1,5-Diarylimidazoles with strong inhibitory activity against COX-2 catalyzed PGE 2 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 article info Article history: 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 abstract A series of 1,5-diarylimidazoles with 4-methylsulfonylphenyl group were prepared and evaluated for the inhibitory activities against COX-2 catalyzed PGE 2 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. 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). Also it was well acknowledged that the nature of central scaf- fold is very important for the activity, therefore, the choice of the 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-diarylimidazoles 7 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 PGE 2 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 K 2 CO 3 as the key step followed by oxidations with oxone Ò 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. Inhibition of COX-2 catalyzed PGE 2 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 0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2010.05.092 * Corresponding author. E-mail address: haeilp@kangwon.ac.kr (H. Park). Bioorganic & Medicinal Chemistry Letters 20 (2010) 4035–4037 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl