Synthesis and antileishmanial activity of new imidazolidin-2-one derivatives

Article abstract of DOI:10.1016/S0223-5234(03)00119-3

N³-acyl, arylsulfonyl and benzyl derivatives of N ¹-(4,6-dimethylpyridin-2-yl), (5-methylthiazol-2-yl) or (3-methylisoxazol-5-yl)imidazolidin-2-ones were synthesized and evaluated as potential antileishmanial agents. Determination of

Full text of DOI:10.1016/S0223-5234(03)00119-3

European Journal of Medicinal Chemistry 38 (2003) 711ꢀ718
/
www.elsevier.com/locate/ejmech
Original article
Synthesis and antileishmanil activity of new imidazolidin-2-one
derivatives
Jean-Michel H. Robert a,*, Caroline Sabourin a, Nidia Alvarez b,
Sylvie Robert-Piessard a, Guillaume Le Baut a, Patrice Le Pape b
a Service de Pharmacochimie, UPRES EA 1155, Faculte´ de Pharmacie, 1, rue Gaston Veil F-44035 Nantes, France
b Service de Parasitologie, UPRES EA 1155, Faculte´ de Pharmacie, 1, rue Gaston Veil F- 44035 Nantes, France
Received 23 December 2002; received in revised form 19 May 2003; accepted 20 May 2003
Abstract
N3-acyl, arylsulfonyl and benzyl derivatives of N1-(4,6-dimethylpyridin-2-yl), (5-methylthiazol-2-yl) or (3-methylisoxazol-5-
yl)imidazolidin-2-ones were synthesized and evaluated as potential antileishmanial agents. Determination of their cytotoxic effect
was carried out using MRC5 cells. Two compounds, 1-(4,6-dimethylpyridin-2-yl)-3-(napht-2-ylsulfonyl)imidazolidin-2-one, 18, and
1-(3-methylisoxazol-5-yl)-3-(4-bromobenzyl)imidazo-lidin-2-one, 25, exerted significant antileishmanial activity in promastigotes of
Leishmania (L) mexicana and Leishmania infantum, with IC50 in the range of 8ꢀ
16 mmol Lꢁ1. Antiparasitical activity of the less
/
toxic compound, 25, was confirmed against intracellular amastigote of L. mexicana, the clinical relevant stage; its low IC50 value
(2.4 mmol Lꢁ1) and its favourable toxicity/activity index (11) constitute encouraging results for ongoing pharmacomodulation in the
corresponding subseries.
´
# 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: Imidazolidin-2-one; Antileishmanial activity; L.mexicana. L infantum; Promastigote
1. Introduction
tion and toxicity. These drawbacks explain that several
investigations are oriented to searching new compounds
for better treatment [7].
Leishmaniasis is a protozoan disease that affects
about 12 millions of persons in the world, particularly
in subtropical and tropical regions, constituting a
serious public health problem [1]. Parasites exist in two
forms: an amastigote in the mammalian host and a
flagellated promastigote in the insect vector. Clinical
manifestations occur in three major forms in human:
visceral, cutaneous and mucocutaneous.
In a first work [8], we described arylcarboxamides
derived from 2-amino-4,6-dimethylpyridine (Fig. 1)
exerting significant inhibition against cultured extracel-
lular promastigotes of L. donovani and L. braziliensis,
such as compounds 1 and 2, with IC50 in the range of 30
mmol Lꢁ1. Compound 1, for example, led to a 75%
parasite burden reduction both in the spleen imprints
and in the microdilution spleen cultures in a Balb/c mice
model of visceral leishmaniasis, after intraperitoneal
administration of 10 mg kgꢁ1 daily for 5 consecutive
days.
The pentavalent antimonials, sodium stibogluconate
(Pentostam†)
and
(Glucantine†), are presently the recommended first
line drugs [2ꢀ4]. However they are not orally active
meglumine
antimoniate
/
and they require long courses of treatment. The second
line drugs, pentamidine, azole derivatives (ketoconazole,
itraconazole) [1,5] and amphotericin B [6], are even less
acceptable because of long-term parenteral administra-
In estimation of this work, we synthesized and
evaluated some new derivatives resulting from the
integration of the amino group of 2-amino-4,6-di-
methylpyridine into an imidazolidin-2-one structure
[9]. These compounds (Fig. 2) were evaluated against
promastigote and amastigote of Leishmania mexicana.
