Design and synthesis of new 1,3-benzthiazinan-4-one derivatives as selective cyclooxygenase (COX-2) inhibitors Afshin Zarghi a, * , Tannaz Zebardast a , Bahram Daraie b , Mehdi Hedayati c a Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University (M.C), Tehran, Iran b Department of Toxicology, Tarbiat Modarres University, Tehran, Iran c Endocrine Research Center, Shahid Beheshti University (M.C), Tehran, Iran article info Article history: Received 14 June 2009 Revised 24 June 2009 Accepted 25 June 2009 Available online 27 June 2009 Keywords: 1,3-Benzthiazinan-4-ones COX-2 inhibition SAR abstract A new group of 1, 3-benthiazinan-4-ones, possessing a methyl sulfonyl pharmacophore, were synthe- sized and their biological activities were evaluated for cyclooxygenase-2 (COX-2) inhibitory activity. In vitro COX-1/COX-2 inhibition studies identified 3-(p-fluoropheny)-2-(4-methylsulfonylphenyl)-1,3- benzthiazinan-4-one (7b) as a potent (IC 50 = 0.05 lM) and selective (selectivity index = 259) COX-2 inhibitor. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction The non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly medications in the world. The mechanism of action of these drugs is the inhibition of cyclooxygenase (COX) en- zyme, which catalyzes the first step of the biosynthesis of PGG 2 from arachidonic acid. 1 A major factor limiting their use is gastro- intestinal toxicity, ranging from ulcer to perforation and bleeding. 2 COX isozymes exist at least in two isoforms, COX-1 and COX-2. 3 The COX isoforms are heme containing enzymes that exhibit dis- tinct expression roles in several physiological processes. The con- stitutive COX-1 isozyme is found in platelets, kidneys, and the gastrointestinal tract and is believed to be responsible for the maintenance of physiological functions such as gastro protection and vascular homeostasis. 4 In contrast, the COX-2 enzyme is the inducible isoform that is produced by various cell types upon expo- sure to cytokines, mitogens, and endotoxins released during injury and therefore molecules that inhibit its enzymatic activity would be of therapeutic value. 5,6 The gastrointestinal side effects associ- ated with NSAIDs are due to the inhibition of gastroprotective PGs synthesized through the COX-1 pathway. 7 Thus, selective inhi- bition of COX-2 over COX-1 is useful for the treatment of inflam- mation and inflammation-associated disorders with reduced gastrointestinal toxicities when compared with NSAIDs. Moreover, recent studies indicating the place of COX-2 inhibitors in cancer chemotherapy 8 and neurological diseases such as Parkinson 9 and Alzheimer’s 10 diseases still continue to attract investigations on development of COX-2 inhibitors. The majority of selective COX- 2 inhibitors belong to a class of diarylheterocycles that possess vic- inal diaryl substitution attached to a mono or bicyclic central ring system. 11–18 In this regard, many classes of selective COX-2 inhib- itors such as coxibs have been developed with desired selectivity. The coxibs (e.g., celecoxib and rofecoxib, Fig. 1) 11,12 for treating pain and inflammation associated with arthritis have been shown to be well tolerated and reduce GI side effects. The recent market withdrawal of some coxibs such as rofecoxib and valdecoxib due to their adverse cardiovascular side effects 19 clearly delineates the need to develop alternative structures with COX-2 inhibitory activity. In addition, some studies have suggested that rofecoxib adverse cardiac events may not be a class effect but rather an intrinsic chemical property related to its metabolism. 20 For this reason novel scaffolds with high selectivity for COX-2 inhibition need to be found and evaluated for their anti-inflammatory effects. Recently, we reported several investigations describing the design, synthesis and molecular modeling studies for 1,3-thiazolidine-4- ones 17 and 1,3-thiazinan-4-ones 18 possessing a five or six mem- bered central ring and methylsulfonyl COX-2 pharmacophore at the para-position of C-2 phenyl ring in conjunction with different substituents at the N-3 of the central ring. For example, 3-(4-fluo- rophenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazolidine-4-one and 3-benzyl-2-(4-methyl sulfonylphenyl)-1,3-thiazinan-4-one (see structures 1 and 2) exhibited highly selectivity for COX-2 inhibi- tion. As a part of our ongoing program to design new types of selec- tive COX-2 inhibitors, we now report the design, synthesis, cyclooxygenase inhibitory and some molecular modeling studies 0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2009.06.056 * Corresponding author. Tel.: +98 21 8820096; fax: +98 21 88665341. E-mail address: azarghi@yahoo.com (A. Zarghi). Bioorganic & Medicinal Chemistry 17 (2009) 5369–5373 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc