Design, synthesis, and in vitro antitumor activity of new 1,4-diarylimidazole-2-ones and their 2-thione analogues

Article abstract of DOI:10.1016/j.bmcl.2007.12.023

A series of new 1,4-diarylimidazol-2(3H)-one derivatives and their 2-thione analogues has been prepared and evaluated in vitro for antitumor activity against the NCI human cancer cell panel. Compounds bearing a 3,4,5-trimethoxyphenyl ring linked to either

Full text of DOI:10.1016/j.bmcl.2007.12.023

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 989–993
Design, synthesis, and in vitro antitumor activity of new
1,4-diarylimidazole-2-ones and their 2-thione analogues
Cenzo Congiu,* Maria Teresa Cocco and Valentina Onnis
`
Dipartimento di Tossicologia, Universita degli Studi di Cagliari, via Ospedale 72, Cagliari I-09124, Italy
Received 15 November 2007; revised 7 December 2007; accepted 11 December 2007
Available online 15 December 2007
Abstract—A series of new 1,4-diarylimidazol-2(3H)-one derivatives and their 2-thione analogues has been prepared and evaluated
in vitro for antitumor activity against the NCI human cancer cell panel. Compounds bearing a 3,4,5-trimethoxyphenyl ring linked to
either N-1 or C-4 position of the imidazole core demonstrated an interesting profile of cytotoxicity with preferential activity against
leukemic cell lines. Compound 13 exhibited a potent antitumor activity against MOLT-4 (GI50 = 20 nM) and SR (GI50 = 32 nM)
cell lines.
Ó 2007 Elsevier Ltd. All rights reserved.
The discovery of anticancer properties of the combre-
tastatins, a group of antimitotic agents isolated from
the bark of the South African willow tree Combretum
caffrum Kuntz,1 has attracted considerable interest of
medicinal chemists in the design of analogues as novel
antitumor agents. Combretastatin A-4 (CA-4, Fig. 1)
appears to be the most active compound in the group,
showing potent inhibitory activity against a variety of
human cancer cells, including multi-drug resistant cell
lines.2 CA-4 is one of the most potent antimitotic agents
and binds to tubulin on the colchicine binding site.3 The
low water solubility of CA-4 limits its efficacy in vivo,
and several attempts have been made to produce an ac-
tive water-soluble derivative.4 The most effective is the
disodium phosphate salt and is the form of CA-4 cur-
rently in Phase II clinical trials.5 Moreover, the Z-con-
figured ethenyl bridge of CA-4 is prone to isomerize to
the E-form during storage and administration leading
to dramatic reduction in both antitubulin activity and
cytotoxicity.5a,6 Therefore, considerable efforts have
gone into modifying CA-4 and discovering its new pos-
sible bioisosteres, based on replacement of the Z-re-
stricted double bond.7 Many synthetic analogues have
been developed following the strategy of design of
two-atom bridgehead analogues utilizing 1,2-oriented
heterocycles.8 In contrast, a limited number of ana-
logues have been successfully designed following the
strategy of three-atom bridgeheads 1,3-oriented with a
MeO
MeO
OH
OMe
OMe
CA-4
O
O
N N
O
MeO
MeO
MeO
Aryl
MeO
MeO
NH2
OMe
Chalcones
A-105972
Figure 1. CA-4 and three-atom bridgehead 1,3-oriented analogues.
linear- or heterocycle-linker inserted between the two
aryl rings of combretastatins. A series of chalcones,
developed by Edwards et al.,9 and a large collection of
oxazoline and oxadiazoline derivatives, analogues of
A-105972 obtained in the Abbott Laboratories,10 consti-
tuted some examples of compound designed following
this strategic approach (Fig. 1).
