Synthesis and bioactivity of some new 1-tolyl-3-aryl-4-methylimidazole-2- thiones

Article abstract of DOI:10.1007/s00044-007-9017-8

Three series of new 1-(isomeric methyl)benzoyl-3-arylthioureas (1-3a-i) were prepared from 2-, 3-, and 4-methylbenzoyl chlorides via isothiocyanate formation followed by treatment with various substituted anilines. The base-catalyzed condensation of thiou

Full text of DOI:10.1007/s00044-007-9017-8

Med Chem Res (2007) 16:143–154
DOI 10.1007/s00044-007-9017-8
ORIGINAL RESEARCH
Synthesis and bioactivity of some new 1-tolyl-3-aryl-4-
methylimidazole-2-thiones
Aamer Saeed Æ Mahira Batool
Received: 30 November 2005 / Accepted: 5 December 2006 / Published online: 18 August 2007
¨
Ó Birkhauser Boston 2007
Abstract Three series of new 1-(isomeric methyl)benzoyl-3-arylthioureas (1–3a–
i) were prepared from 2-, 3-, and 4-methylbenzoyl chlorides via isothiocyanate
formation followed by treatment with various substituted anilines. The base-cata-
lyzed condensation of thioureas (1–3a–i) with acetone was carried out in the
presence of bromine to afford the corresponding 1-(isomeric methyl) benzoyl-3-
aryl-4-methyl-imidazole-2-thiones (4–6a–i) in good yield. Thioureas and the cor-
responding thiones were characterized by spectroscopic data and elemental
analyses. The mass fragmentation pattern of thiones is also discussed. The thiones
were evaluated for antibacterial, antifungal, and insecticidal activities and exhibit
significant antibacterial activity and slight but not significant antifungal and
insecticidal properties.
Keywords 1-Tolyl-3-arylthioureas Á
1-Tolyl-3-aryl-4-methyl-imidazole-2-thiones Á Bioactivities
Introduction
Various derivatives of imidazole-2-thione have attracted widespread attention
owing to their diverse pharmacological properties and bioactivities (Matsuda et al.,
1997; Du Mont et al., 2001). Imidazol-2-thione moiety is also found in nature. Thus,
L-ergothioneine, a rare, essential natural amino acid discovered in the fungus
Claviceps puprurea, is an antioxidant, known to protect against gamma and UV
radiation and in isolated heart against postischemic reperfusion (Xue and Yadan,
1995). 1-Methylimidazole-2-thione (methimazole), a drug well known for its
A. Saeed (&) Á M. Batool
Department of Chemistry, Quaid-I-Azam University, 45320 Islamabad, Pakistan
e-mail: aamersaeed@yahoo.com

144
Med Chem Res (2007) 16:143–154
effective antithyroid activity, has been shown to be a potent inhibitor of the
thyroperoxidase (TPO)-catalyzed iodination of tyrosine, or tyrosyl residues of
thyroglobulin. It is readily oxidized to bis-[1-methylimidazole(2)] disulfide (Engler
et al., 1982; Aragoni et al., 2002). Derivatives of imidazole-2-thiones block
reactions catalyzed by thyroid peroxidase (TPX) and the lactoperoxidase (LPX), and
this property suggests their use as potential antihyperthyroid drugs that block TPX-
catalyzed tyrosine iodination, but do not cause irreversible enzyme inactivation
(Kruse et al., 1990). Some 1-(4-hydroxybenzyl)imidazole-2-thiones show struc-
tural–activity relationships for novel multisubstrate inhibitors of dopamine b-
hydroxylase, evidenced by their effects on in vitro inhibitory potencies resulting
from structural changes at the Cu-binding region of inhibitor. Attempts were made
to determine replacement groups for the thione of the prototypical inhibitor 1-(4-
hydroxybenzyl)imidazole-2-thione. The synthesis and evaluation of oxygen and
nitrogen analogs of the soft thione group demonstrated that the S atom is necessary
for optimal activity (Kruse et al., 1990). The 1-(pyrrolylalkyl) imidazole-2-thiones
and analogs were prepared for use as cardiotonics, antihypertensives, dopamine b-
hydroxylase inhibitors and are shown to lower blood pressure up to 30–40 mm Hg
in rats (Kruse and Ross, 1990). Variously substituted imidazole-2-thiones form
monolayers by self-assembly with diverse functionality in molecularly controlled
proportions. The formation of monolayers and a novel intercalation property that
results from the presence of voids between the alkyl chains in the monolayers has
also been described (Arduengo et al., 1990). A mevalonate derivative, containing
4,5-diphenyl-lH-imidazol-2-y1 moiety, as a pharmacophore inhibits rat hepatic
microsomal ACAT in vitro and thus has beneficial effects in the treatment of
atherosclerosis (Harris et al., 1992). The 1-benzylimidazole-2-thione moiety is
broadly associated with dopamine b-hydroxylase (DBH) inhibitory activity in
spontaneously hypertensive rats (Doerge et al. 1993). Isomeric 2-, 3-, and 4-(l-
pyridylmethyl)imidazole-2-thiones were prepared to exploit the pH differential that
exists across the chromaffin vesicle membrane and were shown to exhibit modest
DBH inhibition in vitro, but produced significant effects in vivo to increase the
vascular ratio of dopamine to norepinephrine and to lower blood pressure (Ross
et al., 1987). 4-Methyl-5-substituted imidazole-2-thiones derivatives reduce the
reperfusion injury that occurs when oxygen is reintroduced into the ischemic tissue.
They also reduced myocardial stunning, i.e., the prolonged loss of contractile
function in the absence of necrosis after short periods of myocardial ischemia. They
prevent, or lessen, reperfusion injury that occurs when oxygen is reintroduced into
the myocardium after a heart attack (Dage et al., 1989; Schnettler et al., 1989). The
oxidation of ascorbic acid to dehydro-ascorbic acid was accelerated by metal ions
such as copper. This stimulation of ascorbate oxidation was inhibited by the
addition of 2-imidazolethiones and is proposed to complex copper through their free
SH groups (Smith and Gore, 1990). A series of N-aminoimidazoline-2-thiones and
N-aminoimidazoles, with an uncommon spectrum of antiretroviral activity, were
synthesized and tested for their potential to inhibit the replication of HIV and SIV in
a cell culture model for acute infection. They were found to be potent inhibitors of
the HIV-1, HIV-2, and SIV replication in MT-4 cells and their structure–activity
relationships were determined and found to mainly act at the HIV-1 RT according to

