Original article Synthesis, biological evaluation and molecular modeling study of 5-trifluoromethyl-D 2 -pyrazoline and isomeric 5/3- trifluoromethylpyrazole derivatives as anti-inflammatory agents Ranjana Aggarwal a, * , Anshul Bansal a , Isabel Rozas b , Brendan Kelly b , Pawan Kaushik c , Dhirender Kaushik c a Department of Chemistry, Kurukshetra University, Kurukshetra, Haryana 136119, India b School of Chemistry, Trinity Biomedical Sciences Institute, Trinity College Dublin,154-160 Pearse St., Dublin 2, Ireland c Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra 136119, India article info Article history: Received 4 May 2013 Received in revised form 23 September 2013 Accepted 28 September 2013 Available online 7 October 2013 Keywords: 5-Trifluoromethyl-D 2 -pyrazolines 3-Trifluoromethylpyrazoles 5-Trifluoromethylpyrazoles Anti-inflammatory activity COX-2 Docking abstract Searching for new anti-inflammatory agents, we have prepared a series of potential COX-2 inhibitors, 1-(4,6- dimethylpyrimidin-2-yl)-5-hydroxy-5-trifluoromethyl-D 2 -pyrazolines (3) and 1-(4,6-dimethylpyrimidin-2- yl)-3-trifluoromethylpyrazoles (4), by refluxing 2-hydrazino-4,6-dimethylpyrimidine (1) with a number of trifluoromethyl-b-diketones (2) in ethanol. Further dehydration of compounds (3) to the corresponding 1-(4,6-dimethylpyrimidin-2-yl)-5-trifluoromethylpyrazoles (5) was also achieved. Fifteen of these com- pounds were screened for their anti-inflammatory activity using the carrageenan-induced rat paw edema assay. While all the compounds exhibited significant anti-inflammatory activity (47e76%) as compared to indomethacin (78%), 3-trifluoromethylpyrazoles (4) were found to be the most effective agents (62e76%). To rationalize this anti-inflammatory activity, docking experiments molecular dynamics simulations were per- formed to study the ability of these compounds to bind into the active site of the COX-2 enzyme. Ó 2013 Elsevier Masson SAS. All rights reserved. 1. Introduction Inflammation plays a fundamental role in the immune response of the human body to microbes, injury or trauma. Recent studies have demonstrated that inflammation is key not only in infection and cancer but also to autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, type I diabetes and Crohn’s disease, or certain neuro-degenerative conditions [1e4]. One of the most important factors in the inflammatory process is the generation of prostaglandins which are produced by the ac- tion of cyclooxygenase (COX) on arachidonic acid. For that reason, this enzymatic system became a popular target for the develop- ment of anti-inflammatory drugs such as the non-steroidal anti- inflammatory drugs or NSAIDs which exert their activity by inhibiting COX, thus preventing the synthesis of prostaglandins [5]. From the known forms of COX, it seems that COX-2 is the one responsible of prostaglandin production in inflammatory condi- tions. Thus, COX-2 inhibitors have been prepared for the treatment of chronic inflammatory diseases like rheumatoid and osteoar- thritis, and many of them, such as celecoxib or SC-588 (Fig. 1), have a similar core, the trifluoromethylpyrazole system [6]. Several pyrazole derivatives have been reported to possess pharmacological activity as anti-inflammatory agents [7e9]. Further, incorporation of the lipophilic trifluoromethyl group on pyrazole ring exerts a variety of dramatic effects on the pharma- cological properties of the molecule making its partition into cell membranes much easier and hence increasing the selectivity, effi- cacy and bioavailability [10]. Also pyrimidine derivatives, the fundamental building blocks for DNA and RNA, have attracted a great deal of attention over many years due to their broad bio- activities, including antitumor [11,12], antimicrobial [13], or anti- inflammatory [14]. In view of these observations and continuing with our work related to the synthesis and spectroscopic and biological studies of trifluoromethylpyrazoles [15e18], we have prepared and evaluated * Corresponding author. Tel.: þ91 1744238734; fax: þ91 1744238277. E-mail addresses: ranjana67in@yahoo.com, ranjanaaggarwal67@gmail.com (R. Aggarwal). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.ejmech.2013.09.052 European Journal of Medicinal Chemistry 70 (2013) 350e357