In our efforts to discover new active antitumor agents,
we were particularly interested in the imidazole ring. Ba-
sic nitrogen atoms of the imidazole ring may lead to
compounds with decreased lipophilicity that can be
formulated into water-soluble salts to give improved
pharmacokinetic properties. As far as the imidazole
derivatives are concerned, a literature survey in the field
Keywords: Imidazole derivatives; Antitumor activity.
*
Corresponding author. E-mail: ccongiu@unica.it
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.12.023

990
C. Congiu et al. / Bioorg. Med. Chem. Lett. 18 (2008) 989–993
NH2
X
H
N
A
N
R'
O
R
B
C
H
N
2
a
R
+
1a: X = O
b: X = S
R
R'
4
O
Br
Figure 2.
b
R'
3
of synthetic antitumor agents revealed that there was an
apparent lack of imidazolone-type compounds. Re-
cently a trisubstituted imidazolone derivative has been
reported to induce apoptosis in human leukemia cells.11
O
H
N
N
R
R'
5-22
Based on these considerations, we designed an easy syn-
thetic approach for preparing of 1,4-diaryl-1H-imidazol-
2(3H)-ones 1a in order to study their antitumor activity
(Fig. 2).
5: R = 3,4,5-(MeO)3; R' = H
6: R = 3,4,5-(MeO)3; R' = 4-F
7: R = 3,4,5-(MeO)3; R' = 4-Cl
8: R = 3,4,5-(MeO)3; R' = 4-MeO
9: R = 3,4,5-(MeO)3; R' = 3,4-(MeO)2
10: R = 3,4-(MeO)2; R' = 4-Cl
In this communication, we wish to report the synthesis
and preliminary anticancer activity of a series of new
imidazolone derivatives, and their 2-thione analogues
1b (Fig. 2). These compounds have been designed fol-
lowing the strategy of three-atom bridgehead 1,3-ori-
ented CA-4 analogues, where the imidazole core (ring
A) serves as a linker between functionalized B- and C-
rings. Some recent reviews have meticulously summa-
rized structure activity relationships of CA-4 and its syn-
11: R = 3,4-(MeO)2; R' = 4-MeO
12: R = 4-F; R' = 3,4,5-(MeO)3
13: R = 4-Cl; R' = 3,4,5-(MeO)3
14: R = 4-MeO; R' = 3,4,5-(MeO)3
15: R = 3,4-(MeO)2; R' = 3,4,5-(MeO)3
16: R = 3-Cl-4-MeO; R' = 3,4,5- (MeO)3
17: R = 3,4-Cl2; R' = 3,4,5-(MeO)3
18: R = 4-Cl; R' = 3,4-(MeO)2
19: R = 4-MeO; R' = 3,4-(MeO)2
20: R = 3-Cl-4-MeO; R' = 3,4-(MeO)2
21: R = 3-Cl-4-MeO; R' = 4-Cl
22: R = 4-Cl; R' = 3,4-Cl2
thetic analogues,12 and outlined that
a
3,4,5-
Scheme 1. Synthesis of N-arylphenacylamines
4
limidazol-2-ones 5–22. Reagents and conditions: (a) NaHCO3, MeOH,
25 °C, 16 h; (b) KOCN, AcOH, 60–65 °C, 1 h.
and 1,4-diary-
trimethoxyphenyl ring was essential for potent antitu-
mor activity. Therefore, we started our study from 4-
phenyl-1-(3,4,5-trimethoxyphenyl)-1H-imidazol-2(3H)-
one 5 and designed systematic structural variations on
1,3-oriented phenyl rings. The antiproliferative proper-
ties of these compounds against the NCI human cancer
cell line panel were evaluated.
S
H
N
a
N
R'
4
R
The synthesis of some 1- or 4-arylimidazol-2(3H)-ones
has been described.13 The only reported 1,4-diaryl deriv-
ative, namely the 1,4-diphenyl-1H-imidazol-2(3H)-one,
has been synthesized by the acid promoted dehydration
of the corresponding 4-hydroxy-2-imidazolidinone.14 In
our approach, 1,4-diaryl-1H-imidazol-2(3H)-one system
was conveniently assembled by first setting a functional-
ized intermediate, bearing substitution patterns on pen-
dant B- and C-rings, and then closing the central A-ring.
Compounds 5–22 were prepared as shown in Scheme 1.
Coupling of an aniline 2, from which the B-ring was de-
rived, with a phenacyl bromide 3, bearing a substitution
pattern desired for the C-ring, afforded a wide array of
N-arylphenacylamines 4. Compounds 4 represent an
easily available key intermediate for introduction of
opportunely substituted B- and C-rings. The reaction
was performed at room temperature, in anhydrous
methanol and in the presence of two equivalents of so-
dium bicarbonate. N-Arylphenacylamines 4 were then
reacted with a large excess of potassium cyanate in ace-
tic acid at 60–65 °C to effect closure of the imidazolone
ring affording compounds 5–22 in 56–92% yields.15
23-37
23: R = 3,4,5-(MeO)3; R' = H
24: R = 3,4,5-(MeO)3; R' = 4-Cl
25: R = 3,4,5-(MeO)3; R' = 4-MeO
26: R = 3,4,5-(MeO)3; R' = 3,4-(MeO)2
27: R = 3,4-(MeO)2; R' = 4-Cl
28: R = 3,4-(MeO)2; R' = 4-MeO
29: R = 4-Cl; R' = 3,4,5-(MeO)3
30: R = 4-MeO; R' = 3,4,5-(MeO)3
31: R = 3,4-(MeO)2; R' = 3,4,5-(MeO)3
32: R = 3-Cl-4-MeO; R' = 3,4,5-(MeO)3
33: R = 4-Cl; R' = 3,4-(MeO)2
34: R = 4-MeO; R' = 3,4-(MeO)2
35: R = 3-Cl-4-MeO; R' = 3,4-(MeO)2
36: R = 3-Cl-4-MeO; R' = 4-Cl
37: R = 4-Cl; R' = 3,4-Cl2
Scheme 2. Synthesis of 1,4-diarylimidazole-2-thiones 23–37. Reagents
and conditions: (a) NH4SCN, 10% aq HCl, reflux, 1.5 h.
Thus, upon reaction between N-arylphenacylamines 4
and ammonium thiocyanate in boiling 10% hydrochloric
acid, compounds 23–37 were obtained in 64–86%
yields.17 Analytical and spectral data accounted for the
assigned structures.
The imidazole-2-thione analogues were prepared by
some modification of established procedures16 (Scheme 2).
Synthesized compounds were submitted to the National
Cancer Institute (NCI, Bethesda, MD) for the human

C. Congiu et al. / Bioorg. Med. Chem. Lett. 18 (2008) 989–993
991
tumor cell screen. Selected compounds were tested ini-
tially at a single high dose (10À5 M) in the full NCI 60
cell panel.18
activity parameter over all cell lines. For the calculation
of MG_MID, insensitive cell lines were included with
the highest concentration tested.
Only compounds which satisfy pre-determined thresh-
old inhibition criteria will progress to evaluation in the
same full panel using five concentrations at 10-fold dilu-
tions, ranging from 10À4 to 10À8 M. For each com-
pound in the 5-dose screen, anticancer activity was
deduced from dose–response curves and expressed by
three parameters (GI50, TGI, LC50) calculated for each
cell line. The GI50 value indicates the concentration of
the compound required to cause 50% inhibition of net
cell growth. The TGI value represents the concentration
of the compound resulting in total inhibition of net cell
growth. The LC50 value refers to the concentration of
the compound leading to 50% net cell death. Moreover,
for each antitumor activity parameter, mean graph mid-
point (MG_MID) was calculated giving an averaged
An overview of antiproliferative activities of imidazole
derivatives compared to the reference compound CA-4
is reported in Table 1. Tested compounds show moder-
ate to significant cytotoxicity, and preferential growth
inhibitory activity against cell lines of the leukemia
sub-panel. The mean GI50 values across the range of
compounds are an unremarkable 10–100 lM; however,
selective cytotoxic effects are elicited depending on sub-
stitution pattern of these new imidazole derivatives.