Med Chem Res (2007) 16:143–154
145
an NNRTI type mode of action (Lagoja et al., 2003). Some lubricating oils and
anticorrosion-antiwear additives consist of 5,5-di(hydrocarbyl-substituted)-4-imi-
dazolidinethiones (Lagoja et al., 2003; Ren 2000; Mukkamala 2003). 4-Substituted
imidazol-2-thi-ones were prepared as antagonists of a-2B and a-2C adrenergic
receptors and were found to be useful for treatment of diseases responsive to
treatment by agonists of ab-adrenergic receptors. The diseases include corneal,
visceral, and neuropathic pain; neurodegenerative diseases; diarrhea; spinal
ischemia; chronic gastrointestinal diseases; psychoses; arthritis, etc. (Chow et al.,
2003). Copper(I) complexes of tri-o-tolylphosphine and heterocyclic thiones ligands
are reported to possess antifungal activity. 1,3-Imidazole-2-thione derivatives
showed an activity against HIV-1 comparable to the activity of Navirapine (Loksha
et al., 2003). Optically pure 1-aryl-5-hydroxy-4-(D-arabino-tetritol-1-yl)-imidazoli-
dine-2-thione may be used as a chiral auxiliary and ligand for asymmetric catalysis
(Gasch et al., 2000). Chiral imidazolidine-2-thione N-and C-nucleoside are
precursors for the synthesis of azidonucleosides and fluoronucleosides known for
their anti-AIDS activity (Fuentes et al., 2002). N-Substituted 1-amino-2,3-dihydro-
1H-imidazol-2-thiones-N-nucleosides and S-glycosides have also been prepared and
tested against HIV-1 and HIV-2 induced cytopathy in human MT-4 lymphocyte
cells (Al-Masoudi etal., 2003).
Although a number of methods appear in the literature for the synthesis of
substituted imidazol-2-thiones (Xu and Yadan, 1995; Schantl and Lagoja, 1997), but
with the exception of two recent references the 1-aroyl-3-aryl-4-methylimidazole-2-
thiones (Fig. 1) are unreported in the literature (Zeng et al., 2003; Wang et al.,
2005). We report the synthesis, characterization, and bioactivities of some new 1-
(isomeric methyl) benzoyl-3-aryl-4-methylimidazole-2-thiones.
Results and Discussion
The isomeric methyl benzoic acids were converted into the corresponding acid
chlorides using thionyl chloride, then treated with a solution of potassium
thiocyanate in acetone to afford aryl isothiocyanate in situ, followed by refluxing
with substituted anilines to provide 1-isomeric methylbenzoyl thioureas in high
yields. The thioureas were purified by recrystallization using aqueous ethanol and
1
were characterized by Fourier transform infrared spectroscopy (FTIR), H-nuclear
magnetic resonance (NMR) spectroscopy, and mass spectrometry (MS) (Saeed and
Parvez, 2005; Saeed and Florke, 2006). The FTIR data of the 1-isomeric
Fig. 1 1-(Isomeric
methyl)benzoyl-3-aryl-4-
methylimidazole-2-thiones
O
S
R
N
N
H3C
CH3

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Med Chem Res (2007) 16:143–154
Table 1 Physical, IR, and mass spectral data of 1-(isomeric methylbenzoyl)-3-aryl thioureas
Compound M.P. (°C) Yield (%) IR (cm–1) C=C CO
EIMS m/z
NH CS
CN
1a
1b
1c
1d
1e
1f
112
145
85
79
75
70
82
80
85
71
83
72
77
71
75
78
69
72
73
68
65
88
82
81
85
82
83
79
81
76
1593
1595
1598
1593
1586
1561
1567
1557
1582
1588
1584
1580
1581
15
1681 3210 1260 1154 270,177,135, 119
1673 3225 1254 1157 304, 306,177.9,119
1684 3301 1257 1161 304,306,170.9,119
1677 3242 1260 1163 304, 306,170.9,119
1678 3208 1256 1159 347.9, 349.9, 212.9
1670 3231 1260 1150 284, 149, 177,119
1681 3241 1253 115 284, 149, 177,119
1676 3256 1245 1158 300, 177, 165, 119
1673 3287 1248 1154 300, 177, 165, 119
1668 3275 1238 1151 270,177,135, 119
1688 324 1272 1163 304, 306,177.9,119
164
160
120
118
92
1g
1h
1i
104
94
2a
2b
2c
2d
2e
2f
137
124
138
148
117
95
1657 3243 1260 1157
1668 3240 1256 1153
—
—
1672 3213 1240 1159 347.9, 349.9, 212.9
1663 3303 1251 1140 284, 149, 177,119
15
2g
2h
2i
1568
1597
1595
1607
1565
1572
1595
1198
1590
1609
1597
1588
2666 3291 1267 1138
1651 3233 1262 1146 300, 177, 165, 119
1673 3332 1278 1148
1667 3321 1259 1155 177,135, 119
1661 3215 1246 1151
1680 3324 1239 1156 304,306,170.9,119
—
194
79
—
3a
3b
3c
3d
3e
3f
128
156
122
1152
170
90
—
1670 3291 1256 1157
1682 3213 1261 1154
—
—
1672 3219 1251 1156 284, 149, 177,119
3g
3h
3i
112
116
98
1676 3275 1263 1152
1672 3291 1261 1157
—
—
1663 3215 1257 1153 300, 177, 165, 119
methylbenzoyl-3-aryl thioureas showed characteristic peaks for NH at 3350, 3200
cm–1 for free and associated NH, at 1670–1685 cm–1 for carbonyl, at 1245–1260
and 1150–1165 for C=S and C–N peaks, in addition to the aromatic C=C peaks at
1550–1597 cm–1 (Table 1). The characteristic broad singlets for HN(1) and HN(3)
appeared at d 9–10.7 and 12.5–12.7 and those for aromatic protons in the region d
7.2–7.8 ppm in 1H-NMR spectra. Mass spectra of the thioureas showed the
molecular ion peak and the base peak at m/z 119 in each case (Table 1).
The base-catalyzed condensation of 1-(isomeric methyl)benzoyl-3-arylthioureas
with acetone was achieved in the presence of bromine. Thus, triethyl amine was
added to a solution of 1-(isomeric methyl)benzoyl-3-arylthiourea (1–3a–i) in dry
acetone, followed by the treatment with an acetone solution of bromine, and stirring
of the resulting reaction mixture under nitrogen from 30 min to 1 h provided the 1-
tolyl-3-aryl-4-methylimidazole-2-thiones (Scheme 1). Cyclization progress was