Two products, 3 and 4, showed a high level of activity
* Corresponding author.
E-mail address: jmrobert@sante.univ-nantes.fr (J.-M.H. Robert).
´
0223-5234/03/$ - see front matter # 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
doi:10.1016/S0223-5234(03)00119-3

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J.-M.H. Robert et al. / European Journal of Medicinal Chemistry 38 (2003) 711ꢀ718
/
Fig. 1. General structure of arylcarboxamide derivatives of 2-amino-
4,6-dimethylpyridine.
Fig. 4. Synthetic methods for the preparation of imidazolidinone
derivatives 8ꢀ25.
/
Fig. 2. General structure of imidazolidin-2-one derivatives of 2-amino-
4,6-dimethylpyridine.
corresponding ureas 5ꢀ7(method A). This condensation
was followed by intramolecular alkylation, under alka-
line conditions, to afford the monosubstituted imidazo-
/
against the intracellular form of the parasite, with IC50
lidin-2-ones 8ꢀ10 (method B). These compounds could
/
(mmol Lꢁ1) of 139
/
0.5, and 7.093.3, respectively.
/
also be obtained, in a ‘one-pot’ procedure, directly from
amines and isocyanate [9], but yields remained lower.
N3-acylation of 8 by acyl chlorides was carried out in
1,2-dichloroethane in presence of triethylamine (TEA),
at room temperature (method C). N3-arylsulfonylated
Moreover, 3 and 4 were more active against the
intracellular than the promastigote form of the parasite,
contrary to the majority of antileishmanial drugs. These
results prompted us to synthesize new derivatives
possessing this imidazolidinone core. We present here
the first results obtained with new N3-acyl, arylsulfonyl
or benzyl N1-(4,6-dimethylpyridin-2-yl)imidazolidin-2-
compounds 14ꢀ
pounds 14ꢀ19) or in presence of the couple NaH/DMF,
at 0 8C to room temperature, (method D), from the
corresponding sulfonyl chlorides (compounds 20ꢀ22).
N3-benzyl derivatives 23ꢀ
25 were exclusively obtained
by method D.
/22 were obtained by method C (com-
/
ones 11ꢀ
/
19 and analogues 20ꢀ26 resulting from the
/
/
replacement of the lutidinyl moiety by -5-methyl-2-
thiazolyl or 3-methyl-5-isoxazolyl fragment (Fig. 3).
/
1
Their structure was confirmed by IR and H-NMR
spectral data and elemental analyses. Structural assign-
ment of the imidazolidinone ring protons was carried
2. Chemistry
out by Cꢀ/H NMR correlation.
The general synthetic procedure used in this work is
25 (Tables
illustrated in Fig. 4. Imidazolidin-2-ones 8ꢀ
/
1ꢀ4) were synthesized according to the previously
/
reported method [4]: 2-chloroethylisocyanate was con-
densed with the appropriate heteroarylamine to give
3. Parasitological results and discussion
In vitro antileishmanial activity results are gathered in
Table 5. Generally speaking N3-substitution induced a
favourable effect in the three subseries. Among the 18
tested compounds, two, 18 and 25, showed a higher
activity against L. (L.) mexicana and L. (L.) infantum
promastigotes with IC50 values of 14.4, 8.4 and 16.0, 9.5
mmol Lꢁ1, respectively. Interestingly, cytotoxicity assay,
carried out with MRC5 cells, brought to the fore that
these two imidazolidin-2-ones possess a satisfactory
toxicity/activity index: 5ꢀ11 (Table 5 and Fig. 5).
/
In attempt to confirm their activity against the
intracellular infective stage of parasite, a L.(L). mex-
icana-infected Balb/c macrophage model was per-
Fig. 3. General structure of new imidazolidin-2-one derivatives.

J.-M.H. Robert et al. / European Journal of Medicinal Chemistry 38 (2003) 711ꢀ
/718
713
Table 1
Physicochemical data of ureas 5ꢀ
/
7
formed. Whereas the N3-(napht-2-ylsulfonyl)derivative
18 exerted an inhibitory activity on amastigotes compar-
able to that of the previously studied N3-tolylsulfonyl
congener 4 (IC50: 10 and 7.3 mmol Lꢁ1), 25 appeared as
the most active imidazolidin-2-one ever studied against
this clinical stage: IC50: 2.4 mmol Lꢁ1. These results
showed that pharmacomodulation in the imidazolidin-
2-one series allows access to more active compounds
than previously stated [9].
