Synthesis and antimicrobial activity of substituted imidazolidinediones and thioxoimidazolidinones

Article abstract of DOI:10.1016/S0014-827X(98)00105-0

Synthesis and physico-chemical properties of new 3-benzyl-4-thioxo-5-arylideneimidazolidine-2-ones and 3-benzyl-5-arylideneimidazolidine-2,4-dione are described. These compounds were synthesized by condensation reaction from aromatic aldehydes and 3-substituted imidazolidine-2,4-diones or 4-thioxoimidazolidine-2-ones. The N-alkylation of 5-benzylideneimidazolidine-2,4-dione led simultaneously to mono- and dialkylated derivatives. The nucleophilic addition of 1-methyl-3-benzylimidazolidine-2,4-dione with 2-cyano-3-(3,4-dichlorophenyl) acrylate also yielded the 3-substituted 5-arylideneimidazolidine-2,4-dione derivative. Antimicrobial in vitro activity was determined on some compounds.

Full text of DOI:10.1016/S0014-827X(98)00105-0

Il Farmaco 54 (1999) 77–82
Synthesis and antimicrobial activity of substituted
imidazolidinediones and thioxoimidazolidinones
J.F.C. Albuquerque a, J.A. Rocha Filho a, S.S.F. Brandao a, M.C.A. Lima a,
E.A. Ximenes a, S.L. Galdino a, I.R. Pitta a, J. Chantegrel b, M. Perrissin b,*,
C. Luu-Duc b
a Departamento de Antibio´ticos, Uni6ersidade Federal de Pernambuco, 50.670-901 Recife, Brazil
b Laboratoire de Chimie-Pharmacie, CNRS UPRES-A 5077, Faculte´ de Pharmacie de Grenoble, F-38706 La Tronche, Cedex, France
Received 5 March 1997; accepted 30 November 1998
Abstract
Synthesis and physico–chemical properties of new 3-benzyl-4-thioxo-5-arylideneimidazolidine-2-ones and 3-benzyl-5-aryli-
deneimidazolidine-2,4-dione are described. These compounds were synthesized by condensation reaction from aromatic aldehydes
and 3-substituted imidazolidine-2,4-diones or 4-thioxoimidazolidine-2-ones. The N-alkylation of 5-benzylideneimidazolidine-2,4-
dione led simultaneously to mono- and dialkylated derivatives. The nucleophilic addition of 1-methyl-3-benzylimidazolidine-2,4-
dione with 2-cyano-3-(3,4-dichlorophenyl) acrylate also yielded the 3-substituted 5-arylideneimidazolidine-2,4-dione derivative.
Antimicrobial in vitro activity was determined on some compounds. © 1999 Elsevier Science S.A. All rights reserved.
Keywords: Imidazolidines; Thioxoimidazolidines; Antimicrobial activity
1. Introduction
2,4-dione (3), 3-benzyl- and 3-(4-chlorobenzyl)-4-thioxo-
imidazolidine-2-ones (5–6) with aromatic aldehydes
(Scheme 1). When this reaction is performed with imi-
dazolidine-2,4-dione (1) and 4-bromobenzaldehyde, the
resulting product (15) submitted to alkylation with
2-chloroacetophenone yields two derivatives: a mono-
alkylated one, the 3-phenacyl-5-(4-bromobenzyli-
dene)imidazolidine-2,4-dione (16) and a dialkylated
one, the 1,3-diphenacyl-5-(4-bromobenzylidene)imida-
zolidine-2,4-dione (17) (Scheme 1). The condensation
reaction between 1-methyl-3-(4-chlorobenzyl)imidazo-
lidine-2,4-dione (19) and substituted aldehydes is very
difficult because the 5-position of imidazolidine ring is
partially hindered by methyl group. An alternative
method can be employed: thus, nucleophilic addition of
19 with ethyl-2-cyano-3-(3,4-dichlorophenyl)acrylate af-
fords1-methyl-3-(4-chlorobenzyl)-5-(3,4-dichlorobenzyl-
idene)imidazolidine-2,4-dione (20) as a mixture of E/Z
isomers in 80:20 ratio due the presence of methyl group
in imidazolidine cycle. This proportion was determined
by mass spectrometry coupled with GC (Scheme 2).