Med Chem Res (2007) 16:143–154
147
NH2
O
COOH
R
i) SOCl2 / 2h reflux
ii) KSCN /acetone
H3C
N
C
S
H3C
/acetone/ 1-2 h reflux
O
S
O
S
R
R
N
N
N
NH
H
H3C
H3C
Et3N, Br2 / acetone / N2
(1-3a-i)
CH3
(4-6a-i)
(4a-i) o-Me, (5a-i) m-Me (6a-i) p-Me
a: R=H, b: R=2-Cl
c: R=3-Cl, d: R=4-Cl
e: R=4-Br, f: R=2-CH3
g: R=3-CH3, h: R=2-OCH3
i: R=3-OCH3
(1a-i) o-Me, (2a-i) m-Me (3a-i) p-Me
a: R=H, b: R=2-Cl
c: R=3-Cl, d: R=4-Cl
e: R=4-Br, f: R=2-CH3
g: R=3-CH3, h: R=2-OCH3
i: R=3-OCH3
Scheme 1 Synthesis of 1-(isomeric methyl)benzoyl-3-aryl-4-methylimidazole-2-thiones
monitored by thin-layer chromatography (TLC), with the thiones showing lower Rf
values compared to those of the corresponding thioureas. The melting points of
thiones are lower than those of the thioureas and percent yields of o-tolyl- and p-
tolyl thiones are higher than those of m-tolyl thiones. The compounds were
characterized by the complete absence of NH absorptions of the thiourea moiety and
the appearance of the characteristic peaks for C=O and C=S peaks at 1670–1713 and
1230–1260 cm–1, respectively, in addition to the aromatic and methyl peaks at
1550–1605 and 2851–2965 cm–1 in the IR spectra (Table 2). In the 1H-NMR
spectra, the characteristic singlets for H-C(4) appeared at d 6.30–6.43 and those for
Me-C(4) at d 2.0–2.06 in addition to the peaks for an aromatic methyl at d 2.49 and
two aromatic rings at d 7.1–7.3 and 7.5–7.95 ppm (Table 3). In MS, in addition to
the molecular ion peak M+, the major fragments corresponded to [M+-tolyl]+ and the
base peak at m/z 119 [CH3PhCO]+ which originated from methylbenzoyl part of the
molecule (Scheme 2).
Bioactivities
The thiones (4a–i), (5a–i), and (6a–i) were screened in vitro for antibacterial
activity against the pathogenic bacteria Escherichia coli, Pseudomonas areuginosa,
Staphylococcus aureus, and Bacillus subtilis using the agar well diffusion technique
(Atta-ur-Rahman et al., 2001). Bioactivity was determined via growth inhibition, in
millimeters of each clear zone. Obviously, all of the thiones showed significant
activity against E. coli (Table 4), which in the majority of cases is even more potent
than that of the standard drug, amoxicillin. In general, the following order of activity
among the three series of 1-(isomeric methylbenzoyl)-3-aryl-4-methylimidazole-2-

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Med Chem Res (2007) 16:143–154
CH3
.
.
.
H3C
N
O
N
m/z 65 (22 %)
m/z 91 (67 %)
m/z 215 (37 %)
S
.
CH3
O
.
N
CH3
N
O
N
H3C
Cl
.
S
H3C
O
N
Cl
m/z 119 (100 %)
m/z 342 (1%), 344 (1%)
S
m/z 251 (16 %), 253 (16 %)
CH3
CH3
NH
.
.
.
NH
NH
N
N
O
N
S
m/z 113 (12 %)
m/z 99 (4 %)
m/z 141 (8 %)
S
S
Scheme 2 Mass fragmentation pattern of 1-(2-methylbenzoyl)-3-(4-chlorophenyl)imidazole-2-thione
thiones was observed: 4-methyl benzoyl (4a–i) [ 2-methylbenzoyl (5a–i) [ 3-
methylbenzoyl (6a–i). Compounds 6b–6g bearing 2-, 3-, 4-chloro, 4-bromo, 2-, and
3- methyl substituents, respectively, have comparatively shown the best antibac-
terial activity against each of the four strains of bacteria; compound 6c especially
gave the best response.
1-(Isomeric methylbenzoyl)-3-aryl-4-methylimidazole-2-thiones were also
examined for antifungal activity against pathogenic fungi species: Trichphyton
longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium
solani, and C. glabrata. This was determined by the agar dilution method (Atta-ur-
Rahman et al., 2001) and the results were reported as linear growth (%) mm using
miconazole and amphotericin B as the internal standards. Growth inhibition was
calculated with reference to +ve control. As shown in Table 5, the thiones are
generally inactive as fungicides/fungistatics except for compounds 5d, 5e 6d, and 6e
which exhibited slight but nonsignificant activity.
The insecticidal activity of some selected thiones was determined by the contact
toxicity (Atta-ur-Rahman et al., 2001) method against Tribolium castaneum,
Sitophilus oryzae, Rhyzopertha dominica, and Callosbruchus analis. Table 6 shows
that the majority of these compounds are either inactive or show very weak
insecticidal activity.
In conclusion, the method for the preparation of 1-aroyl-3-aryl-4-substituted
imidazole-2-thiones (4–6) by the cyclization of corresponding 1-aroyl-3-arylthiou-
reas with acetone, in the presence of bromine and triethylamine, has been
established by synthesis of three series of (1-isomeric methyl)benzoyl-3-aryl-4-

