors. The most potent compound is (R)-5-methoxymethyl-3-(1H-pyrrol-1-yl)-2-oxazolidinone (1b), endowed with very high potency (K_iMAO-A=4.9 nM) and A-selectivity (A-selectivity=10,200, about 116-fold greater than that of befloxatone).

Full text of DOI:10.1016/S0014-827X(03)00016-8

Il Farmaco 58 (2003) 231Á241
/
www.elsevier.com/locate/farmac
Synthesis and biological evaluation of enantiomerically pure pyrrolyl-
oxazolidinones as a new class of potent and selective monoamine
oxidase type A inhibitors
A. Mai a,*, Marino Artico a, M. Esposito a, R. Ragno b, G. Sbardella c, S. Massa d
a Dipartimento Studi Farmaceutici, Universita` degli Studi di Roma ‘La Sapienza’, P.le A. Moro 5, 00185 Rome, Italy
b Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Universita` degli Studi di Roma ‘La Sapienza’, P.le A. Moro 5,
00185 Rome, Italy
c Dipartimento di Scienze Farmaceutiche, Universita` degli Studi di Salerno, via Ponte Don Melillo, 84084 Fisciano (SA), Italy
d Dipartimento Farmaco Chimico Tecnologico, Universita` degli Studi di Siena, via Aldo Moro, 53100 Siena, Italy
Accepted 24 July 2002
Abstract
Due to the key role played by monoamine oxidases (MAOs) in the metabolism of neurotransmitters, MAO inhibitors (MAOIs)
represent an useful tool for the treatment of several neurological diseases. Among selective MAOIs, MAO-A inhibitors (e.g.
clorgyline) are used as antidepressant and antianxiety drugs and are claimed to protect neuronal cells against apoptosis, and selective
MAO-B inhibitors (e.g. L-deprenyl) can be used in the treatment of Parkinson’s disease either alone or in combination with L-
DOPA. However, they engender covalent bonds with the active site of the enzyme and induce irreversible inhibition; moreover, they
tend to lose their initial selectivity at high dosages or with repeated administrations. Phenyloxazolidinones belong to third-
generation-MAOIs, characterized by a selective and reversible inhibition of the enzyme. Among these molecules, the most
representative are toloxatone and befloxatone, two selective and reversible MAO-A inhibitors used in therapy as antidepressant
drugs. Going on our searches on CNS potentially active compounds containing a pyrrole moiety we prepared 3-(1H-pyrrol-1-yl)-2-
oxazolidinones (1) and isomeric 3-(1H-pyrrol-2-and -3-yl)-2-oxazolidinones (2 and 3) as anti-MAO agents. Such derivatives resulted
selective and reversible MAO-A inhibitors. The most potent compound is (R)-5-methoxymethyl-3-(1H-pyrrol-1-yl)-2-oxazolidinone
(1b), endowed with very high potency (KiMAO-A
of befloxatone).
´
ꢀ
/
4.9 nM) and A-selectivity (A-selectivityꢀ10,200, about 116-fold greater than that
/
# 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: MAO; MAO inhibitors; Oxazolidinones; Antimycobacterial agents
1. Introduction
phenyl-1,2,3,6-tetrahydropyridine (MPTP) into 1-meth-
yl-4-phenylpyridinium (MPPꢁ), a Parkinson producing
Monoamine oxidase (MAO, EC 1.4.3.4) is a flavo-
protein located at the outer membranes of mitochondria
in neuronal, glial, and other cells. It catalyses the
oxidative deamination of monoamine neurotransmitters
such as serotonin (5-hydroxytryptamine, 5-HT), nore-
pinephrine, and dopamine, and appears to play impor-
tant roles in several psychiatric and neurological
disorders [1,2] (Figs. 1 and 2). In addition, it is also
responsible for the biotransformation of 1-methyl-4-
neurotoxin [3Á5]. Recently, it has been shown that
/
MAO contributes to the apoptotic process because
inhibition of MAO activity suppresses cell death [6].