The most interesting series of compounds are those
bearing a 3,4,5-trimethoxyphenyl ring linked to either
N-1 or C-4 position of imidazole core. Replacement
of the 2-carbonyl function of imidazole ring by 2-thio-
carbonyl always results in modification of cell
chemosensitivity.
Table 1. Overview of antiproliferative activities of imidazole derivatives and CA-4 against the NCI human cancer cell panela
Compound
5
7
11
13
16
22
31
32
33
35
36
CA-4b
Panel/cell line
Leukemia
CCRF-CEM
HL-60 (TB)
MOLT-4
<4
4.2
<4
<4
<4
>8.0
<4
<4
4.4
<4
6.4
<4
<4
<4
<4
4.3
4.4
4.5
<4
<4
6.2
<4
<4
5.3
ntd
<4
5.5
<4
5.4
5.5
<4
<4
4.1
<4
<4
4.2
<4
4.4
4.3
nt
7.0
7.5
<4
5.8
<4
7.0 (6.2)c
7.7
<4
7.5 (4.4)c
4.7
4.2
5.3 (4.8)c
5.2
<4
5.6 (5.1)c
7.0
6.8
6.9 (4.1)c
RPMI-8226
SR
4.9
<4
Non-small cell lung cancer
EKVX
HOP-92
4.6
4.7
4.5
nt
<4
<4
<4
<4
<4
4.8
4.5
4.8
<4
<4
4.4
4.5
4.9
6.5 (5.1)c
4.4
4.4
4.4
4.8
6.4
6.7 (4.4)c
Colon cancer
HCT-116
HCT-15
4.2
4.1
4.5
<4
<4
<4
<4
<4
<4
<4
4.8
<4
<4
<4
4.6
<4
5.4
5.3
<4
<4
4.3
<4
7.5
7.5
CNS cancer
SF-295
SF-539
4.4
4.7
4.9
4.5
4.6
4.6
<4
<4
4.6
<4
<4
<4
4.4
4.5
5.2
4.6
4.7
4.7
<4
<4
4.2
4.4
4.7
4.7
5.2
4.5
4.8
4.4
4.4
5.3
4.6
7.2
7.4
6.1
4.70
4.7
SNB-75
Melanoma
LOX IMVI
SK-MEL-5
UACC-62
<4
4.4
4.4
4.2
4.5
4.6
<4
4.2
<4
<4
<4
<4
<4
<4
4.3
4.4
4.4
4.6
<4
<4
<4
5.2
4.6
<4
5.8 (5.5,c 5.2e)
<4
<4
<4
4.0
4.4
4.1
8.0 (4.9)c
8.0
8.0
5.5
nt
Renal cancer
786-0
4.6
4.4
nt
4.8
4.8
nt
<4
<4
nt
<4
<4
<4
<4
4.6
<4
nt
4.7
4.6
4.5
4.6
<4
<4
<4
<4
4.6
5.3
4.8
4.4
5.2
5.5
5.5
4.4
4.3
<4
nt
4.7
4.6
4.6
4.7
7.7
7.4
6.1
6.7
CAKI-1
RXF 393
UO-31
4.4
4.7
<4
<4
<4
Prostate cancer
PC-3
DU-145
4.4
5.8
4.8
4.2
<4
<4
<4
<4
<4
nt
4.2
4.5
<4
<4
4.3
4.5
4.2
4.9
<4
<4
4.5
4.4
7.5
8.0
Breast cancer
HS 578T
TD-47D
MG_MIDf
4.5
4.5
4.1
nt
<4
4.3
<4
<4
4.5
<4
4.8
4.6
<4
<4
4.8
4.5
4.7
5.2
4.4
<4
4.6
4.7
6.8
4.3
4.43
4.50
4.13
4.17
4.13
4.55
4.05
4.50
4.88
4.09
4.37
7.00
a Values are reported as pGI50, the Àlog of molar concentration of the compound required to cause 50% inhibition of net cell growth.