5. Experimental
5.1. Chemistry
Melting points were determined on a Tottoliꢀ
¨
apparatus (Buchi, Flawil, Switzerland) and are uncor-
¨
rected. Structures of the described products were
1
supported by IR, H-NMR and microanalytical data.
/Buchi
IR spectra were run with KBr pellets with a Perkinꢀ
Elmer FT-IR Paragon 1000 grating infrared spectro-
photometer (PerkinꢀElmer, St Quentin-en-Yvelines,
/
/
1
France). H-NMR spectra were recorded on a Bruker
AC 250 spectrometer (250 MHz) (Bruker, Wissem-
bourg, France), using CDCl3 as solvent; chemical shifts
(d) are reported in parts per million (ppm) from internal
Me4Si. Deuterated solvents were purchased from S.D.S.
(Peypin, France). Microanalysis were performed on a
4. Conclusion
Altogether these results demonstrate the in vitro
antileishmanial activity of new N1-azaaryl-imidazoli-
din-2-ones. These compounds, and especially 25, could
represent new attractive drug candidates for extended
pharmacomodulation studies and putative drugs for
treatment of cutaneous and visceral leishmaniasis. In
vivo antileishmanial activity evaluation of 25, in a Balb/
c mice model, is now in progress.
PerkinꢀElmer CHN 240 apparatus. Analytical TLC was
/
performed on precoated silica gel aluminum plates (1.2
mm, GF 254, E. Merck, Darmstadt, Germany). Spots
were located by UV-illumination. Evaporations were
made under vacuum (rotating evaporator). Anhydrous
sodium sulfate was always used as the drying agent.
Purifications of synthesized compounds were made
In attempt to elucidate the molecular target of these
new antileishmanial compounds, we had demonstrated
that the first imidazolidin-2-one derivatives inhibit
parasite phospholipase A2 (PLA2). This inhibition leads
to a reduced capacity of parasite to invade macrophages
[9]. Because PLA2 is activated after phosphorylation by
protein kinase C (PKC), the interference of imidazoli-
din-2-one derivatives with PKC must be investigated.
through columns of silica gel (silica gel 60, 70ꢀ
mesh, E. Merck) with an appropriate solvent (generally
diethyl oxide). Chemicals were purchased from Sigmaꢀ
/
230
/
Aldrich-Fluka (St Quentin Fallavier, France), Lancaster
Synthesis (Bischheim, France) or Avocado (La Tour du
Pin, France).

714
J.-M.H. Robert et al. / European Journal of Medicinal Chemistry 38 (2003) 711ꢀ718
/
Table 2
Physicochemical data of 1-(4,6-dimethylpyridin-2-yl)imidazolidin-2-ones 8 and 11ꢀ19
/
3H, 4-CH3); 2.42 (s, 3H, 6-CH3); 3.73ꢀ
CH2ꢀ
CH2); 6.38 (s, 1H, pyr H5); 6.57 (s, 1H, pyr H3);
8.25 (t, 1H, COꢀNH ꢀCH2, Jꢂ5.6 Hz); 10.26 (s; 1H;
pyrꢀNHꢀCO). Anal. C10H14ClN3O (C, H, N).
/
3.76 (m, 4H,
Yields and physical data of compounds 8ꢀ
/
25 are
/
given in Tables 1ꢀ4.
/
/
/
/
/
/
5.1.1. General procedure for the preparation of ureas 5ꢀ7
/
(method A)
5.1.1.2. 1-(2-Chloroethyl)-3-(5-methylthiazol-2-yl) urea
(6). Compound 6 was prepared as described above for
5.1.1.1. 1-(2-Chloroethyl)-3-(4,6-dimethylpyridin-2-
5. Yieldꢂ
(nCꢁ
O); 1H-NMR(CDCl3) d: 2.30 (s, 3H, 5-CH3);
3.54ꢀ
3.71 (m, 4H, CH2CH2); 6.93 (s, 1H, H4); 7.49
(bs, 1H, COꢀ
/
53%; IR (KBr) (cmꢁ1): 3371 (nNH); 1683
yl)urea (5). To a solution of 2-amino-4,6-dimethylpyr-
idine (7.06 g, 58 mmol) in chloroform (500 mL) was
added 2-chloroethyl isocyanate (5 mL, 58 mmol), and
the resulting mixture was refluxed for 3 h. After cooling,
the solvent was evaporated under reduced pressure, and
the residue was chromatographed on a silicagel (EtOEt);
/
/
/
NH ꢀ
/
CH2). 9.12 (s, 1H, Thiaz-2-NHꢀ
/
CO). Anal. C7H10ClN3SO (C, H, N).