Med Chem Res (2007) 16:143–154
149
Table 2 Physical, IR and elemental analysis data of 1-isomeric methylbenzoyl-3-aryl-4-methylimidaz-
ole-2-thiones 4–6a–i
Compound M.P. Yield IR cm–1 CO
CS
CN
Calcd./found C % H % N % S %
°C
%
C=C
4a
4b
4c
172
50
1577
1666 1248 2953 70.10; 5.23; 9.08; 10.40 70.21; 5.10;
9.14; 10.35
206
240
53
50
1567
1560
1653 1236 2851 63.06; 10.34; 8.17; 9.35 63.02; 10.12;
8.09;9.41
1658 1227 2880 63.06; 10.34; 8.17; 9.35 62.97; 10.41;
8.24; 9.41
4d
4e
124
162
58
60
1582
1581
1684 1260 2871 63.06; 10.34; 8.17; 9.35 —
1677 1231 2945 55.82; 3.90; 7.23; 8.28 55.71; 3.92;
7.31; 8.20
4f
190
82
64
61
59
1584
1592
1600
1713 1237 2938 70.78; 5.63; 8.69; 9.94 70.81; 5.67;
8.71; 9.90
4g
4h
1701 1240 2921 70.78; 5.63; 8.69; 9.94 70.69; 5.60;
8.61; 9.89
194
1671 1243 2932 67.43; 5.36; 8.28; 9.47 67.18; 5.21;
8.39; 9.51
4i
172
142
63
52
1603
1593
1660 1260 2965
—
5a
1683 1259 2936 70.10; 5.23; 9.08; 10.4069.93; 5.37;
9.13; 10.57
5b
5c
221
194
55
59
1580
1595
1679 1263 2942
—
1663 1261 2913 63.06; 10.34; 8.17; 9.35 63.02; 10.12;
8.17; 9.41
5d
5e
5f
127
175
230
64
66
49
1598
1588
1594
1667 1268 2920
1690 1271 2938
—
—
1656 1256 2924 70.78; 5.63; 8.69; 9.94 70.84; 5.67;
8.71; 9.89
5g
5h
220
117
45
50
1593
1591
1668 1246 2919
—
1660 1260 2938 67.43; 5.36; 8.28; 9.47 67.18; 5.21;
8.39; 9.51
5i
109
181
53
73
1603
1590
1660 1260 2965 67.43; 5.36; 8.28; 9.4767.40; 5.56;
8.14; 9.63
6a
1665 1191 2938 70.10; 5.23; 9.08; 10.40 69.93; 5.37;
9.13; 10.57
6b
6c
6d
243
179
162
71
68
75
1585
1563
1586
1639 1260 2938
1679 1268 2921
—
—
1660 1250 2922 63.06; 10.34; 8.17; 9.3563.02; 10.12;
8.17; 9.41
6e
184
79
1580
1673 1240 2934 55.82; 3.90; 7.23; 8.2855.71; 3.92;
7.31; 8.20
6f
191
132
212
66
57
67
1557
1600
1599
1680 1252 2927
1670 1257 2917
—
—
6g
6h
1656 1263 2934 67.43; 5.36; 8.28; 9.47 67.18; 5.21;
8.39; 9.51
6i
220
65
1582
1679 1248 2948
—

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Med Chem Res (2007) 16:143–154
Table 3 1H-NMR and mass spectral data of 1-isomeric methylbenzoyl-3-aryl-4-methylimidazole-2-
thiones 4-6a-i
Compound
d CDCl3 ppm
EIMS m/z
C4-H
C5-Me
M+.
[M-91]+
[ArCO]
4a
4b
4c
4d
4e
4f
6.30
6.32
6.34
6.38
6.31
6.35
6.37
6.36
6.34
6.38
6.34
6.34
6.28
6.30
6.37
6.41
6.40
6.45
6.38
6.34
6.34
6.28
6.30
6.42
6.40
6.40
6.43
2.05
2.05
2.05
2.03
2.02
2.02
2.02
2.02
2.07
2.06
2.05
2.05
2.03
2.02
2.04
2.02
2.02
2.07
2.06
2.05
2.05
2.03
2.02
2.02
2.02
2.02
2.07
308
342
342
342
386
322
322
338
338
308
—
217, 189
251, 215
251, 215
251, 215
295, 215,
342, 215,
342, 215,
247, 233,
247, 233,
217,189,
119
119
119
119
119
119
119
119
119
119
4g
4h
4i
5a
5b
5c
5d
5e
5f
342
—
251, 215,
295, 215,
119
119
386
—
5g
5h
5i
322
338
—
342, 215,
247, 233,
119
119
6a
6b
6c
6d
6e
6f
308
—
217,119
322
328
—
231, 119
291, 119
—
6g
6h
6i
—
—
—
methylimidazole-2-thiones. The thiones exhibit significant antibacterial activity and
slight but not significant antifungal and insecticidal properties.
Experimental
Melting points were recorded via a MEL TEMP MP-D apparatus and are
uncorrected. 1H-NMR spectra were determined in CDCl3 at 400 MHz using a
Bruker AM-400 machine. FTIR spectra were recorded on an FTS 3000 MX
spectrophotometer and mass spectra (EI, 70eV) on a MAT 312 instrument.
Elemental analyses were conducted using a LECO-183 CHNS analyzer. Bioactiv-
ities were carried out at the International Centre for Chemical Sciences Karachi,
Pakistan.