b http://dtp.nci.nih.gov/dtpstandard/dwindex/index.jsp.
c pTGI, the Àlog of molar concentration of the compound resulting in total inhibition of net cell growth.
d nt, not tested.
e pLC50, the Àlog of molar concentration of the compound required to cause 50% net cell death.
f MG_MID (mean graph midpoint) is the averaged activity parameter over all cell lines.

992
C. Congiu et al. / Bioorg. Med. Chem. Lett. 18 (2008) 989–993
Among imidazolone derivatives, compound 5 shows
moderate activity against the full NCI 60 cell panel, with
a MG-MID value of 4.43. However, 5 exhibits high
selectivity against the DU145 prostate cancer cell line
(pGI50 = 5.8). The 4-chlorophenyl analogue 7 also re-
tains moderate activity in the full NCI 60 cell panel
(MG-MID = 4.50), but it shows nanomolar selective
inhibitory potency (pGI50 > 8) against the CCRF-
CEM leukemic cell line. Inversion of pendant aryl rings
on the imidazolone core of 7 leads to compound 13
which inhibits in nanomolar concentration the growth
of HL-60 (TB) (pGI50 = 6.4), MOLT-4 (pGI50 = 7.7),
and SR (pGI50 = 7.5) leukemic cell lines. These are very
good results as compared to pGI50 values of reference
compound CA-4 (Table 1). Replacement of 4-chloro-
phenyl of 7 with a 4-methoxyphenyl gives the inactive
compound 8. While, the lack of 5-methoxy group in tri-
methoxyphenyl ring of 8 affords imidazolone 11 that
selectively inhibited in sub-micromolar concentrations
the growth of leukemic SR cell line at GI50
(pGI50 = 7.0) and TGI (pTGI = 6.2) levels. This pTGI
value as well as those of compounds 13 and 22 (4.4
and 4.8, respectively) are better than that of CA-4
(4.1) (Table 1).
tend SAR. Compounds bearing a 3,4,5-trimethoxy-
phenyl ring linked to either N-1 or C-4 position of
imidazole core show the most interesting profile of cyto-
toxicity with preferential activity against cell lines of the
leukemia sub-panel, in some cases with GI50 values in
nanomolar concentrations. In contrast, the imidazole-
2-thione 33, bearing a 3,4-dimethoxyphenyl group at
C-4 position, shows expanded activity spectrum with
GI50 values in micromolar concentrations. Moreover,
several derivatives have been found to be more cytotoxic
than CA-4.
Acknowledgments
The authors thank the Developmental Therapeutics
Program of the National Cancer Institute, Bethesda,
MD, for providing the in vitro antitumor screening
data.
References and notes
1. Pettit, G. R.; Cragg, G. M.; Singh, S. B. J. Nat. Prod.
1987, 50, 386.
2. McGown, A. T.; Fox, B. W. Cancer Chemother. Pharma-
col. 1990, 26, 79.
In the series of imidazole-2-thione analogues, compound
32, which retains the 3,4,5-trimethoxyphenyl group at
C-4, shows good potency and selectivity against the
CCRF-CEM cell line (pGI50 = 6.2) of leukemia sub-pa-
nel. Imidazolethione 32 shows a clear improvement of
growth inhibitory activity compared to the imidazolone
analogue 16. Lack of 5-methoxy group in trimethoxy-
phenyl ring of 32 gives compound 35 and results in
diminished inhibitory potency. In contrast, replacement
of 3-chloro-4-methoxyphenyl of 35 with a 4-chloro-
phenyl ring gives the analogue 33 and results in remark-
able enhancement of antiproliferative activity. As a
result, 33 exhibits the best MG_MID value (4.88), with
inhibitory potency in low micromolar values against 27
cell lines, being NSCLC HOP-92 the most sensitive
(pGI50 = 6.5, pTGI = 5.1).