MAO exists in two forms, namely, MAO-A and
MAO-B, distinguishable by their molecular cloning,
substrate and inhibitor selectivity, and tissue distribu-
tion [7Á10]. MAO-A preferentially oxidizes serotonin
/
and is irreversibly inhibited by low concentrations of
clorgyline [8]. MAO-B preferentially oxidizes b-pheny-
lethylamine (PEA) and benzylamine, and it is irrever-
sibly inactivated by low concentrations of L-deprenyl
[11]. Dopamine, tyramine, and tryptamine are common
* Corresponding author.
E-mail address: antonello.mai@uniroma1.it (A. Mai).
´
0014-827X/03/$ - see front matter # 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
doi:10.1016/S0014-827X(03)00016-8

232
A. Mai et al. / Il Farmaco 58 (2003) 231Á241
/
Fig. 1. Oxidative deamination catalysed by monoamine oxidase (MAO) enzymes.
intron organization, and they are probably derived from
the duplication of a common ancestral gene [16]. When
the MAO-A gene is deficient in humans [17] and mice
[18] higher 5-HT and norepinephrine levels and a
phenotype characterized by increased aggressive beha-
vior is observed. Disruption of the MAO-B gene in mice
results in increased PEA but not 5-HT, norepinephrine,
or dopamine and confers a resistance to the Parkinson-
ism-inducing toxin MPTP [5] (Tables 1 and 2).
Due to the key role played by the two MAO forms in
the metabolism of monoamine neurotransmitters, MAO
inhibitors (MAOIs) can represent an useful tool for
treatment of several neurological diseases. MAOIs such
as phenelzine, tranylcypromine and isocarboxazid were
introduced in psychiatry during the late 1950s and were
the first of many antidepressants (ADs) to enter the
clinical medicine (Fig. 4). However, their use became
limited, to the profit of tricyclic ADs, as they were found
to induce severe food (tyramine rich/cheese effect) and
drug interactions.
Fig. 2. Simplified scheme of the reaction catalyzed by MAOs.
substrates for both MAOs. MAO-A and MAO-B
consist of 527 and 520 amino acids, respectively, and
have a 70% amino acid identity [7]. Each isoenzyme has
a FAD moiety covalently linked to a cysteine residue,
Cys406 (MAO-A) or Cys397 (MAO-B), through an 8a-
cysteinyl-riboflavin (Fig. 3) [12Á
/
15]. They are closely
linked to the X-chromosome and exibit identical exonÁ
/
A second generation of MAOIs emerged with the
discovery of selective inhibitors of the A and B forms of
the enzyme. Since 5-HT and norepinephrine are pre-
ferentially deaminated by MAO-A and since dopamine
and tyramine are substrates of both forms, selective
MAOIs opened new frontiers for the use of MAOIs as
antidepressants (Fig. 4). They should result more
selective in terms of both target symptoms and adverse
reactions than the earlier drugs and, compared with
Fig. 3. Chemical structure of flavin-adenin diphosphate (FAD)
covalently bound to a cysteine of the FAD-peptide in human MAO-
A and MAO-B.

A. Mai et al. / Il Farmaco 58 (2003) 231Á
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233
Table 1
Concentration of MAO-A and MAO-B in membrane preparations from various brain areas, extracerebral tissues and cell lines
MAO-A (pmol/mg)
MAO-B (pmol/mg)
MAO-A/MAO-B ratio
Human
Frontal cortex
Hypothalamus
Substantia nigra
Raphe
2.69
/
0.4
7.19
17.89
13.39
20.79
20.79
5.69
0.89
6.99
3.19
/
2.0
5.1
3.0
5.8
5.8
1.6
0.3
0.3
0.3
0.37
0.29
5.29
/
1.0
/
2.49
3.49
3.49
2.59
/
0.2
0.8
0.8
0.4
/
0.18
0.16
/
/
Hippocampus
Cerebellum
Placenta
/
/
0.16
0.45
/
/
101.79
nd
9.49
/
36.5
/
126.00
Platelets
/
a
Hep G2
/0.5
/
3.30
Rat
Frontal cortex
Cerebellum
PC 12b
12.29
3.09
13.09
12.29
/
0.4
0.4
0.9
0.4
2.99
2.29
nd
22.99
/
0.3
4.20
1.40
/
/
0.4
/
Liver
/
/
2.4
0.53
ND: not detected.
a
Human hepatoma epithelial-like cell line.