5.1.1.3. 1-(2-Chloroethyl)-5-(3-methylisoxazol-5-yl)
10.96 g of urea 5 were isolated as white crystals. Yieldꢂ
/
urea (7). Compound 7 was obtained as described for
compound 5. Yieldꢂ
89%; IR (KBr) (cmꢁ1): 3370
(nNH); 1680 (nCꢁ
O); 1H-NMR(CDCl3) d: 2.37 (s,
83%; IR (KBr) (cmꢁ1): 3350, 3210 (nNH); 2920, 2870 (n
/
1
O); H-NMR (CDCl3) d: 2.25 (s,
aliph.CH); 1680 (nCꢁ
/
/

J.-M.H. Robert et al. / European Journal of Medicinal Chemistry 38 (2003) 711ꢀ
/718
715
Table 3
Physicochemical data of 1-(5-methylthiazol-2-yl)imidazolidin-2-ones 9 and 21ꢀ
/
23
3H, 5-CH3), 3.64ꢀ
H4); 7.25 (bs, 1H, CONHCH2); 9.39 (s, 1H, Isox-5-
NHꢀCO). Anal. C7H10ClN3O2 (C, H, N).
/
3.68 (m, 4H; CH2CH2); 5.98 (s, 1H,
After cooling and filtration, the resulting filtrate was
concentrated under reduced pressure. The resulting
brown-colored oil was dissolved in dichloromethane
(80 mL) and purified with activated charcoal. The
mixture was filtered and after concentration of the
filtrate under vacuum, crystallization of the isolated
colorless oil from diisopropyl ether afforded 2.41 g of
/
5.1.2. General procedure for the synthesis of N1-
substituted imidazolidin-2-ones 8ꢀ10 (method B)
/
the imidazolidin-2-one 8. Yield 64%; IR (KBr) (cmꢁ1):
5.1.2.1. 1-(4,6-Dimethylpyridin-2-yl)imidazolidin-2-one
(8). To a solution of urea 5 (4.5 g, 19.8 mmol) in
acetonitrile (80 mL) was added sodium carbonate (3g,
28.3 mmol) and the mixture was refluxed during 16 h.
1
N); H-NMR
3210 (nNH); 1670 (nNCON); 1615 (nCꢁ
/
(CDCl3) d: 2.20 (s, 3H, 4-CH3); 2.36 (s, 3H, 6-CH3);
bꢂ7.9 Hz); 4.35 (t, 2H, Ha); 6.51
3.70 (t, 2H, Hb, JH
/
/
/
a
H
Table 4
Physicochemical data of 1-(3-methylisoxazol-5-yl)imidazolidin-2-ones 10 and 22ꢀ25
/

716
J.-M.H. Robert et al. / European Journal of Medicinal Chemistry 38 (2003) 711ꢀ718
/
Fig. 5. Toxicity/activity relationship for imidazolidin-2-ones 8ꢀ25.
/
(s, 1H, pyr H5); 6.63 (s, 1H, pyr H3); 9.64 (s, 1H, NH).
Anal. C10H13N3O (C, H, N).
1H-NMR(CDCl3) d: 2.38 (d, 3H, 5-CH3, J4HMeH
ꢂ0.8
/
Hz); 3.63 (t; 2H, Hb, JH
/
/
bꢂ8.4 Hz); 3.99 (t, 2H, Ha):
/
a
H
5.34 (s, 1H, NH); 6.69 (d, 1H, H4). Anal. C7H9N3O2 (C,
H, N).
5.1.2.2. 1-(5-Methylthiazol-2-yl) imidazolidin-2-one (9).
IR (KBr) (cmꢁ1): 1713 (nNCON); 1613 (nCꢁ
1
N); H-
1.3 Hz);
/
NMR (CDCl3) d: 2.33 (d, 3H, 5-CH3, JH4 MeH
ꢂ
/
5.1.3. Acylation and sulfonylation of imidazolidin-2-one 8
(method C)
3.51 (t, 2H, Hb, JH
/
/
bꢂ
/
8.6 Hz); 4.00 (t, 2H, Ha); 7.04
a
H
(d, 1H, H4); 7.53 (s, 1H, NH). Anal. C7H9N3SO (C, H,
N).