3. Pettit, G. R.; Singh, S. B.; Hamel, E.; Lin, C. M.; Alberts,
D. S.; Garcia-Kendall, D. Experientia 1989, 45, 209.
4. (a) Dorr, R. T.; Dvorakova, K.; Snead, K.; Alberts, D. S.;
Salmon, S. E.; Pettit, G. R. Invest. New Drug 1996, 14,
131; (b) Ohsumi, K.; Nakagawa, R.; Fukuda, Y.; Hata-
naka, T.; Morinaga, Y.; Nihei, Y.; Ohishi, K.; Suga, Y.;
Akiyama, Y.; Tsuji, T. J. Med. Chem. 1998, 41, 3022.
5. (a) Pettit, G. R.; Temple, C., Jr.; Narayanan, V. L.;
Varma, R.; Simpson, M. J.; Boyd, M. R.; Rener, G. A.;
Bansal, N. C. Anti-Cancer Drug Des. 1995, 10, 299; (b)
Chaplin, D. J.; Pettit, G. R.; Hill, S. A. Anticancer Res.
1999, 19, 189; (c) Nabha, S. M.; Mohammad, R. M.; Wall,
N. R.; Dutcher, J. A.; Salkini, B. M.; Pettit, G. R.; Al
Katib, A. M. Anticancer Drugs 2001, 12, 57; (d) West, C.
M.; Price, P. Anticancer Drugs 2004, 15, 179.
6. (a) Pettit, G. R.; Rhodes, M. R.; Herald, D. L.; Chaplin,
D. J.; Stratford, M. R. L.; Hamel, E.; Pettit, R. K.;
Chapuis, J.-C.; Oliva, D. Anti-Cancer Drug Des. 1998, 13,
981; (b) Nam, N. H.; Kim, Y.; You, Y.-J.; Hong, D.-H.;
Ki, H.-M.; Ahn, B.-Z. Bioorg. Med. Chem. Lett. 2001, 11,
3073.
At present, a molecular target responsible for the ob-
served antiproliferative activity of this new series of
compounds has not be identified, and a reasonable
explanation of SAR described above is not yet possible.
Among synthesized compounds, imidazolones 7, 13, and
imidazolethiones 31, 32, bearing a trimethoxyphenyl
group, were the most potent and selective in the
in vitro assay. Because a trimethoxyphenyl group is con-
sidered a structural feature typical for inhibitors of
tubulin polymerization,19 at least for these analogues
an antimitotic mechanism of action could be postulated.
7. Nam, N. H. Curr. Med. Chem. 2003, 10, 1697, and
references therein.
8. (a) Ohsumi, K.; Hatanaka, T.; Fujita, K.; Nakagawa, R.;
Fukuda, Y.; Nihei, Y.; Suga, Y.; Morinaga, Y.; Akiyama,
Y.; Tsuji, T. Bioorg. Med. Chem. Lett. 1998, 8, 3153; (b)
Wang, L.; Woods, K. W.; Li, Q.; Barr, K. J.; McCroskey,
R. W.; Hannick, S. M.; Gherke, L.; Bruce Credo, R.; Hui,
Y.-H.; Marsh, K.; Warner, R.; Lee, J. Y.; Zielinski-
Mozng, N.; Frost, D.; Rosenberg, S. H.; Sham, H. L.
J. Med. Chem. 2002, 45, 1697.
Thus, compounds 7, 13, and 32 are now submitted to
further biological studies, and the relative possible re-
sults will be disclosed in due course.