Rat pheochromocytoma cell line.
b
sion), severe hypertensive reactions and sexual distur-
bances [23,24].
Table 2
Favoured substrates of cerebral MAO-A (A) and MAO-B (B)
During the 1980s a third generation of MAOIs
appeared: the reversible and selective inhibitors, which
from theoretical considerations were expected to have
higher selectivity over a wide dose range and during
chronic use, thereby inducing minimal adverse side
effects.
Reported reversible MAOIs belong to the morpholino
[25], piperidino [26], 2-aminoethylcarboxamide [27], and
2-oxazolidinone series [28] (Fig. 5). Toloxatone
(Humoryl†), a new antidepressant agent marketed in
France in 1985, is the prototype of 3-phenyl-2-oxazoli-
dinones, a class of MAOIs highly active mainly against
Substrate
In vivo
In vitro
Man
Rat
5-Hydroxytryptamine
Norepinephrine
Epinephrine
A
A
A
A
A
B
A
A (B)
A
Aꢁ
Aꢁ
Aꢁ
/B
/B
Dopamine
2-Phenylethylamine
Tyraminea
MPTPb
B (A)
B
/B
B
Aꢁ
/
B
Aꢁ
/
B
AꢁB
/
B
B
B
a
Exogenous tyramine is mainly metabolized by MAO-A in the
intestinal tract.
b
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
the A isoform of the enzyme [29Á32]. Chemical mod-
/
ifications performed on toloxatone have led to cimox-
atone and, more recently, befloxatone, an anti-MAO
agent active at nanomolar range and more A-selective
than toloxatone (Fig. 5) [33,34]. However, such chemical
manipulations have regarded the substituent(s) located
on the phenyl ring at the N3 position or at the C5
methylene group of the 2-oxazolidinone ring, while little
or no attention has been devoted to the replacement of
phenyl with heteroaromatic rings [35].
tricyclic ADs, they appeared to have a wide spectrum of
action that included the relief of anxiety disorders [19].
Among selective MAOIs, MAO-A inhibitors (e.g. clor-
gyline [8]) are used as antidepressant and antianxiety
drugs and are claimed to protect neuronal cells against
apoptosis [20], and selective MAO-B inhibitors (e.g.
deprenyl [21]) can be used in the treatment of Parkin-
L-
son’s disease either alone or in combination with
DOPA [22].
L-
Pursuing our searches on synthesis and biological
evaluation of pyrrole-containing compounds active on
However, they engender covalent bonds with the
active site of the enzyme and induce irreversible inhibi-
tion; moreover, second-generation-MAOIs tend to lose
their initial selectivity at high dosages or with repeated
administrations. This way of action produces many
important limitations to the use of these compounds in
therapy, such as central nervous effects (insomnia,
irritability, agitation, hypomania, suppression of REM
sleep), cardiovascular disfunctions (orthostatic hypoten-
central nervous system [36Á39], we planned the pre-
/
paration of pyrrole derivatives containing the 2-oxazo-
lidinone nucleus linked at different position of the
pyrrole ring. Three diverse series of pyrrolyl-oxazolidi-
nones have been synthesized and tested as new anti-
MAO agents: (i) 3-(1H-pyrrol-1-yl)-2-oxazolidinones;
(ii) 3-(1H-pyrrol-2-yl)-2-oxazolidinones; and (iii) 3-
(1H-pyrrol-3-yl)-2-oxazolidinones.

234
A. Mai et al. / Il Farmaco 58 (2003) 231Á241
/
Fig. 4. Irreversible MAOIs belonging to different chemical classes.