Med Chem Res (2007) 16:143–154
151
Table 4 Antibacterial bioassay of (1-(isomeric methyl)benzoyl-3-aryl-4-methylimidazole-2-thiones
(4–6a–i)
Compound
Escherichia coli Bacillus subtilis Staphylococcus aureus Pseudomonas aeruginosa
4a
4b
4c
4d
4e
4f
13
14
15
18
16
18
15
12
13
13
13
13
13
13
13
13
12
17
20
19
14
18
12
10
11
—
17
10
—
14
12
10
11
13
13
17
15
15
13
—
14
—
15
14
13
17
18
10
12
13
34.89
—
17
19
10
—
13
12
14
—
13
13
—
—
—
—
—
—
21
18
20
14
22
18
-
—
7
—
13
10
—
—
6
4g
4h
4i
11
—
—
—
—
—
—
—
—
12
16
17
13
10
14
-
5b
5c
5d
5e
5f
5g
5h
5i
6b
6c
6d
6e
6f
6g
6h
6i
-
-
Amoxicillin 13.26
25
10
Concentration = 2 mg/ml of DMSO; diameter of well = 6 mm
Synthesis of 1-(isomeric methylbenzoyl)-3-arylthioureas
To a stirred solution of potassium thiocyanate (20 mmol) in dry acetone (10 ml)
was added, dropwise, isomeric methylbenzoyl chloride (20 mmol). After the initial
reaction had subsided, the mixture was heated for 30 min and then a hot solution
of suitably substituted aniline (20 mmol) in acetone (10 ml) was added slowly
with constant stirring followed by reflux for 1 h. The mixture was poured into five
times its volume of cold water when the 1-(isomeric methylbenzoyl)-3-arylthiou-
reas precipitated as solids, or as slowly crystallizing oils that were recrystallized
from aqueous ethanol. The physical, IR, and elemental analysis data are given in
Table 1.

152
Med Chem Res (2007) 16:143–154
Table 5 Antifungal bioassay of (1-isomeric methyl)benzoyl-3-aryl-4-methylimidazole-2-thiones (4–6a–
i)
Compound
LINEAR GROWTH (mm)
Trichphyton
longifusus
Candida
albicans
Aspergillus
flavus
Pseudomonas
aeruginosa
Fusarium
solani
Candida
glabrata
4a
100
100
90
100
100
75
–100
80
100
100
100
90
100
85
100
100
100
100
100
100
100
79
4b
4c
69
100
100
100
100
100
100
100
100
76
4d
80
100
100
100
100
80
65
4e
100
100
100
100
100
100
100
75
100
100
100
100
100
100
100
89
100
100
100
67
4f
4g
4h
4i
100
100
100
65
65
76
5b
100
100
100
78
100
89
5c
5d
100
100
100
100
100
100
100
100
95
83
5e
77
89
60
90
5f
100
100
100
100
100
90
100
100
100
100
100
100
100
68
100
100
100
100
100
86
100
100
100
100
100
100
60
100
100
100
100
100
90
5g
5h
5i
6a
6b
6c
80
100
69
100
100
100
100
100
100
100
0
6d
79
100
100
100
100
100
100
0
85
6e
90
80
100
100
100
100
100
0
68
6f
100
100
100
100
0
100
92
100
100
100
100
0
6g
6h
100
100
0
6i
+ ive Control
-ive Control
Standard drug
100
70a
100
110.8a
100
20b
100
98.4a
100
73.23a
100
110.8a
Conc. 200 mg/ml of media SDA (Sabuoraud dextrose agar). The values for standard drugs indicate linear
growth inhibition (%). Standard drugs are a: miconazole, b: amphotericin B
Synthesis of (1-isomeric methyl)benzoyl-3-aryl-4-methylimidazole-2-thiones
To a stirred solution of 1-(isomeric methyl)benzoyl-3-arylthiourea (2 mmol) in 20
ml of dry acetone and triethylamine (3 ml, 2 mmol) was added, dropwise, a solution
of bromine 0.1 ml (2 mmol) in dry acetone (10 ml) under nitrogen and the reaction
mixture stirred for 30 min to 1 h. After the reaction was completed, the reaction
mixture was filtered and the filtrate was concentrated to afford crude 1-(isomeric