The 5-arylideneimidazolidine-2,4-diones can present
Z–E isomerism. The condensation of imidazolidine-
Imidazolidinedione and thiazolidinedione derivatives
are widely studied because of their pharmacological
properties [1–3]. Synthesis of some 5-arylideneimidazo-
lidine-2,4-diones, substituted in the 3-position by a
benzyl group, has been previously reported [4–6]. In
the present paper, we describe the synthesis and the
physico–chemical characteristics of the 3-(4-fluoroben-
zyl)-5-(4-fluorobenzylidene)imidazolidine-2,4-dione (7)
and of some new 3-benzyl- and 3-(4-chlorobenzyl)-4-
thioxo-5-arylideneimidazolidine-2-ones (8–14). Antimi-
crobial activity of some of these compounds has been
investigated against cocci and bacilli.
2. Chemistry
These compounds were synthesized by a condensa-
tion reaction between 3-(4-fluorobenzyl)imidazolidine-
* Corresponding author.
0014-827X/99/$ - see front matter © 1999 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(98)00105-0

78
J.F.C. Albuquerque et al. / Il Farmaco 54 (1999) 77–82
Scheme 1.
Scheme 2.
[11], and 3-(4-chlorobenzyl)imidazolidine-2,4-dione (4),
m.p. 164°C [12], with phosphorus pentasulfide in hot
dioxane, the 3-benzyl-4-thioxoimidazolidine-2-one (5)
and 3-(4-chlorobenzyl)-4-thioxoimidazolidine-2-one (6)
[4] are obtained. The condensation of these thioxoimi-
dazolidines with aromatic aldehydes is performed in
acetic acid in presence of anhydrous sodium acetate.
Physico–chemical and 1H NMR data of the com-
pounds 8–14 are listed in Table 1 and mass spectral
data in Table 2.
2,4-diones, unsubstituted in the 1-position, with aro-
matic aldehydes in acid medium, leads always to Z
isomer [7]. The coupled 13C NMR study giving the
3
coupling constant JC–H (4.8–6.4 Hz) between the
methylidene proton and the carbon in the 4-position
shows that imidazolidine-2,4-diones present Z configu-
ration [4,8]. The crystallographic study has confirmed
these results [9]. The 5-arylideneimidazolidine-2,4-
diones and 5-arylidene-4-thioxoimidazolidine-2-ones
prepared by us show Z configuration, except for the
above-mentioned compound 20.
The 3-alkylation of imidazolidine takes place in two
steps: firstly, the activation of the 3-position by forma-
tion of the sodium or potassium salt; then, the conden-
sation with halides in hot ethanol [10]. By treatment of
the 3-benzylimidazolidine-2,4-dione (2), m.p. 135°C
3. Experimental
Melting points were determined with a capillary
Bu¨chi apparatus and are uncorrected. IR spectra were

J.F.C. Albuquerque et al. / Il Farmaco 54 (1999) 77–82
79
taken on a Perkin–Elmer 1310 spectrophotometer in
2% KBr pellet except for compound 20, mixture E+Z,
for which an IFS 66 Bruker spectrophotometer was
used. 1H and 13C NMR spectra were recorded in CDCl3
or in DMSO-d6 with a Bruker AC-200 spectrometer
except for compound 20, mixture E+Z, for which a
Bruker AC-300P spectrometer was used. Chemical
shifts (l) are given in ppm and coupling constants (J)
in Hz. Electronic impact mass spectra (70 eV) were
measured with a R-1010C Delsi–Nermag spectrometer
except for compounds 7 and 20 for which a HPG
1019A spectrometer coupled with a GC (HP 5890) was
used. Thin layer chromatography was performed on
silica plates pre-coated with Merck Kiesegel 60F254 and
column chromatography with silica gel (mesh 70–230).