2. Chemistry
The synthesis of 3-(1H-pyrrol-1-yl)-2-oxazolidinones
starts from 1-(phenylmethoxy carbonylamino)-1H-pyr-
role, which was prepared from benzyl carbazate and 2,5-
dimethoxytetrahydrofuran in ethanol/acetic acid med-
ium. After treatment with n-butyl lithium in hexanes at
2.1. 3-(1H-Pyrrol-1-yl)-2-oxazolidinones (1)
ꢂ70 8C, the lithiated intermediate reacted with enantio-
/
3-(1H-Pyrrol-1-yl)-2-oxazolidinones are characterized
by the pyrrole moiety linked to the 2-oxazolidinone ring
merically pure glycidyl butyrate to furnish directly, after
spontaneous hydrolysis of the butyrate function, the
(R)-5- and (S)-5-hydroxymethyl-3-(1H-pyrrol-1-yl)-2-
oxazolidinones 1a and 1n, depending on the R- or S-
glycidyl butyrate used, respectively.
The alcohols were converted into the corresponding
methanesulfonates with methanesulfonyl chloride and
triethylamine, and these compounds were subjected to
through a Nꢀ/N linkage, and bear different substituents
(i.e. hydroxy-, alkoxy-, azido-, alkylamino-, acyloxy-,
acylamidomethyl, etc.) at the C5 position of the oxazo-
lidinone (Fig. 6). As a chiral center is aroused into the
oxazolidinone moiety by the insertion of a C5 substitu-
tent, both the enatiomerically pure (R and S) series of
compounds have been synthesized and tested.
Fig. 5. Reversible and selective third-generation-MAOIs.

A. Mai et al. / Il Farmaco 58 (2003) 231Á
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235
2.2. 3-(1H-Pyrrol-2- and -3-yl)-2-oxazolidinones 2 and 3
The synthesis of derivatives 2 and 3 was performed
starting from the appropriate 1-alkyl-1H-pyrrole-2- and
3-carboxylic acids, previously prepared by alkylation of
1H-pyrrole-2-carboxylic acid (commercially available)
or by oxidation of 1-alkyl-1H-pyrrole-3-carboxalde-
hydes. The pyrrolecarboxylic acids were reacted with
diphenylphosphonic azide, benzyl alcohol and triethy-
lamine at high temperature to give after Curtius
transposition the corresponding carbamoyl derivates,
which were then cyclized with n-butyl lithium and R-
glycidyl butyrate as previously reported to furnish the
key intermediates 5-hydroxymethyl-1-alkyl-1H-pyrrol-
2- and 3-yl-2-oxazolidinones. Subsequent transforma-
tions of these alcohols into the corresponding methane-
sulfonates, azides, amines, and alkylethers, were
performed as described for the synthesis of the above
reported series of pyrrole-containing oxazolidinones
(Scheme 2).
Fig. 6. 3-(1H-Pyrrol-1-yl)-2-oxazolidinones.
3. Biological evaluation: results and discussion
nucleophilic displacement by sodium alcohoxides, alky-
5-Substituted-3-(1H-pyrrolyl)-2-oxazolidinones 1Á3
/
lamines, hydrazine and sodium azide to give 1b
/
g, jÁq.
/
were evaluated for their ability to inhibit MAO-A and
MAO-B, in comparison with toloxatone as reference
drug. Bovine brain mitochondria were used as the
enzyme source. Activities of MAO-A and MAO-B
were determined by a fluorimetric method with kynur-
amine as substrate. The Ki values against the two
isoenzymatic MAO forms and the A-selectivity (ex-
pressed as KiMAO-B/KiMAO-A ratio) were determined.
Á
5-Aminomethyl- and 5-dimethylaminomethyl derivates
1h, i, r were obtained by catalitic reduction of the
azidomethyl analogs with hydrogen (aminomethyl) or
with hydrogen and formaldehyde in excess (dimethyla-
minomethyl) (Scheme 1). A sample of toloxatone was
synthesized and used as reference drug in biological tests
of derivatives 1.