5.1.3.1. 3-(3,5-Difluorobenzoyl)-1-(4,6-dimethylpyridin-
2-yl)imidazolidin-2-one (12). To a solution of 8 (3 g,
15.69 mmol) and TEA (3 mL) in 1,2-dichloroethane (50
mL), was added dropwise a solution of 3,5-difluoroben-
5.1.2.3. 1-(3-Methylisoxazol-5-yl)imidazolidin-2-one
(10). IR (KBr) (cmꢁ1): 1670 n(NCON); 1613 n(Cꢁ
/N);
Table 6
IR and 1H-NMR data of 3-substituted derivatives of 1-(4,6-dimethylpyridin-2-yl)imidazolidin-2-one 8
No. IR (KBr) cmꢁ1 1H-NMR (CDCl3) d
11 1706 n(Cꢁ
/
O) 1672 n(N CON) 1608 n(Cꢁ
/
0.94ꢀ
/
1.15 (m, 4H, CH2CH2 cycloprop.); 2.28 (s, 3H, pyr 4-CH3); 2.47 (s, 3H, pyr 6-CH3); 3.71 (m,
7.8 Hz); 4.35 (t, 2H, Ha); 6.58 (s, 1H, pyr H5); 6.71 (s,
1H, cycloprop.H1); 4.05 (t, 2H, Hb, JH
/
bꢂ
/
/a
N)
H
1H, pyr H3)
2.29 (s, 3H, pyr 4-CH3); 2.48 (s, 3H, pyr 6-CH3); 4.05 (t, 2H, Hb, JH
/
bꢂ
/
7.8 Hz); 4.33 (t, 2H, Ha);
7.33 (m, 5 arom H)
/a
13 1718 n(Cꢁ
/
O) 1670 n(N CON) 1608 n(Cꢁ
/
H
N)
4.54 (s, 2H, benz.CH2); 6.51 (s, 1H, pyr H5); 6.72 (s, 1H, pyr H3); 7.26ꢀ
/
/a
14 1695 n(N CON) 1605 n(Cꢁ
n as. and s. (SO2)
/
N) 1363, 1176 2.33 (s, 3H, pyr 4-CH3); 2.40 (s, 3H, pyr 6-CH3); 4.05 (t, 2H, Hb, JH
/
bꢂ
/
7.2 Hz); 4.36 (t, 2H, Ha);
H
6.44 (s, 1H, pyr H5); 6.67 (s, 1H, pyr H3); 7.52 (d, 2H, H3?H5?, JH
/
5?ꢂ
/JH
/
6?ꢂ
8.7 Hz); 8.10 (d,
/
/3?
/2?
H
H
2H, H2?H6?)
/a
15 1692 n(N CON) 1605 n(Cꢁ
/
N) 1362, 1172 2.23 (s, 3H, pyr 4-CH3); 2.40 (s, 3H, pyr 6-CH3); 4.05 (t, 2H, Hb, JH
/
bꢂ7.3 Hz); 4.36 (t, 2H, Ha);
/
H
n as. and s. (SO2)
6.44 (s, 1H, pyr H5); 6.67 (s, 1H, pyr H3); 7.17ꢀ
/
7.27 (m, 2 arom.H, H3?H5?); 8.15ꢀ
/
8.23 (m, 2 arom
H, H2?H6?)
N) 1378, 1184 2.23 (s, 3H, pyr 4-CH3); 2.41 (s, 3H, pyr 6-CH3); 4.12 (t, 2H, Hb, JH
/
bꢂ
/
7.2 Hz); 4.53 (t, 2H, Ha);
/a
16 1720 n(N CON) 1605 n(Cꢁ
/
H
n as. and s. (SO2)
6.38 (s, 1H, pyr H5); 6.67 (s, 1H, pyr H3); 7.71ꢀ
/
7.79 (m, 3H, H4?H5?H6?); 8.58 (m, 1H, H3?)
N) 1370, 1170 1.35 (s, 9H, C(CH3)3; 2.23 (s, 3H, pyr 4-CH3); 2.41 (s, 3H, pyr 6-CH3); 4.06 (t, 2H, Hb, JH
/
bꢂ
7.2
/
/a
17 1698 n(N CON) 1606 n(Cꢁ
/
H
5?
