Synthesis and characterization of novel oxazines and demonstration that they specifically target cyclooxygenase 2 V. Srinivas a,  , Chakrabhavi Dhananjaya Mohan b,  , C. P. Baburajeev a,  , Shobith Rangappa c , Swamy Jagadish b , Julian E. Fuchs d , Alexey Yu. Sukhorukov e , Chandra f , Daniel J. Mason d , Kothanahally Shivaramu Sharath Kumar b , Mahendra Madegowda f , Andreas Bender d , Basappa a,⇑ , Kanchugarakoppal Subbegowda Rangappa b,⇑ a Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College Campus, Palace Road, Bangalore 560001, India b Department of Studies in Chemistry, Manasagangotri, University of Mysore, Mysore 570006, India c Frontier Research Center for Post-genome Science and Technology, Hokkaido University, Sapporo 060-0808, Japan d Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, United Kingdom e N.D. Zelinsky Institute of Organic Chemistry, Leninsky Prospect, 47, Moscow 119991, Russia f Department of Studies in Physics, Manasagangotri, University of Mysore, Mysore 570006, India article info Article history: Received 10 February 2015 Revised 7 May 2015 Accepted 15 May 2015 Available online 27 May 2015 Keywords: COX2 Oxazines SCS-Bi 2 O 3 Proinflammatory disease abstract In the present study, we used solution combustion synthesis-bismuth oxide (Bi 2 O 3 ) as catalyst for the simple and efficient synthesis of 1,2-oxazine based derivatives of 6-fluoro-3-(piperidin-4- yl)benzo[d]isoxazoles, 1-arylpiperazine and carbazoles. (4aR,8aR)-4-(4-Methoxyphenyl)-3-((4-(4- methoxyphenyl)piperazin-1-yl)methyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[e][1,2]oxazine was found to be the most potent compound with a high degree of selectivity in inhibition towards COX2 (1.7 lM) over COX1 (40.4 lM) demonstrating the significance of 1,2-oxazine derivatives in developing COX2 specific inhibitors. Molecular docking analyses demonstrated that an isoleucine residue in the active site of COX1 is responsible for lower affinity to COX1 and increased potency towards COX2. Overall, our study reveals that the new 1,2-oxazine-based small molecules qualify as lead structures in developing COX2- specific inhibitors for anti-inflammatory therapy. Ó 2015 Elsevier Ltd. All rights reserved. Inflammation is a defensive response of the host immune sys- tem against harmful antigenic invasion to minimize the deleterious effects. 1,2 Prolonged infection or delayed elimination of antigens result in the constant triggering of the host immune system which may lead to proinflammatory diseases including cancer, rheuma- toid arthritis, atherosclerosis, inflammatory bowel diseases and psoriasis. 3–5 Therefore, inflammation can rightly be called as dou- ble-edged sword. 6 The comprehensive research in the previous dec- ade has established the role of several proinflammatory mediators in development of aforesaid diseases. The entanglement of cyclooxygenase (COX) as one of the key proinflammatory mediators has been well-demonstrated and found to be the good therapeutic target in treating several proinflammatory diseases. 7,8 COX1 and COX2 are the two isoforms of cyclooxygenase in which the former is constitutively expressed in normal tissues to maintain homeosta- sis and latter is renowned to express on cytokine induction in inflammatory cells. 9 Unfortunately, during chronic inflammation, COX2 is overexpressed which leads to exaggerated way of immune response and ultimately results in developing proinflammatory dis- eases. 10 Copious efforts are underway to design the inhibitors against COX2 to treat these ailments. Nonsteroidal anti-inflamma- tory drugs (NSAIDs) such as Celecoxib and Rofecoxib were imple- mented as inhibitors of COX2 in treating osteoarthritis and rheumatoid arthritis. Recently, patients administered with Rofecoxib were found to be prone to myocardial infarction and thus Celecoxib is now considered a risk with regard to enhancing vascu- lar complications. 11 Given the relevance with increased adverse effects of existing drugs, there is an immediate need for developing the selective COX2 inhibitors with high specificity and minimal adverse effects to treat proinflammatory diseases. Oxazine, benzoxazine and isoxazoline derivatives possess wide variety of biological activities including anti-inflammatory, antiox- idants, neurosedatory and PI3 kinase inhibition. 12–16 Furthermore, diaryl heterocycles have been extensively studied as COX inhibitors 17 and many of COX inhibitors possess 1,2-diaryl substi- tution on a four to six membered central ring system. In addition, N-substituted phenyl piperidine, phenyl piperizine and carbazole http://dx.doi.org/10.1016/j.bmcl.2015.05.047 0960-894X/Ó 2015 Elsevier Ltd. All rights reserved. ⇑ Corresponding authors.   These authors contributed equally to this work. Bioorganic & Medicinal Chemistry Letters 25 (2015) 2931–2936 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl