Introduction The inflammation process involves sequential ac

Introduction The inflammation process involves sequential activation of signaling molecules, pro-inflammatory mediators, such as prostaglandins, leukotrienes, and oxygen free radicals [1]. Two cyclooxygenases MLN 8237 were responsible for activation of the production of prostaglandins (PG1s) and other inflammatory mediators. Cyclooxygenase-1 (COX-1) is a constitutive form which regulates the gastrointestinal cytoprotection and maintains the renal functions [2]. The other cyclooxygenase-2 isozyme (COX-2) catalyses the (PG1s) formation and is responsible for pain, fever and other inflammatory symptoms [3], [4]. Traditional NSAIDs as ibuprofen, aspirin or indomethacin, suffered from many adverse effects including gastric ulceration, renal injury, and cardiotoxicity [5]. These drawbacks are due to non-selective inhibition of both COX-1 and COX-2 isozymes [6], [7]. Selective COX-2 inhibitors like coxibs have been developed to limit those adverse effects. In spite of coxibs safety, they are still suffering from cardiovascular side effects. Regarding that, there is a continual need for more selective and safer COX-2 inhibitors. The selective COX-2 inhibitors, coxibs family and its members celecoxib (I), rofecoxib (II) and valdecoxib (III) (Fig. 1), all candidates contain a pyrazole core with a diaryl substituted with a sulphamoyl or methanesulphonyl group as selective COX-2 pharmacophores [8], [9]. Also, the pyrazole and their fused pyrazolopyrimidine drug cores are of increasing interest. These drugs containing molecules based on the pyrazolo[3,4-d]pyrimidine ring system exhibited a multitude of wide pharmacological properties including anti-inflammatory agent [10], [11], anticancer [12], [13], [14], tuberculostatic [15], [16] and antimicrobial [17], [18]. Recently, several novel series of pyrazolo[3,4-d]pyrimidine derivative (IV) have been prepared and showed a comparable anti-inflammatory activity (AI) to that of ketorolac against carrageenan-induced rat paw edema [10]. Also, the sulfamoyl pyrazolopyrimidine derivative (V) exhibited good anti-inflammatory activity compared to celecoxib (dose = 25 mg/kg) [19]. Furthermore, compound (VI) with an amino substitution at position-4 was reported to inhibit selectively and potently COX-2 activity in human monocytes (IC50 = 0.9 nM for COX-2 vs. IC50 = 59.6 nM for COX-1) with an anti-angiogenic activity as well [20]. Moreover, different pharmacophores such as pyrazole [21], [22], triazole [23], [24], [25], oxadiazole [26], [27] and Schiff base [28], [29] were Found to have anti-inflammatory activity. Due to the presence of additional side pocket at COX-2 active site increase its volume to accommodate more bulky structures. Guided by the previously mentioned studies and to a continuation of previous work [30], [31], [32], [33], our strategy is to synthesize new pyrazolo[3,4-d]pyrimidine derivatives aiming to be more selective COX-2 inhibitors. The presence of an additional side pocket on COX-2 active site increases its volume to accommodate more bulky structures. So the design of the synthesized compounds depends on the presence of a more bulky pyrazolopyrimidine core than pyrazole, central ring of coxibs in a way to increase fitting with larger COX-2 receptor site. This pyrazolopyrimidine central ring substituted with phenyl ring or p-methylsulfonyl (COX-2 pharmacophore) phenyl at N1. Another amino substitution at position- 4 was placed to increase the incidence of hydrogen bonds with receptor. In addition, this amino group was decorated with different moieties such as Schiff bases (7a-f), triazoles (8a, 8b, and 9a-f), oxadiazoles (10a and 10b) and pyrazoles (13a and 13b). The resulted compounds were evaluated against COX-1\\COX-2. Also, carrageenan-induced rat paw edema model and histopathological study was operated to determine their AI and gastric safety. In addition, docking study was performed to predict the mode of action of the target compounds inside the COX-2 active site aiming to get new anti-inflammatory compounds with improved activity and minor drawbacks.