/
n as. and s. (SO2)
Hz); 4.35 (t, 2H, Ha); 6.46 (s, 1H, pyr H5); 6.66 (s, 1H, pyr H3); 7.56 (d, 2H, H3?H5?, JH
/3?
H
/2?
ꢂ/
JH
/
6?=6.8 Hz); 8.07 (d, 2H, H2?H6?)
H
/a
18 1714 n(N CON) 1605 n(Cꢁ
/
N) 1372, 1169 2.19 (s, 3H, pyr 4-CH3); 2.39 (s, 3H, pyr 6-CH3); 4.12 (t, 2H, Hb, JH
/
bꢂ7.0 Hz); 4.35 (t, 2H, Ha);
/
H
n as. and s. (SO2)
6.39 (s, 1H, pyr H5); 6.64 (s, 1H, pyr H3); 7.58 (dd, 1H, H8?); 7.64 (d, 1H, H5?); 7.89 (dd, 1H, H7?);
7.97 (dd, 1H, H4?); 8.00 (dd, 1H, H6?); 8.14 (dd, 1H, H3?); 8.78 (d, 1H, H1?, JH
/1?
/
3?ꢂ
1.8 Hz;
/
H
6?
/8?
/
4?ꢂ
1.5 Hz)
/
8.7 Hz; JH
/
6?ꢂ
/
7.0 Hz; JH
/
7?ꢂ
/
7.0 Hz; JH
/
7?ꢂ
/
1.5 Hz; JH
/
8?ꢂ
/
7.1 Hz; JH
/3?
/5?
/6?
/5?
/7?
JH
/
H
H
H
H
H
H
ꢂ/
/a
19 1702 n(N CON) 1608 n(Cꢁ
/
N) 1345, 1167 2.19 (s, 3H, pyr 4-CH3); 2.37 (s, 3H, pyr 6-CH3); 4.27 (t, 2H, Hb, JH
/
bꢂ
/
7.3 Hz); 4.45 (t, 2H, Ha);
7.72 (m, 3H, H3?H6?H7?); 8.13 (dd,
H
n as. and s. (SO2)
6.24 (s, 1H, pyr H5); 6.61 (s, 1H, pyr H3); 7.72 (dd, 1H, H5?); 7.56ꢀ
/
1H, H4?); 8.60 (dd, 1H, H8?); 8.76 (dd, 1H, H2?); JH
/
3?ꢂ
/
8.5 Hz; JH
/
4?ꢂ
/0.8 Hz; JH
/
4?ꢂ
8.5 Hz;
/
/2?
/2?
/3?
H
H
H
/5?
/7?
/5?
/6?
JH
/
6?ꢂ
/
JH
/
8?ꢂ
/7.5 Hz; JH
/
7?ꢂ
/
1.1 Hz; JH
H
/
8?ꢂ
1.0 Hz
/
H
H
H

J.-M.H. Robert et al. / European Journal of Medicinal Chemistry 38 (2003) 711ꢀ
/718
717
Table 7
IR and 1H-NMR data of 3-substituted derivatives of 1-thiazolyl and 1-isoxazolylimidazolidin-2-ones 9 and 10.
No. IR (KBr) cmꢀ 1
1H-NMR (CDCl3) d
4ꢂ
/
1.3 Hz); 4.13 (m, 4H, Ha and Hb); 7.04 (d, 1H, H4); 7.85 (d, 2H, H3? and H5?, JH
/
3?ꢂ
H
/
/Me
/2?
21 1736 n(N CON) 1614
2.38 (d, 3H, 5-CH3, JH
6?ꢂ
/
H
8.3 Hz); 8.26 (d, 2H, H2? and H6?)
/5?
n(Cꢁ
22 1738 n(N CON) 1610
n(CꢁN)
/
N)
JH
/
/
H
2.35 (d, 3H, 5-CH3, JH
/
4ꢂ
/
0.7 Hz); 2.45 (s, 3H, 4-CH3); 3.90 (t, 2H, Hb, JH
/
bꢂ8.3Hz); 4.04 (t,2H, Ha); 6.60 (d,
/
/Me
/a
H
H
/
1H, H4); 7.35 (d, 2H, H3? and H5?,JH
/
3?ꢂ
/
JH
/
6?ꢂ
/
8.3 Hz); 7.95 (d, 2H, H2? and H6?)
/2?