Med Chem Res (2007) 16:143–154
153
Table 6 Insecticidal bioassay of some selected 1-(4-methylbenzoyl)-3-aryl-4-methylimidazole-2-
thiones
Compound % Mortality
Tribolium castaneum Sitophilus oryzae Rhyzopertha dominica Callosbruchus analis
+ve Control 100
100
0
100
0
100
0
-ve Control
0
4a
4c
4d
4e
5b
5c
5d
5e
6b
6c
6d
6e
0
0
0
0
0
0
0
0
51
23
0
32
20
0
10
31
0
20
32
0
29
0
31
26
19
43
14
10
31
26
25
34
25
18
20
19
0
60
0
23
20
20
19
20
10
30
0
0
Concentration = 200 lg/ml; standard drug = Permethrin (Coopex)
methylbenzoyl)-3-aryl-4-methylimidazole-2-thiones, then purified by recrystalliza-
tion from suitable solvents. The physical, IR, and elemental analysis data appear in
Table 2 and 1H-NMR and EIMS data in Table 3, respectively.
Acknowledgments This work was supported by the Quaid-I-Azam University Islamabad Research
Fund, Project No. DFNS/2006–382.
References
Al-Masoudi AI, Khodair AI, Al-Soud YA, Al-Masoudi NA (2003) Synthesis of N-Substituted 1-Amino-
2,3-dihydro-1H-imidazole-2-thione-N-nucleosides and S-Glycosylated Derivatives, Nucleosides.
Nucleotides and Nucleic Acids 22:299–307
Aragoni MC, Arca M, Demartin F, Devillanova FA, Garau A, Isaia F, Lippolis V, Verani G (2002) Anti-
Thyroid Drug Methimazole: X-ray Characterization of Two Novel Ionic Disulfides Obtained from
Its Chemical Oxidation by I2. J. Am. Chem. Soc. 124:45388–45389
Arduengo AJ, Moran JR, Rodriguez-Parada J, Ward MD (1990) Molecular control of self-assembled
monolayer films of imidazole-2-thiones: adsorption and reactivity, J. Am. Chem. Soc. 112:6153–
6154
Atta-ur-Rahman, Choudhary MI, Thomsen J (2001) In Bioassay Techniques for Drug Development,
Harwood Academic Publishers, The Netherlands, pp.16, 22, 67
Chow K, Heidelbaugh T, Gil D, Garst M, Micheal LA, Nguyen PX, Gomex DG (2003) Preparation of 4-
substitued imidazole-2-thiones and imidazol-2-ones as agonists of alpha-2B and alpha -2C
adrenergic receptors, PCT Int. Appl.WO 03 99,795 (2002). Chem. Abstr. 140:5050k
Dage RC, Schnettler RA (1989) Reducing reperfusion injury with imidazole-2-thiones, Eur.Pat. Appl.EP
284,925 (1987). Chem. Abstr. 110:88630d
Doerge DR, Decker CJ, Takazawall RS (1993) Chemical and enzymic oxidation of benzimidazoline-2-
thiones: a dichotomy in the mechanism of peroxides inhibition Biochemistry 32:58–65

