1,5-Diarylimidazoles with strong inhibitory activity against COX-2 catalyzed PGE2 production from LPS-induced RAW 264.7 cells

Article abstract of DOI:10.1016/j.bmcl.2010.05.092

A series of 1,5-diarylimidazoles with 4-methylsulfonylphenyl group were prepared and evaluated for the inhibitory activities against COX-2 catalyzed PGE₂ production from LPS-induced RAW 264.7 cells. Most of synthesized 1,5-diarylimidazoles exhibited strong inhibitory activities regardless of the position of the 4-methylsulfonylphenyl group. The 1,5-diarylimidazoles with a halogen atom (3c-3h, 3n-3p) gave mostly excellent inhibitory activities regardless of the position and species of the halogen atom. Whereas the 1,5-diarylimidazoles with two fluorine atoms (3k, 3l, 3r, 3s) showed rather reduced inhibitory activities.

Full text of DOI:10.1016/j.bmcl.2010.05.092

Bioorganic & Medicinal Chemistry Letters 20 (2010) 4035–4037
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
1,5-Diarylimidazoles with strong inhibitory activity against COX-2 catalyzed
PGE2 production from LPS-induced RAW 264.7 cells
Haiyan Che a, Truong Ngoc Tuyen a,b, Hyun Pyo Kim a, Haeil Park a,
*
a College of Pharmacy, Kangwon National University, Chunchon 200-701, Republic of Korea
b Ho Chi Minh University of Medicine & Pharmacy, Ho Chi Minh, Viet Nam
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 1,5-diarylimidazoles with 4-methylsulfonylphenyl group were prepared and evaluated for the
inhibitory activities against COX-2 catalyzed PGE2 production from LPS-induced RAW 264.7 cells. Most of
synthesized 1,5-diarylimidazoles exhibited strong inhibitory activities regardless of the position of the 4-
methylsulfonylphenyl group. The 1,5-diarylimidazoles with a halogen atom (3c–3h, 3n–3p) gave mostly
excellent inhibitory activities regardless of the position and species of the halogen atom. Whereas the
1,5-diarylimidazoles with two fluorine atoms (3k, 3l, 3r, 3s) showed rather reduced inhibitory activities.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 4 March 2010
Revised 20 May 2010
Accepted 24 May 2010
Available online 27 May 2010
Keywords:
1,5-Diarylimidazoles
Prostaglandin production
COX-2 Inhibitors
Anti-inflammatory activity
4-Methylsulfonylphenyl group
Inflammatory process comprises of several aspects provoked by
different chemicals and biologicals including proinflammatory en-
zymes/cytokines, small molecular chemicals such as eicosanoids
and tissue degradation enzymes. Among these factors, cyclooxy-
genase (COX), is a key proinflammatory enzyme which catalyzes
the conversion of arachidonic acid to prostaglandins (PGs). Cyclo-
oxygenase exists in two isoforms. Cyclooxygenase-1 (COX-1) is a
constitutive enzyme processing homeostasis function, while cyclo-
oxygenase-2 (COX-2) is an inducible one and known as a major iso-
form found in the inflammatory lesions.1 Therefore, COX-2
selective inhibitors are useful drugs for the treatment of acute pain
and chronic inflammatory diseases with reduced side effects such
as gastrotoxicity.
Extensive efforts have been reported toward the development
of selective COX-2 inhibitors over the past two decades. Structural
variation of the central heterocycle in the tricyclic series has been a
popular area of research and diverse heterocycles have been ex-
plored.2 From the previous SAR studies, it has been well known
that the diarylheterocycle COX-2 selective inhibitors require a 4-
methylsulfonylphenyl or a 4-sulfonamidophenyl group attached
to an unsaturated ring system in which an additional vicinal lipo-
philic moiety is present to possess good activity and selectivity
(Fig. 1).
central scaffold is crucial for the activity as well as selectivity. As
the central scaffold, diverse regioisomeric imidazoles such as
1,2-,3 1,5-4,5,6, and 4,5-diarylimidazoles7 have been explored, how-
ever, only 1,5-diarylimidazole made success and is pursued in fur-
ther development.
As part of our research to discover novel COX-2 selective inhib-
itors, 1,5-diarylimidazole analogs with a 4-methylsulfonylphenyl
group at 1- or 5-position were synthesized and evaluated for their
inhibitory activities against COX-2 catalyzed PGE2 production from
LPS-induced RAW 264.7 cells. 5-(4-Methylsulfonylphenyl) imida-
zoles (3a–l) were obtained by 1,3-dipolar cycloadditions of 4-
methylsulfanylbenzylidenearylamines and tosylmethyl isocyanide
(TosMIC)8–10 in the presence of K2CO3 as the key step followed by
oxidations with oxoneÒ as shown in Scheme 1. 4-Methylsulfanylb-
enzylidene arylamines (1a–l) were prepared from 4-methylsulfa-
nylbenzaldehyde and the corresponding arylamines in good
yields. 1-(4-Methylsulfonylphenyl) imidazoles were prepared fol-
lowing the same procedure. Reactions of N-(4-methylsulfanylphe-
nyl)benzylidene amines and TosMIC followed by oxidations
yielded the corresponding 1,5-diarylimidazoles 3m–t (Scheme 1).
The N-(4-methylsulfanylphenyl)benzylideneamines (1m–t) were
prepared from 4-methylsulfanylaniline and the corresponding
arylaldehydes in good yields. The chemical yields for each com-
pound are summarized in Table 1.
Also it was well acknowledged that the nature of central scaf-
fold is very important for the activity, therefore, the choice of the
Inhibition of COX-2 catalyzed PGE2 production from LPS-in-
duced RAW 264.7 cells by 1,5-diarylimidazoles was determined
according to the published procedure.11 RAW 264.7 cells obtained
from American Type Culture Collection were cultured with DMEM
* Corresponding author.
E-mail address: haeilp@kangwon.ac.kr (H. Park).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.05.092

4036
H. Che et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4035–4037
Table 1
supplemented with 10% FBS and 1% CO2 at 37 °C and activated with
LPS. Briefly, cells were plated in 96-well plates (2 Â 105 cells/well).
Each 1,5-diarylimidazole and LPS (1 g/ml) were added and incu-
bated for 24 h. Cell viability was assessed with MTT assay based
on the experimental procedures described previously. PGE2 con-
centration in the medium was measured using EIA kit for PGE2
according to the manufacture’s recommendation. All experiments
were carried out at least twice and they gave similar results. The
inhibitory activities of imidazoles on COX-2 catalyzed PGE2 pro-
duction from LPS-induced RAW 264.7 cells were estimated and
the results are shown in Table 1.
As demonstrated in Table 1, most 1,5-diarylimidazole analogs
exhibited strong inhibitory activities against COX-2 catalyzed
PGE2 production from LPS-induced RAW 264.7 cells regardless of
the position of the 4-methylsulfonylphenyl group. Surprisingly
the 1,5-diarylimidazole (3j) with 4-methylsulfonylphenyl group
at both 1- and 5-positions totally lost its inhibitory activity. The
1,5-diarylimidazoles with a halogen atom (3c–3h, 3n–3p) gave
mostly excellent inhibitory activities regardless of the position
and species of the halogen atom. Whereas the 1,5-diarylimidazoles
with two fluorine atoms (3k, 3l, 3r, 3s) showed rather reduced
inhibitory activities. Our results are quite different from those of
the previously reported results that introduction of a small substi-
tuent at the b-position of 4-methylsulfonylphenyl group showed
remarkable inhibitory activities.3,6
Yields of each compounds and % inhibitory activities of 1,5-diarylimidazoles (3a–3s)
against COX-2 catalyzed PGE2 production from LPS-induced RAW 264.7 cell
Code No.
R1 or R2
Yields (%)
% Inhibition (10 lM)
1a/2a/3a
1b/2b/3b
1c/2c/3c
1d/2d/3d
1e/1e/3e
1f/2f/3f
1g/2g/3g
1h/2h/3h
1i/2i/3i
1j/2j/3j
1k/2k/3k
1l/2l/3l
1m/2m/3m
1n/2n/3n
1o/2o/3o
1p/2p/3p
1q/2q12/3q13
1r/2r/3r
4-H
4-CH3
4-F
3-F
2-F
4-Cl
3-Cl
4-Br
4-OCH3
4-SO2CH3
2,4-F2
3,4-F2
4-CH3
4-F
94/70/95
90/75/90
97/64/93
95/85/97
93/63/96
98/85/96
95/92/99
90/92/97
93/30/95
89/40/80
89/25/90
92/90/91
90/73/89
95/65/92
93/75/89
92/80/92
96/80/90
93/86/93
94/83/97
91
99
93
86
96
100
100
100
98
13
89
55
90
100
100
84
100
90
4-Cl
4-Br
4-OCH3
2,4-F2
3,4-F2
Celecoxib/NS-398
1s/2s/3s
References
97
99/100
(a) All compounds were treated at 10
PGE2 production (10.0 M) from the basal level of 0.5
tion = 100 Â [1 À (PGE2 of LPS with the flavones treated group- PGE2 of the basal)/
(PGE2 of LPS treated group- PGE2 of the basal)]. (c) Celecoxib and NS-398 were used
as the reference compound. (d) All data are the arithmetic means S.D. (n = 3).
l
M. Treatment of LPS to RAW cells increased
M. (b)% Inhibi-
l
l
CF3
O
CH3
N
O
O
N
N
SO2NH2
SO2CH3
H3C
SO2NH2
Valdecoxib
Rofecoxib
CHF2
Celecoxib
Cl
N
N
Cl
CH3
N
N
N
F
N
H3CO
SO2NH2
SO2NH2
H3C
SO2CH3
Cimicoxib
Lumiracoxib
Etoricoxib
Figure 1. Structures of COX-2 inhibitors in the market.
R1
R1
R1
TosMIC
Oxone®
N
N
N
K2CO3
THF-H2O
N
N
H3CS
SO2CH3
1a-1l
SCH3
2a-2l
SCH3
3a-3l
SO2CH3
SCH3
Oxone®
THF-H2O
R2
R2
TosMIC
N
N
N
R2
N
K2CO3
N
1m-1s
3m-3s
2m-2s
Scheme 1. Synthesis of 1,5-diarylimiazoles with a 4-methylsulfonyphenyl group.

H. Che et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4035–4037
4037
8. Van Leusen, A. M.; Wildeman, J.; Oldeniel, O. H. J. Org. Chem. 1977, 42, 1153.
9. John, B.; Jerome, S. J. Heterocycl. Chem. 1998, 35, 859.
In conclusion, introduction of a halogen atom and a 4-methyl-
sulfony group to any aryl groups of the 1,5-diarylimidazole im-
proved bioactivity. Further COX-2 and COX-1 inhibitory activity
tests of the synthesized 1,5-diarylimidazoles are under investiga-
tion to determine the COX-2 versus COX-1 selectivity.
10. Kuwano, E.; Takeya, R.; Eto, M.; Asano, S. U.S. Patent 4,812,473 (1989).
11. Chi, Y. S.; Cheon, B. S.; Kim, H. P. Biochem. Pharmacol. 2001, 61, 1195.
12. Reaction conditions for 1-(4-methylthiophenyl)-5-(4-methoxyphenyl)imidazole
(2q): To the solution of an imine (2 mmol) in anhydrous MeOH (10 mL) was
added anhydrous K2CO3 (0.83 g, 6 mmol) and 0.39 g (2 mmol) of p-
toluenesulfonylmethylisocyanide (TosMIC).The reaction mixture was refluxed
for overnight. After cooling, the solvent was distilled off under reduced
pressure, and the residue was extracted with ether.
Acknowledgments
After washing with brine, the ethereal extract was dried over MgSO4. The
solvent was distilled off under reduced pressure. Purification of the residue by
silica gel column chromatography with CHCl3/MeOH (20:1) yielded product in
80% yield as a white solid. mp 150–151 °C; 1H NMR (200 MHz, CDCl3) d 7.70 (s,
1H, H2-imidazole), 7.27–7.20 (m, 2H, Ar-H), 7.12–7.03 (m, 4H, Ar-H), 7.11 (s,
1H, H4-imidazole), 6.84–6.77 (m, 2H, Ar-H), 3.78 (s, 3H, OCH3), 2.49 (s, 3H,
SCH3); 13C NMR (50 MHz, CDCl3) d 160.0, 140.0, 138.7, 136.1, 134.1, 130.3,
127.9, 127.5, 126.6, 122.1, 114.7, 55.9, 16.1; m/z 297 (M+, 74), 296 (100), 282
(45), 281 (80), 269 (49), 258 (61), 254 (57).
The authors thank the Pharmacal Research Institute and the
Central Laboratory of Kangwon National University for the use of
bioassay facilities and analytical instruments.
References and notes
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13. Reaction conditions for 1-(4-methylsulfonylphenyl)-5-(4-methoxyphenyl)imida-
zole (3q): To the solution of the methylthioimidazole (2q, 1 mmol) in THF
(10 mL) at À10 °C, OxoneÒ (1.6 g, 2.6 mmol) in H2O (14 mL) was added
dropwise. The resulting mixture was stirred at 23 °C for 24 h. The reaction
mixture was quenched with ice, extracted with CH2Cl2, washed with brine and
dried over MgSO4. After filtration, the filtrate was evaporated under reduced
pressure. The residue was recrystallized in ethyl acetate to give the title
product in 90% yield as white solid. mp 186–187 °C; 1H NMR (200 MHz, CDCl3)
d 7.97 (d, J = 8.4 Hz, 2H, Ar-H), 7.77 (s, 1H, H2-imidazole), 7.36 (d, J = 8.4 Hz, 2H,
Ar-H), 7.22 (s, 1H, H4-imidazole), 7.04 (d, J = 8.4 Hz, 2H, Ar-H), 6.83 (d,
J = 8.4 Hz, 2H, Ar-H), 3.80 (s, 3H, OCH3), 3.08 (s, 3H, SO2CH3); m/z 328 (M+, 34),
296 (100), 283 (56), 240 (43).
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