/5?
H
H
4ꢂ
/
1.3 Hz); 3.52 (t, 2H, Hb, JH
/
bꢂ7.9 Hz); 4.09 (t, 2H, Ha); 4.64 (s, 2H, CH2); 7.00 (d,
/
/Me
/a
23 1715 n(N CON)
2.37 (d, 3H, 5-CH3, JH
/
H
H
1H, H4); 7.17 (ddd, 1H, H4?); 7.31(ddd, 1H, H5?); 7.39 (dd, 1H, H6?); 7.57 (dd, 1H, H3?); JH
/
6?ꢂ
/7.2 Hz; JH
4?ꢂ
/
/5?
/3?
/
H
H
7.9 Hz; JH
/
5?ꢂ
/
8.0 Hz; JH
/
5?ꢂ
/
1.2 Hz; JH
/
6?ꢂ
/
1.9 Hz
/4?
/3?
/4?
H
H
H
4ꢂ
/
0.6 Hz); 3.51 (t, 2H, Hb, JH
/
bꢂ8.0 Hz); 3.88 (t, 2H, Ha); 4.63 (s, 2H, CH2); 6.75 (d,
/
/Me
/a
24 1736 n(N CON) 1613
N)
2.39 (d, 3H, 5-CH3, JH
/
H
H
1H, H4); 7.18 (ddd, 1H, H4?); 7.28ꢀ
/
7.38 (m, 2H, H6?and H5?); 7.58 (dd, 1H, H3?); JH
/
4?ꢂ
/7.8 Hz; JH
/
5?ꢂ
7.8 Hz;
/
/3?
/4?
n(Cꢁ
/
H
H
/4?
/3?
JH
/
6?ꢂ
/
2.2 Hz; JH
/
5?ꢂ
1.8 Hz
/
H
H
4ꢂ
/
0.7 Hz); 3.40 (t, 2H, Hb, JH
/
bꢂ
/
7.6 Hz); 3.85 (t, 2H, Ha); 4.41 (s, 2H, CH2); 6.73 (d,
8.3 Hz); 7.95 (d, 2H, H2? and H6?)
/Me
/a
25 1690 n(N CON) 1613
n(CꢁN)
2.38 (d, 3H, 5-CH3, JH
/
H
H
1H, H4) 7.17 (d, 2H, H3? and H5?, JH
/
3?ꢂ
/
JH
/
6?ꢂ
/
/2?
/5?
/
H
H
zoyl chloride (3.0 g, 17 mmol) in the same solvent (10
mL). The mixture was stirred at room temperature for 2
h. Then, after filtration and concentration under re-
duced pressure, the residue was chromatographed on a
silica gel column with diethyl ether as eluent, to afford
5.1.4. N3-Sulfonylation and benzylation of imidazolidin-
2-ones 9 and 10 (method D)
5.1.4.1. 1-(5-Methylthiazol-2-yl)-3-(p-
toluenesulfonyl)imidazolidin-2-one (20). To a solution of
9 (1 g, 5.46 mmol.) in dry DMF (10 mL) was added
NaH (0.34 g, 16 mmol); the resulting suspension was
placed under stirring at 0 8C for 20 min. Then, p-
toluene-sulfonyl chloride (3.24 g, 17 mmol) was added
and the mixture stirred for 2 h at room temperature. At
the end of this time, the reaction was stopped by water
addition (50 mL), and the mixture was extracted by
12 (2.42 g) as a white crystalline powder. Yieldꢂ
IR (KBr) (cmꢁ1): 1720 (nCꢁ
O); 1672 (nNCON); 1609
N); H-NMR(CDCl3) d: 2.22 (s, 3H; 4-CH3); 2.40
/47%;
/
1
(nCꢁ
/
(s, 3H, 6-CH3); 4.15 (t, 2H, Hb, JH
/
/
bꢂ
/
7.5 Hz); 4.50 (t,
2H, Ha); 6.25 (s, 1H, pyr H5); 6.65 (s, 1H, pyr H3); 6.68ꢀ
6.72 (m, 1H, H4); 7.22ꢀ7.27 (m, 2H, H2and H6). Anal.
C17H15F2N3O2 (C, H, N).