No elemental analysis was performed on the new com-
pounds, but all mass spectra agree with their proposed
structure.
3.1. 3-(4-Fluorobenzyl)imidazolidine-2,4-dione (3)
A solution of hydroxide sodium (5.3 g, 0.13 mmol) in
50% ethanol (50 ml) was added dropwise to a stirred
suspension of imidazolidine-2,4-dione (13.3 g, 0.13 mol)
in 50% ethanol (200 ml). After 10 min, the 4-fluoroben-
zyl chloride (20.0 g, 0.14 mol) was added. The reaction
mixture was stirred for 5 min then refluxed for 20 h.
After cooling, the precipitate was filtered and recrystal-
lized from 95% ethanol. Yield 50%. M.p. 187–188°C.
TLC: (CHCl3/CH3COOC2H5 1:1) Rf 0.50. IR (KBr): w
1
3245, 1770, 1720, 1605 cm−1. H NMR (DMSO-d6): l
3.96 (s, 2H, CH2-5); 4.50 (s, 2H, CH2-Ph), 7.10–7.18
(m, 2H, aromatic H); 7.27–7.34 (m, 2H, aromatic H),
8.14 (s, 1H, NH).
3.2. 3-Benzyl-4-thioxoimidazolidine-2-one (5)
A mixture of 3-benzylimidazolidine-2,4-dione (2) (5.2
g, 27 mmol) and phosphorus pentasulfide (2.5 g, 11
mmol) in anhydrous dioxane (40 ml) is refluxed for 60
min. Then 0.1 g of zinc powder and 0.1 g of charcoal
are added; the mixture is heated for another 10 min,
hot filtered and concentrated to half. After addition of
crushed ice, the precipitate is filtered and purified by
column chromatography (C6H6/CH3COCH3 99:1).
Yield 73%. M.p. 134°C. TLC: (C6H6/CH3COCH3 9:1)
1
Rf 0.65. IR (KBr): w 3230, 1755, 1490 cm−1. H NMR
(DMSO-d6): l 4.34 (d, 2H, CH2-5); 5.05 (s, 2H,CH2-
Ph); 6.17 (s, 1H, NH); 7.29–7.37 (m, 3H, aromatic H);
7.46–7.50 (m, 2H, aromatic H).
3.3. 3-(4-Fluorobenzyl)-5-(4-fluorobenzylidene)-
imidazolidine-2,4-dione (7)
A
mixture of 3-(4-fluorobenzyl)imidazolidine-2,4-
dione (3) (3.1 g, 15 mmol), 4-fluorobenzaldehyde (2.2 g,

80
J.F.C. Albuquerque et al. / Il Farmaco 54 (1999) 77–82
Table 2
Thioxoimidazolidinones: main molecular peaks and their relative intensities
No. Formula
M+ (%)
MS m/z (%)
8
9
10
11
C17H13ClN2OS 328 (3.9)
C17H13ClN2OS 328 (79.2)
C17H13FN2OS 312 (100)
C17H11Cl3N2OS 397 (1.6)
330 (1.4), 294 (23), 293 (100), 292 (31), 91 (82)
329 (40.7), 330 (28.3), 293 (48), 292 (18), 91 (100), 89 (14)
313 (25.5), 311 (80), 91 (77)
398 (1.8), 361 (100), 362 (22), 363 (64), 127 (40), 125 (87), 99 (22), 90 (27), 89 (90), 86 (37)
12
13
14
C18H15ClN2OS 342 (100)
C19H17ClN2OS 356 (40.1)
C19H18ClN3OS 371 (100)
343 (46.0), 344 (41.2), 327 (40), 125 (62), 103 (22), 90 (19), 89 (65), 86 (39)
358 (14.5), 343 (38), 342 (24), 341 (100), 127 (29), 125 (70), 91 (25), 90 (20), 89 (64), 86 (30)
372 (35.2), 373 (41.7), 203 (17), 160 (22), 159 (17), 125 (21), 89 (37)
18 mmol), sodium acetate (1.5 g) and glacial acetic acid
(6.0 ml) is heated at 140–150°C for 3 h. After cooling,
the precipitate is filtered, washed with water and recrys-
tallized from methanol. Yield 39%. M.p. 225°C. TLC:
(CHCl3/CH3OH 9:1) Rf 0.66. IR (KBr): w 3240, 1760,
added dropwise to a stirred suspension of 5-(4-bromoben-
zylidene)imidazolidine-2,4-dione (15) (1.3 g, 4.9 mmol) in
50 ml of absolute ethanol. The mixture is refluxed for 2
h. After cooling, the precipitated compound is filtered,
washed with ethanol and dried. A mixture of potassium
salt of the 5-(4-bromobenzylidene)imidazolidine-2,4-
dione (1.2 g, 6.2 mmol) and of 2-chloroacetophenone (0.8
g, 5.2 mmol) in dimethylformamide (50 ml) is refluxed
for 3 h. The precipitated compound is filtered, washed
with minimal quantity of ethanol and purified by column
chromatography with CHCl3/CH3OH (98:2) as eluent.