Scheme 1. Synthesis of 3-(1H-pyrrol-1-yl)-2-oxazolidinones (1).

236
A. Mai et al. / Il Farmaco 58 (2003) 231Á241
/
Scheme 2. Synthesis of 3-(1H-pyrrol-2-and-3-yl)-2-oxazolidinones 2 and 3.
Table 3
Monoamine oxidase inhibitory activity of compounds 1
a
Compd.
C5 configuration
R
Ki MAO-A (mM)
Ki MAO-B (mM)
A selectivity
1a
1b
R
R
R
R
R
R
R
S
OH
OCH3
0.09
0.0049
0.002
0.014
0.6
9
50
1.6
4
100
10,200
800
286
53
1c
1d
OCH2CH3
OCH2CH2CH3
OCH(CH3)2
OCH2CH2CH2CH3
N3
1e
32
10
200
4.4
140
22
5
1f
1g
0.97
0.2
10.3
1000
0.08
3.5
1h
1i
NH2
53
40
S
N(CH3)2
NHCH3
NHCH2CH3
NHCH(CH3)2
NHNH2
OH
1j
1k
S
0.06
0.017
0.006
0.9
367
295
5500
28
S
1l
1m
S
33
25
2
S
1n
1o
S
1.2
1
1.7
S
OCH3
23
50
24
34
2.7
10
15
0.22
23
1p
1q
R
S
NHCH3
N3
NH2
0.063
2.5
1.2
794
9.6
28
1r
R
R
R
1s
OCOCH3
OCOPh
0.0065
0.06
0.38
0.0025
415
167
39.5
88
1t
(R/S) toloxatone
(R,R) befloxatone
b
a
Data represent mean values of at least three separate experiments.
Ref. [33].
b

A. Mai et al. / Il Farmaco 58 (2003) 231Á
/241
237
Table 4
Monoamine oxidase inhibitory activity of compounds 2,3
a
Compd.
X
R
Ki MAO-A (mM)
Ki MAO-B (mM)
A selectivity
2a
2b
CH3
CH3
OH
OCH3
N3
0.087
0.020
0.004
0.01
0.1
3.6
1
41.4
50
2c
2d
CH3
CH3
4
1000
2500
500
9.8
NH2
OH
25
50
5.9
4
2e
CH2CH3
CH2CH3
CH2CH3
CH2CH3
2f
2g
OCH3
N3
0.6
0.2
20
2h
2i
NH2
OH
0.2
45
5
225
11.6
12.5
14.3
137.5
1.4
CH2CHꢁ
CH2CHꢁ
CH2CHꢁ
CH2CHꢁ
CH2ꢀ
CH2ꢀ
CH2ꢀ
CH2ꢀ
/
CH2
CH2
CH2
CH2
0.43
0.52
0.35
0.04
50
2j
2k
/
OCH3
N3
6.5
5
/
2l
2m
/
NHCH3
OCH3
N3
5.5
70
77
80
0.5
/
Ph
Ph
Ph
Ph
2n
/
30
2.6
2o
2p
/
NH2
NHCH3
OH
50
1.6
3.6
/
0.14
1
3a
3b
CH3
CH3
CH3
ꢀ/
10
ꢀ10
/
OCH3
N3
OH
0.3
0.2
170
360
625
2
567
1800
1786
20
3c
3d
3e
CH2CHꢁ
CH2CHꢁ
SO2ꢀPh
/CH2
0.35
0.1
/CH2
NHCH3
OH
3f
/
0.4
0.38
0.0025
0.1
15
0.22
0.25
39.5
88
(R/S) toloxatone
(R,R) befloxatone
b
a
Data represent mean values of at least three separate experiments.