9. Edwards, M. L.; Stemerick, D. M.; Sunkara, P. S. J. Med.
Chem. 1990, 33, 1948.
10. Wu-Wong, J. R.; Alder, J. D.; Alder, L.; Burns, D. J.;
Han, E. K.; Credo, B.; Tahir, S. K.; Dayton, B. D.; Ewing,
P. J.; Chiou, W. J. Cancer Res. 2001, 61, 1486.
11. Fang, L.; He, Q.; Hu, Y.; Yang, B. Cancer Chemother.
Pharmacol. 2007, 59, 397.
In summary, herein reported preliminary results confirm
the validity of our approach providing practical access
to imidazolone-based antitumor agents. The reported
methods of synthesis have general applicability, so that
a large series of compounds would be prepared to ex-
12. Hsieh, H. P.; Liou, J. P.; Mahindroo, N. Curr. Pharm.
Des. 2005, 11, 1655.

C. Congiu et al. / Bioorg. Med. Chem. Lett. 18 (2008) 989–993
993
13. (a) Li, C.; Lee, M. H.; Sartorelli, A. C. J. Med. Chem.
1979, 22, 1030; (b) Devan, B.; Rajagopalan, K. Tetrahe-
dron Lett. 1994, 35, 1585.
14. Cortes, S.; Liao, Z.-K.; Watson, D.; Kohn, H. J. Med.
Chem. 1985, 28, 601.
15. General procedure for synthesis of 1, 4-diaryl-1H-imidazol-
2(3H)-ones 5–22. A mixture of 4 (1 mmol) and potassium
cyanate (1.2 g, 15 mmol) in acetic acid (2 mL) was stirred
for 1 h at 60–65 °C. After cooling, water (20 mL) was
added. The insoluble product was filtered off and washed
with water, then with cold methanol, to give 5–22 in 56–
92% yields. Compound 7: yield 81%; mp 186–188 °C
(EtOH); IR 3142, 1690, 1597 cm1;1H NMR (300 MHz,
DMSO-d6) d 3.79 (s, 3H), 3.94 (s, 6H), 7.25 (s, 2H Ar),
7.59 (d, J = 8.5 Hz, 2H, Ar), 7.72 (m, 2H, Ar + 1H,
imidazolic), 11.21 (broad, 1H, NH).
M.; Panico, S.; Simonetti, N. Farmaco Ed. Sci. 1985, 40,
404.
17. General procedure for synthesis of 1,4-diaryl-1H-imidazole-
2(3H)-thiones 23–37. A mixture of 4 (1 mmol) and
ammonium thiocyanate (146 mg, 1.5 mmol) in 10%
hydrochloric acid (10 mL) was refluxed for 1.5 h. After
cooling, the insoluble product was filtered off and washed
with water, then with cold MeCN, to give 23–37 in 64–
86% yields. Compound 33: yield 78%; mp 206–208 °C
(EtOH/MeCN); IR (Nujol) 3146, 3069, 1624, 1595 cm1;1H
NMR (300 MHz, DMSO-d6) d 3.89 (s, 3H), 3.92 (s, 3H),
7.11 (d, J = 8.5 Hz, 1H Ar), 7.42 (d, J = 8.5 Hz, 1H Ar),
7.49 (s, 1H Ar), 7.71 (d, J = 8.5 Hz, 2H Ar), 7.88 (d,
J = 8.5 Hz, 2H Ar), 7.92 (s, 1H, imidazolic), 13.01 (broad,
1H, NH).
18. Boyd, M. R.; Paull, K. D. Drug Dev. Res. 1995, 34, 91.
19. Hadfield, J. A.; Ducki, S.; Hirst, N.; McGown, A. T. Prog.
Cell Cycle Res. 2003, 5, 309.
16. (a) Dodson, R. M.; Ross, F. J. Am. Chem. Soc. 1950, 72,
1478; (b) Porretta, G. C.; Scalzo, M.; Artico, M.; Biava,