TLC (CHCl3/CH3OH 98:2): two spots Rf 0.90 and 0.76.
1
1705, 1655 cm−1. H NMR (DMSO-d6): l 4.64 (s, 2H,
CH2); 6.55 (s, 1H, CHꢀ); 7.16 (t, 2H, J=8.7 Hz, aromatic
H); 7.23 (t, 2H, J=8.7 Hz, aromatic H); 7.27–7.30 (m,
2H, aromatic H); 7.67–7.75 (m, 2H, aromatic H). MS:
m/z (%)=314 (57.2), 315 (11.0), 109 (100), 108 (9.0).
3.4. 3-Benzyl- and 3-(4-chlorobenzyl)-4-thioxo-5-
arylideneimidazolidine-2-ones (8–14)
3.6.1. Compound 16
Yield 25%. TLC: (CHCl3/CH3OH 96:4) Rf 0.77. M.p.
An equimolar mixture of 3-benzyl-4-thioxoimidazo-
lidine-2-one (5) (0.51 g, 2.5 mmol) or 3-(4-chlorobenzyl)-
4-thioxoimidazolidine-2-one (6) (0.24 g, 1 mmol),
aldehyde, sodium acetate and glacial acetic acid is heated
at 110–120°C for the time reported in Table 1. After
cooling, theprecipitatedproductiswashedwithwaterand
diethyl ether. Some 3-benzyl-and 3-(4-chlorobenzyl)-4-
thioxo-5-benzylideneimidazolidine-2-ones did not need
another purification. Some compounds were purified by
column chromatography as specified in Table 1.
305–306°C. IR (KBr): w 3230, 2930, 1765, 1710, 1690,
1
1585 cm−1. H NMR (DMSO-d6): l 5.13 (s, 2H, CH2);
6.58 (s, 1H, CHꢀ); 7.62 (s, 4H, aromatic H); 7.59–7.73
(m, 3H, aromatic H); 8.07 (d, 2H, J=7.1 Hz, aromatic
H); 11.06 (bs, 1H, NH). MS m/z (%): 384 (10.5), 386 (8.9),
243 (60), 165 (25), 105 (100), 89 (21).
3.6.2. Compound 17
Yield 2%. TLC: (CHCl3/CH3OH 98:2) Rf 0.90. M.p.
193°C. IR (KBr): w 2930, 1775, 1725, 1695, 1600 cm−1
.
3.5. 5-(4-Bromobenzylidene)imidazolidine-2,4-dione (15)
1H NMR (DMSO-d6): l 4.91 (s, 2H, CH2); 5.13 (s, 2H,
CH2); 6.90 (s, 1H, CHꢀC); 7.02 (d, 2H, J=8.5 Hz,
aromatic H); 7.23 (d, 2H, J=8.4 Hz, aromatic H);
7.35–7.65 (m, 8H, aromatic H); 8.02 (dd, 2H, J=6.6 Hz,
aromatic H). 13C NMR (CDCl3): l 45.18 (CH2), 48.33
(CH2), 111.40 (CH), 122.53 (C), 127.48 (2 CH), 128.11
(2 CH), 128.60 (2 CH), 128.86 (2 CH), 129.54 (C), 130.54
(2 CH), 131.23 (C), 131.42 (2 CH), 133.77 (C), 133.95
(CH), 134.09 (CH), 134.17 (C), 155.35 (CO), 162.91 (CO),
190.36 (CO), 191.24 (CO). MS m/z (%): 502 (4.7), 504
(4.6), 318 (5), 208 (6), 129 (9), 105 (100), 77 (27).