N3-acyl compounds 11, 13 and N3-arylsulfonyl com-
pounds 14ꢀ19 (Table 2) were synthesized according to
a
H
/
/
dichloromethane (3ꢃ100 mL). The organic fraction
/
was collected, dried over Na2SO4 and concentrated
under reduced pressure. The oily residue was purified
by column chromatography on silica gel, using diethyl
ether as eluent. The isolated compound 20 was crystal-
lized from diethyl ether to afford 0.96 g of a white
/
this general procedure.
Table 5
In vitro antileishmanial activity of imidazolidin-2-ones 8ꢀ25
/
product. Yieldꢂ
CON); 1610 (nCꢁ
3H, 5-CH3, J4HMeH
4.05ꢀ
4.10 (m, 4H, Ha and Hb) 7.01 (d, 1H, H4); 7.36 (d,
2H, H3?H5?, JH
H2?H6?). Anal. C14H15N3S2O3 (C, H, N).
All N3-arylsulfonyl and benzyl derivatives of imida-
zolidinones 9 and 10 (Tables 3 and 4) were synthesized
according to this procedure. IR and NMR data of the
corresponding compounds are gathered in Tables 6 and
7.
/
52%; IR (KBr) (cmꢁ1): 1724 (nN
N); 1H-NMR(CDCl3) d: 2.36 (d,
1.2 Hz); 2.45 (s, 3H, 4?-CH3);
/
Compounds Antileishmanial activity in
promastigotes (mmol Lꢁ1)
Cytotoxicity (mmol Lꢁ1
)
ꢂ
/
/
2?
2?
/
L. mexicana
L. infantum
MRC5
/
/
3?ꢂ
/
JH
/
6?ꢂ
8.4 Hz); 7.98 (d, 2H,
/
H
H
8
67.9
84.6
62.8
35.0
35.1
22.9
51.8
72.1
131.6
108.3
112.0
49.8
93.7
90.5
96.5
55.8
55.8
72.0
69.0
91.0
84.6
52.3
96.8
55.3
102.0
9
ꢀ
ꢀ/
/
163.8
179.4
33.2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
20.1
ꢀ
/
97.0
40.7
85.9
50.0
18.9
8.4
ꢀ
ꢀ/
/
82.0
85.9
29.2
52.2
14.4
58.0
69.0
52.1
46.7
24.1
23.5
16.0
ꢀ
/
5.2. Parasitological assays
5.2.1. Parasites
14.0
17.0
76.6
93.3
20.4
33.9
9.5
L.(L). infantum (MHOM/FR/91/LEM2259), and
L.(L). mexicana (MHOM/MX/95/NAN1) strains were
cultured at 26 8C in Schneider’s insect media (Sigma
Chemical Co., St. Louis, MO), supplemented with 15%
ꢀ
ꢀ
/
/
ꢀ/
of fetal calf serum (Sigma), penicillin (100 UI mLꢁ1
and streptomycin (100 mg mLꢁ1).
)

718
J.-M.H. Robert et al. / European Journal of Medicinal Chemistry 38 (2003) 711ꢀ718
/
5.2.2. In vitro antileishmanial activity
L.(L). infantum and L.(L). mexicana promastigotes
Acknowledgements
(2ꢃ
/
106 mLꢁ1) in the exponential stage were inoculated
This work was supported by funds provided by
Project No. CF99S03 (ECOS Nord-French and Colom-
bian Cooperative programme) ECOS/ICFEX/COL-
CIENCIAS/ICETEX. We thank M. Biron, C. Picot
and M. Ravily for technical assistance.
into 96-well plates and exposed to triplicate concentra-
tions of imidazolidinone derivatives. Cultures were
incubated for 96 h at 26 8C. The anti-proliferative effect
was determined by MTT method based on the tetra-
zolium salt reduction by mitochondrial dehydrogenases.
Absorbance was determined at 570 nm [10] and IC50 was
calculated. L.(L). mexicana-Balb/c-infected macro-
phage model was developed in order to determine the
anti-Leishmania activity against intracellular amasti-
gotes. Peritoneal macrophages were adjusted to 106 cells
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103.
mLꢁ1 of RPMI 1640ꢄ
15% FBS into 24 well plates.
/
/43.
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promastigotes at 37 8C and 5% CO2. After a contact
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/
/
/
699.
/
5.2.3. Cytotoxicity
/
Cytotoxicity was studied after 96 h-incubation of
human diploid fibroblasts (MRC5) with imidazolidin-2-
one derivatives. Cytotoxic effect was measured using an
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/
484.
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/
¸