154
Med Chem Res (2007) 16:143–154
Du Mont W-W, Mugesh G, Wismach C, Jones PG (2001) Reactions of Organo-selenenyl Iodides with
Thiouracil Drugs: An Enzyme Mimetic Study on the Inhibition of Iodothyronine Deiodinase,
Angew. Chem., Int. Ed. 40:2486–2489
Engler H, Taurog A, Nakashima T (1982) Mechanism of inactivation of thyroid peroxidase by
thioureylene drugs. Biochem. Pharmacol. 31:3801–3806
Fuentes J, Angulo M, Pradera MA (2002) Fluoronucleosides, Isothiocyanato C Nucleosides, and
Thioureylene Di-C-nucleosides via Cyclic Sulfates. J. Org. Chem. 67:2577–2587
Gasch C, Pradera MA, Salameh BAB, Molina JL, Fuentes J (2000) Chiral thioxohydroimidazoles with
two sugar moieties. N-, C-, and spironucleosides Tetrahedron Asymmetry 11:435–452
Harris NV, Smith C, Ashton MJ, Bridge W, Bush RC, Coffee ECJ, Dron DI, Harper MF, Lythgoe DJ,
Newton CG, Riddell D (1992) Acyl-CoA:cholesterol O-Acyl Transferase (ACAT) Inhibitors. 1. 2-
(Alkylthio)-4,5-diphenyl-1H-imidazoles as Potent Inhibitors of ACAT J. Med. Chem. 35:4384–3492
Kruse LI, Kaiser C, DeWolf WE, Walter E, Finkelstein JA, Frazee JS, James S, Hilbert EL, Ross ST,
Stephen T, Flaim KE, Sawyer JL (1990) Substrate inhibitors of dopamine-b-hydrolase. 4. Structure
activity relationships at the copper binding site. J. Med. Chem. 33:781–789
Kruse HP, Matthias Heydenreich M, Engst W, Schilde W, Krolla J (2005) The identification of 1,3-
oxazolidine-2-thiones and 1,3-thiazolidine-2-thiones from the reaction of glucose with benzyl
isothiocyanate, Carbohyd. Res. 340:203–210
Lagoja IM, Pannecouque C, Aerschot AV, Myriam W, Debyser Z, Alzarini JB, Herdewijin P, Clercq ED
(2003) N-Aminoimidazole Derivatives Inhibiting Retroviral Replication via a Yet Unidentified
Mode of Action, J. Med. Chem. 46:1546–1553
Loksha YM, El-Badawi MA, El-Barbary AA, Pedersen EB, Nielsen C (2003) Synthesis of 2-
methylsulfanyl-1H-imidazoles as novel non-nucleoside reverse transcriptase inhibitors (NNRTIs),
Arch. Pharm. 336:175–180
Matsuda K, Yanagisawa I, Isomura Y, Mase T, Shibanuma T (1997) One-Pot Preparation of 1-Substituted
Imidazole-2-thione from Isothiocyanate and Amino Acetal, Synth. Commun 27:3565–3569
Mukkamala R (2003) Lubricating oil anticorrosion-antiwear additives consisting of alkylated imidaz-
olidinethiones and zinc diththiophosphates, U.S. Pat. Appl. Publ. US 2002 198,115 (2002). Chem.
Abstr. 138:58652y
Ren J, Nichols C, Bird LE, Fujiwara T, Sugimoto H, Stuart DI, Stammers DK (2000) Binding of the
second generation non-nucleoside inhibitor S-1153 to HIV-1 reverse transcriptase involves
extensive main chain hydrogen bonding. J. Biol. Chem. 275:14316–14320
Ross ST, Kruse LI, Ohlstein EH, Erickson R, Ezekiel RW, Flaim M, Sawyer KE, Berkowitzi BA (1987)
Inhibitors of dopamine beta-hydroxylase. Some 1-(pyridylmethyl)imidazole-2-thiones. J. Med.
Chem. 30:1309–1313
Saeed A, Florke U (2006) 1-(2-Chlorophenyl)-3-(4-methylbenzoyl)thiourea, Acta Cryst. E.62:2403–2405
Saeed A, Parvez M (2005) The Crystal Structure of 1-(4-Chlorophenyl)-3-(4-methyl benzoyl) thiourea.
Cent. Eur. J. Chem. 3: 780–791
Schantl JG, Lagoja IM (1997) Direct Synthetic Approach to N-substitued 1-Amino-2,4-dihydro-1H-
imidazole-2-thiones, Heterocycles 45:691–700
Schnettler RA, Dage RC, Grisar JM, Palpoloi FP (1990) Reducing reperfusion injury with 1,3-dihydro-4-
methyl-5-[4-(methylthio)benzoyl]-2H-imdazole-2-thione, U.S. US 4,868,187 (1989). Chem. Abstr.
112:70022p
Smith RC, Gore JZ (1990) 2-Imidazolethiones Protect Ascorbic Acid From Oxidation Induced by
Copper, Biochim. Biophys. Acta. 1034:263–267
Wang X-C, Wang F, Quan Z-J, Wang M-G, Z Li (2005) An efficient and clean synthesis of 1-aroyl-3-
aryl-4-substituted imidazole-2-thiones in water. J. Chem. Res. 61:689–690
Xu J, Yadan J-C (1995) A new and convenient synthesis of imidazol-2-thiones from imidazoles, Synlett.
239–241
Xue J, Yadan JC (1995) Synthesis of L-(+)-Ergothioneine, J. Org. Chem. 60:6296–6301
Zeng RS, Zou J-P, Zhi S-J, Chen J, Shen Q (2003) Novel Synthesis of 1-Aroyl-3-aryl-4-substituted
Imidazole-2-thiones. Organic Lett. 61:1657–1659