A mixture of imidazolidine-2,4-dione (1) (1.0 g, 10
mmol), 4-bromobenzaldehyde (2.2 g, 12 mmol), sodium
acetate (3.3 g) and glacial acetic acid (14 ml) is heated
at 130–140°C for 5 h. After cooling, the precipitated
product is filtered, triturated with water and diethyl ether
then recrystallized from acetic acid. Yield 50%. M.p.
300°C. TLC: (CHCl3/CH3OH 96:4) Rf 0.28. IR (KBr):
w 3270, 3220, 1790, 1735, 1665 cm−1. 1H NMR (DMSO-
d6): l 6.36 (s, 1H, CHꢀC); 7.55 (s, 4H, aromatic H); 10.91
(s, 1H, NH).
3.6. 3-Phenacyl-5-(4-bromobenzylidene)imidazolidine-
2,4-dione (16) and 1,3-diphenacyl-5-(4-bromobenzyli-
dene)imidazolidine-2,4-dione (17)
3.7. 1-Methylimidazolidine-2,4-dione (18)
According to the method described by Miller and
Robson [13], a mixture of N-methylglycine (5.4 g, 60
mmol) and potassium cyanate (4.9 g, 60 mmol) in 20 ml
A potassium hydroxide solution (0.3 g, 5.3 mmol) is

J.F.C. Albuquerque et al. / Il Farmaco 54 (1999) 77–82
81
of water is refluxed for 30 min. Concentrated HCl is
added up to pH 3.0 and the refluxing is continued for a
further 30 min. After evaporation, the residue is
purified by successive crystallizations from absolute
ethanol. Yield 75%.
The Mueller–Hinton agar has been used as a
medium of reference for antimicrobial activity tests [14].
Overnight cultures grown at 37°C in Mueller–Hinton
broth are diluted to obtain an opacity equivalent to 0.5
on the McFarland scale. Serial 2-fold dilutions of each
drug are prepared in DMSO/Tween 80/water (1:1:8) to
give concentrations 10-fold higher than the final desired
concentration. A concentration of 5120 or 1280 mg/ml
was used as a starting concentration, providing a final
concentration of 512 or 128 mg/ml in agar. A series of
8–11 dilutions (to final concentrations of 512–0.5 or
128–0.5 mg/ml) is prepared.
M.p. 153–154°C (lit. [13] 155–156°C). TLC: (CHCl3/
CH3OH 97:3) Rf 0.63. IR (KBr): w 3140, 3040, 1770,
1
1710 cm−1. H NMR (DMSO-d6): l 2.77 (s, 3H, CH3);
3.88 (s, 2H, CH2); 10.68 (bs, 1H, NH).
3.8. 1-Methyl-3-(4-chlorobenzyl)imidazolidine-2,4-dione
(19)
Plates of Petri are prepared by mixing one part of
each dilution of drug with nine parts of the Mueller–
Hinton agar medium. Each plate, including a drug-free
control plate, is inoculated by streak using a calibrated
loop (0.05 ml). The plates are examined for the pres-
ence or absence of growth after 18 h of incubation at
37°C. The minimal inhibitory concentration (MIC) is
considered to be the lowest drug concentration for
which there is no microbial growth [15]. It was verified
that DMSO was completely inactive on the tested mi-
croorganisms at these concentrations. The ciprofloxacin
was used as the reference antibiotic. Its MIC was 0.25
mg/ml against M. fla6us and 2 mg/ml against B. cereus.
