Synthesis and Effects of 4,5-Diaryl-2-(2-alkylthio-5-imidazolyl) Imidazoles as Selective Cyclooxygenase Inhibitors

Document Type: Original Article


1 School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad , Iran


In recent years highly selective COX-2inhibitors were withdrawn from the market because of an increased risk of cardiovascular complications. In this study we were looking for potent compounds with moderate selectivity for cox-2. So, four analogues of 4, 5-diaryl-2-(2-alkylthio-5-imidazolyl) imidazole derivatives were synthesized and their anti-inflammatory and anti-nociceptive activities were evaluated on male BALB/c mice (25-30 g). Molecular modeling and in vitro COX-1 and COX-2 isozyme inhibition studies were also performed.
Materials and Methods
2-(2-Alkylthio-5-imidazolyl)-4,5-diphenylimidazole compounds were obtained by the reaction of benzyl with 2-alkylthio-1-benzylimidazole-5-carbaldehyde, in the presence of ammonium acetate. Spectroscopic data and elemental analysis of compounds were obtained and their structures elucidated. Anti-nociception effects were examined using writhing test in mice. The effect of the analogues (7.5, 30, 52.5 and 75 mg/kg) against acute inflammation were studied using xylene-induced ear edema test in mice. Celecoxib (75 mg/kg) was used as positive control.
All four analogues exhibited anti-nociceptive activity against acetic acid induced writhing, but did not show significant analgesic effect (P< 0.05) compared with celecoxib. It was shown that analogues injected 30 min before xylene application reduced the weight of edematic ears. All analogues were found to have less selectivity for COX-2 in comparison to celecoxib.
Injected doses of synthesised analogues possesses favorite anti-nociceptive effect and also has anti‌inflammatory effects, but comparing with celecoxib this effect is not significantly different. On the other hand selectivity index for analogues is less than celecoxib and so we expect less cardiovascular side effects for these compounds.


1.Fu JY, Masferrer JL, Seibert K, Raz A, Needleman P. The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes. J Biol Chem 1990; 265:16737-16740.

2.Xie WL, Chipman JG, Robertson DL, Erikson RL, Simmons DL. Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc Natl Acad Sci USA 1991; 88:2692-2696.

3.Smith WL, Dewitt DL. Prostaglandin endoperoxide H synthases-1 and -2. Adv Immunol 1996; 62:167-215.

4.Herschman HR. Prostaglandin synthase 2. Biochim Biophys Acta 1996; 1299:125-140.

5.Kawamori T, Rao CV, Seibert K, Reddy BS. Chemopreventive activity of celecoxib,a specific cyclooxygenase-2 inhibitor, against colon carcinogenesis. Cancer Res 1998; 58:409-412.

6.Katori M, Majima M. Cyclooxygenase-2: Its rich diversity of roles and possible application of its selective inhibitors. Inflamm Res 2000; 49:367-392. 

7.Vane JR, Botting RM. Anti-inflammatory drugs and their mechanism of action. Inflamm Res 1998; 47:S78-87.

8.Bing RJ, Lomnicka M. Why do cyclo-oxygenase-2 inhibitors cause cardiovascular events? J Am Coll Cardiol 2002; 39:521-522.

9.Chen C-S, Tan C-M, Huang C-H, Chang L-C, Wang J-P, Cheng F-C, et al. Discovery of 3-(4-bromophenyl)- 6-nitrobenzo[1.3.2]dithiazolium ylide 1,1-dioxide as a novel dual cyclooxygenase/5-lipoxygenase inhibitor that also inhibits tumor necrosis factor-[alpha] production. Bioorg Med Chem 2010; 8:597-604.

10.Penning TD, Talley JJ, Bertenshaw SR, Carter JS, Collins PW, Docter S. Synthesis and biological evaluation of the 1.5 diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)- 1H-pyrazol-1-yl]benze nesulfonamide (SC-58635, celecoxib). J Med Chem 1997; 40:1347-1365.

11.Prasit P, Wang Z, Brideau C, Chan CC, Charleson S, Cromlish W, et al.The discovery of rofecoxib, [MK 966, VIOXX®, 4-(4'-methylsulfonylphenyl)-3-phenyl-2(5H)-furanone],an orally active cyclooxygenase-2 inhibitor. Bioorg Med Chem Lett 1999; 9:1773-1778.

12.Friesen RW, Dube D, Fortin R, Frenette R, Prescott S, Cromlish W, et al. Novel 1,2-diarylcyclobutenes: Selective and orally active COX-2inhibitors. Bioorg Med Chem Lett 1996; 6:2677-2682.

13.Talley JJ, Brown DL, Carter JS, Graneto MJ, Koboldt CM, Masferrer JL, et al. 4-[5-Methyl-3-phenylisoxazol-4-yl]- benzenesulfonamide, valdecoxib: a potent and selective inhibitor of COX-2. J Med Chem 2000; 43:775-777.

14.Zarghi A, Rao PN, Knaus EE. Design and synthesis of new rofecoxib analogs as selective cyclooxygenase-2 (COX-2) inhibitors: replacement of the methanesulfonyl pharmacophore by a N-acetylsulfonamido bioisostere. J Pharm Pharm Sci 2007; 10:159-167.

15.Isikdag I, Meric A. Syntheses and analgesic activities of some 2-substituted-4,5-diphenyl and 1,2-disubstituted 4.5-diphenyl imidazole derivatives. Boll Chim Farm 1999; 138:24-29.

16.Hadizadeh F, Vosooghi R. Synthesis of a-[5-(5-Amino-1,3,4-thiadiazol-2-yl)-2-imidazolylthio]acetic acids. J Heterocyclic Chem 2008; 45:1477-1479.

17.Morris GM, Doodsell DS, Holliday RS, Huey R, Hart WE, Belew RK, et al. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 1998; 19:1639-1662.

18.Hosseinzadeh H, Ramezani M, Salmani G. Antinociceptive, anti-inflammatory and acute toxicity effects of Zataria multiflora Boiss extracts in mice and rats. J Ethnopharmacol 2000; 73:379-385.

19.Rowlinson SW, Kiefer JR, Prusakiewicz JJ, Pawlitz JL, Kozak KR, Kalgutkar AS, et al. A novel mechanism of cyclooxygenase-2 inhibition involving interactions with Ser-530 and Tyr-385. J Biol Chem 2003; 278:45763-45769.

20.Wallace AC, Laskowski RA, Thornton JM. LIGPLOT: a program to generate schematic diagrams of protein- ligand interactions. Protein Eng 1995; 8:127-134.