Ref. [33].
b
The majority of compounds showed inhibitory activ-
ity against the A isoform of MAO enzyme higher than
that exerted against the MAO-B. Furthermore, all
derivatives displayed a reversible mode of action since
dialysis for 24 h in a cold room against 0.1 M potassium
alkylation of this compound afforded, i.e. (R)-5-meth-
oxymethyl-3-(1H-pyrrol-1-yl)-2-oxazolidinone (1b), a
MAO-A inhibitor endowed with very high potency
and A-selectivity. In fact, compound 1b (KiMAO-A
nM), is equipotent to befloxatone (R,R form) (KiMAO-
Aꢀ2.5 nM), a new toloxatone analog, and it is
characterized by very high selectivity towards the
MAO-A isoenzyme (A-selectivityꢀ10,200, about 116-
ꢀ4.9
/
phosphate buffer (pH 7.2) was able to restore 90Á
of the enzyme activity (Table 3).
Among compounds 1, derivatives 1aÁ
/
100%
/
/e, g, j, k, p, s, t
/
were the most active with concentration values of MAO-
A inhibitory activity in the nanomolar range. In
particular, in our experiments we found that (R/S)-
toloxatone and the related pyrrole analog (racemic
mixture of 1a and 1n) were equipotent as MAO-A
inhibitors, the latter being 6-fold less MAO-A selective
than the former. Furthermore, the assays performed on
the R (1a) and S (1n) enantiomers showed 1a to possess
the best activity and selectivity. Replacement of OH
with other hydrophilic groups (amino, azido and
dimethylamino) gave derivatives less potent and some-
times less selective than 1a. On the contrary, O-
fold greater than that of befloxatone).
Compounds 2 and 3, tested as anti-MAO agents, were
more active against the A than against the B isoform of
the enzyme (Table 4).
In compounds 2 and 3 the 2-oxazolidinone ring has
been placed at C2 and C3 position of the pyrrole ring,
respectively, while the pyrrole N1 position remains free
to be linked by groups with growing steric hindrance.
Nevertheless, the introduction of such N1 substituents
decreases the MAO inhibitory activity of the com-
pounds leading to derivatives less potent and selective
than the 1 counterparts. This potency abatement is

238
A. Mai et al. / Il Farmaco 58 (2003) 231Á241
/
Fig. 7. AM1 calculations of optimal torsion angles of toloxatone (left) and 1a (right).
Fig. 8. Global minima conformations for toloxatone (left) and 1a (right).
strictly dependent on the steric hindrance exerted by N1-
alkyl substituents: N1-methyl-pyrrole derivatives repre-
sent the products belonging to the most active serie,
followed by the N1-ethyl and N1-allyl analogues. N1-
Benzyl derivatives are practically inactive as anti-MAO
agents, with the exception of the R-5-methylamino-3-(1-
benzyl-1H-pyrrol-2-yl)-2-oxazolidinone (2p), which is
endowed with both anti-MAO-A and anti-MAO-B
4. Preliminary molecular modelling studies
X-ray diffraction-crystallographic studies coupled
with conformational and electronic characterization
(by the ab initio molecular orbital method) performed
on toloxatone [30,31] showed that the drug is a planar
molecule within the presence of an electron delocaliza-
tion of both the oxazolidinone and phenyl rings. Such
structural and electronic properties account for the
existence of a charge-transfer complex between tolox-
atone and riboflavine and establish the mechanism of
MAO-A reversible inhibition exerted by toloxatone.
Starting from these data, we performed conforma-
tional analysis on pyrrole analogue of toloxatone, 1a, to
activities (KiMAO-A
Among derivatives 2 and 3, the most active compound
ꢀ
/
0.14 mM; KiMAO-B
ꢀ0.5 mM).
/
resulted the R-5-azidomethyl-3-(1-methyl-1H-pyrrol-2-
yl)-2-oxazolidinone 2c (Ki against MAO-Aꢀ
Ki against MAO-Bꢀ4 mM; A-selectivityꢀ1000), being
as potent as befloxatone and 10 times more A-selective.