Compounds 18–20 presented a MIC superior to 512
mg/ml for all microorganisms tested except for com-
pound 20 whose active concentration is 32 mg/ml
against M. fla6us. For compounds 3, 5, 7, 8, 10, 16 and
17, the MIC was superior to 128 mg/ml except for
compound 3, whose active concentration against M.
fla6us and B. cereus is inferior to 0.5 mg/ml, and for
compound 7 that inhibited B. cereus at the concentra-
tion of 16 mg/ml.
A mixture of 1-methylimidazolidine-2,4-dione (18)
(8.8 g, 77 mmol), 4-chlorobenzyl chloride (12.4 g, 77
mmol) and sodium hydroxide (4.0 g) in ethanol at 50°C
is refluxed for 20 h. After cooling, 200 g of iced water
are added. The precipitated compound 19 is filtered and
recrystallized from water. Yield 58%. M.p. 128–129°C.
TLC (CHCl3/CH3OH 99:1) Rf 0.76. IR (KBr): w 2920,
1
1775, 1700 cm−1. H NMR (CDCl3): l 2.98 (s, 3H,
CH3); 3.85 (s, 2H, CH2-5); 4.60 (s, 2H, CH2-Ph); 7.27
(d, 2H, J=8.5 Hz, aromatic H); 7.35 (d, 2H, J=8.6
Hz, aromatic H).
3.9. 1-Methyl-3-(4-chlorobenzyl)-5-(3,4-dichlorobenzyli-
dene)imidazolidine-2,4-dione (20, mixture E+Z)
An equimolar mixture of 1-methyl-3-(4-chloroben-
zyl)imidazolidine-2,4-dione (19) (0.74 g, 2.7 mmol) and
ethyl 2-cyano-3-(3,4-dichlorophenyl)acrylate in absolute
ethanol (20 ml) is refluxed for 2 h with 0.25 ml of
piperidine. After cooling, the precipitated compound is
purified by column chromatography with chloroform as
eluent. Yield 27%. M.p. 195–196°C. TLC (CHCl3) Rf
1
0.60. IR (KBr, E+Z): w 1762, 1710, 1631 cm−1. H
5. Conclusion
NMR (CDCl3, E+Z): l 3.23 (s, 3H, CH3); 4.73 (s, 2H,
CH2); 6.10 (s, 1H, CHꢀC); 7.30 (d, 1H, J=8.8 Hz,
aromatic H); 7.38 (d, 1H, J=8.4 Hz, aromatic H); 7.44
(d, 2H, J=8.5 Hz, aromatic H); 7.74 (dd, 2H, J=8.4
and 2.5 Hz, aromatic H); 8.03 (d, 1H, J=2.2 Hz,
aromatic H). MS m/z (%): (Z 80%): 394 (43.7), 396
(43.3), 398 (15.4), 184 (12), 127 (33), 125 (100); (E 20%):
394 (36.9), 396 (36.0), 398 (12.4), 184 (12), 127 (33), 125
(100).
Some new imidazolidinediones and thioxoimidazo-
lidinones have been synthesized and characterized by
their physico–chemical and spectroscopic properties.
The fragments observed by electronic impact mass
spectrometry are in agreement with the proposed
structures.
Ten compounds were evaluated as potential antimi-
crobial agents against six microorganisms. They present
an activity inferior to ciprofloxacin, the reference
antibiotic.
4. Biological activity
The antimicrobial activity of compounds 3, 5, 7, 8,
10, and 16–20 was determined in vitro against six
microorganisms (cocci, Gram-positive and Gram-nega-
tive bacilli): Staphylococcus aureus, Micrococcus fla6us,
Bacillus cereus, Proteus 6ulgaris, Salmonella enteritidis
and Escherichia coli.
Acknowledgements
This work was supported by the CNPq (Conselho
Nacional de Desenvolvimento Cient´ıfico e Tecnolo´gico)
Brasil.

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[8] U. Vo¨geli, W. Von Philipsborn, K. Nagarajan, M.D. Nair, Helv.
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