/
0.004 mM;
/
/

A. Mai et al. / Il Farmaco 58 (2003) 231Á
/241
239
Fig. 9. Phenyl-oxazolidinones as antibacterial and antimycobacterial agents.
Scheme 3. Synthesis of 3-(1-aryl-1H-pyrrol-1-yl)-2-oxazolidinones 4aÁf.
/
verify if such co-planarity between pyrrole and oxazo-
lidinone rings could exist also in our molecule. Surpris-
ingly, we found that global minima conformations for
toloxatone and 1a (from MOPAC93 calculations)
from the Upjohn Co. reported on the development of
two S-5-acetamidomethyl-2-oxazolidinones, U-100592
and U-100766 (eperezolid and linezolid), which are now
under clinical trials (the former) or approved by FDA
(the latter) as novel potent and selective broad-spectrum
antibacterial agents [40,41] (Fig. 9).
resulted quite different, being optimal torsion anglesꢀ
/
ꢂ
/
1.288 (toloxatone) and ꢁ70.18 (1a) (Figs. 7 and 8).
/
A great number of modifications were performed on
various oxazolidinone-containing compounds to obtain
antibacterial agents, having as unchanged moiety the 3-
phenyl-2-oxazolidinone structure. Very little is reported
about heterocyclic analogues of the above lead com-
pounds.
Starting from these findings, we prepared pyrrolyl-
oxazolidinones 4 showing an aryl moiety as substituent
at the N1 position of the pyrrole ring and carrying an
hydroxymethyl, aminomethyl, and acetamidomethyl
chains at the C5 position of the 2-oxazolidinone nucleus
to test as antibacterial and antimycobacterial agents
(Scheme 3).
5. 3-(1-Aryl-1H-pyrrol-3-yl)-2-oxazolidinones (4) as
antimycobacterial agents
After the discovery, in late 1984, of 5-acetamido-
methyl-3-aryl-2-oxazolidinones as new synthetic anti-
bacterial agents, the 3-aryl-2-oxazolidinone moiety has
received much attention by the researchers. DuP 721,
described by the DuPont group in 1987, was the first
lead compound and clinical candidate active against
gram-positive and -negative pathogens, as well as
against Mycobacterium tuberculosis. In 1995 a team

240
A. Mai et al. / Il Farmaco 58 (2003) 231Á241
/
Table 5
Antimycobacterial activity of compounds 4
a
Compd.
MIC50 (mM)
M. tuberculosis ATCC
M. tuberculosis clin. isol. 1104
MAC
M. smegmatis
4a
4b
19
10.5
nd
4
9.8
4.2
3.6
12.9
1.9
12.9
9.8
0.1
0.1
2.0
4.6
1.4
16.5
5.8
0.2
0.7
4c
4d
9.4
nd
14.5
10.3
42.6
34
4e
4f
49
12.2
0.2
0.5
linezolid
U-100480
0.3
0.5
a
Minimum inhibitory concentration required to reduce the number of viable Mycobacteria by 50%, as determined by the MTT method.
Table 6
Antimycobacterial activity of compounds 4 against drug-resistant strains
a
Compd.
MIC50 (mM)
M. tuberculosis ATCC 35820
M. tuberculosis ATCC 35828
M. tuberculosis ATCC 35837
4a
4b
5.6
1.1
50.3
10
23.8
7.0
4c
4d
0.9
0.8
18.4
21.5
7.0
13.5
63.5
nd
4e
4f
4.9
ꢀ/
100
nd
nd
Linezolid
U-100480
Streptomycin
Pyrazinamide
Ethambutol
0.2
0.006
0.6
0.1
0.15
0.06
ꢀ100
/
ꢀ100
/
ꢀ100
/
a
Minimum inhibitory concentration required to reduce the number of viable Mycobacteria by 50%, as determined by the MTT method.
gliari, 09042 Cagliari, Italy) for antimicrobial tests. This
work was supported in part by Italian MURST.
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smegmatis, and also against some M. tuberculosis
strains resistant to known drugs (Tables 5 and 6).
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