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The present work describes the design and synthesis of novel series of ten pyrazolo[3,4- d ]pyrazolo derivatives. Four compounds 3a , 3d , 4d and 4f were notable for their anti-inflammatory activity that was comparable to that of the clinically available cyclooxygenase-2 inhibitor celecoxib. They are even more potent than non-sterodial anti-inflammatory drug cyclooxygenase inhibitor diclofenac sodium. Our best hit 4d appears to adopt similar binding modes to the standard COX-2 inhibitor, celecoxib, proposing room for possible selectivity. The in silico findings come in line with the in vitro and in vivo assay results and also suggest that these compounds have the potetntial to be COX-2 selective inhibitors since they have typical binding modes of the benchmark drug celecoxib. • Design and synthesis of novel series of pyrazolo[3,4- d ]pyrazolo derivatives. • The best hit, 4d with COX-1 IC 50 of 28 µM and COX-2 IC 50 of 23 µM. • 4d adopt similar binding modes to the standard COX-2 inhibitor, celecoxib. • 3a , 3d , 4d and 4f exhibited anti-inflammatory activity that was comparable to celecoxib. In this study, the acid chlorides of pyrazolo[3,4- d ]pyrimidine compounds were prepared and reacted with a number of nucleophiles. The novel compounds were experimentally tested via enzyme assay and they showed cyclooxygenase-2 inhibition activity in the middle micro molar range (4b had a COX-1 IC 50 of 26 µM and a COX-2 IC 50 of 34 µM, 3b had a COX-1 IC 50 of 19 µM and a COX-2 IC 50 of 31 µM, 3a had a COX-2 IC 50 of 42 µM). These compounds were analyzed via docking and were predicted to interact with some of the COX-2 key residues. Our best hit, 4d (COX-1 IC 50 of 28 µM, COX-2 IC 50 of 23 µM), appears to adopt similar binding modes to the standard COX-2 inhibitor, celecoxib, proposing room for possible selectivity. Additionally, the resultant novel compounds were tested in several in vivo assays. Four compounds 3a (COX-2 IC 50 of 42 µM), 3d , 4d and 4f were notable for their anti-inflammatory activity that was comparable to that of the clinically available COX-2 inhibitor celecoxib. Interestingly, they showed greater potency than the famous non-steroidal anti-inflammatory drug, Diclofenac sodium. In summary, these novel pyrazolo[3,4- d ]pyrimidine analogues showed interesting anti-inflammatory activity and could act as a starting point for future drugs. [ABSTRACT FROM AUTHOR]

Two new series of pyrazolo[3,4- d ]pyrimidine bearing thiazolidinone moiety were designed and synthesized. The newly synthesized compounds were evaluated for their in vitro (COX-1 and COX-2) inhibitory assay . Compounds that showed promising COX-2 selectivity were further subjected to in vivo anti-inflammatory screening applying formalin induced paw edema (acute model) and cotton-pellet induced granuloma (chronic model) assays using celecoxib and diclofenac sodium as reference drugs . The histopathological and ulcerogenic potential were also determined. In vivo anti-inflammatory data showed that compounds 2 , 6 , 7d displayed anti-inflammatory activity higher than both references in the formalin induced paw edema model. On the other hand, compounds 2 , 3d , 3e , 7b and 7d displayed anti-inflammatory activity greater than or nearly equivalent to diclofenac sodium in the cotton pellet-induced granuloma assay. Moreover, most of the tested compounds revealed good gastrointestinal safety profile. Collectively, compounds 2 and 7d were considered as promising candidates in managing both acute and chronic inflammation with safe gastrointestinal margin. [ABSTRACT FROM AUTHOR]

• Rational design and synthesis of novel derivatives of pyrrolo[3,4- d pyridazinone have been described. • All new derivatives inhibit both cyclooxygenase enzymes. • Comprehensive in vitro and in silico studies confirmed that the most potent is 7b. • Novel Mannich base derivatives prevent DNA strand breaks caused by an increase in intracellular ROS. • All new derivatives bind to the active site of the enzyme in a way very similar to meloxicam. Novel Mannich base analogues of pyrrolo[3,4- d pyridazinone 7a , b - 13a , b are designed and synthesized as potential anti-inflammatory agents. The title compounds are obtained via convenient one-pot synthesis with good yields. Their structures and properties are described by spectroscopic techniques and elemental analyses. The aim of this study is to evaluate the inhibitory activity of the new derivatives against both cyclooxygenase isoforms COX1 and COX2 as well as their cytotoxicity. The results clearly indicate that the tested compounds 7a , b - 13a , b are not toxic, all show better affinity towards isoform COX-2, and some of them act as selective COX-2 inhibitors. Moreover, every examined derivative of pyrrolo[3,4- d pyridazinone demonstrates better inhibitory activity towards COX-2 and a superior COX-2/COX-1 selectivity ratio compared to the reference drug meloxicam. Molecular docking studies confirm that compounds 7a,b-13a,b preferably bind COX-2 and all of them bind to the active site of cyclooxygenase in a way very similar to meloxicam. Subsequently, taking into account that inflammation is strongly correlated with oxidative stress and both of these processes can potentiate each other, synthesized Mannich bases are evaluated for potential antioxidant activity. Most of the investigated derivatives reduce induced oxidative and nitrosative stress. Moreover, compounds 7a , b , 8a , 10a,b , 11b , 12a , b - 13a , b protect chromatin from oxidative stress and decrease the number of DNA strand breaks caused by intracellular growth of free radicals. Finally, a study of the binding mechanism between compounds 7a , b - 13a , b and bovine serum albumin (BSA) was carried out. According to spectroscopic and molecular docking studies, all examined derivatives interact with BSA, which suggests their potential long half-life in vivo. [ABSTRACT FROM AUTHOR]

• Efficient synthesis of 1,3,4-thiadiazole-4-thiazolidinone hybrids modified at the 5th position of thiadiazole and/or thiazolidinone. • The in vitro and in vivo anti-inflammatory activities were determined. These activities affected significantly by the size of the substituent at the 5th position. • New compounds with potent dual COX-2/15-LOX inhibition, good in vivo activity and good gastric safety profile were obtained. Herin we report the design, synthesis, full characterization and biological investigation of new 15-LOX/COX dual inhibitors based on 1,3-thiazolidin-4-one (15-lipoxygenase pharmacophore) and 1,3,4-thiadiazole (COX pharmacophore) scaffolds. This series of molecular modifications is an extension of a previously reported series to further explore the structural activity relationship. Compounds 3a , 4e , 4n , 4q, 7 and 8 capable of inhibiting 15-LOX at (2.74, 4.2, 3.41, 10.21, 3.71 and 3.36 µM, respectively) and COX-2 at (0.32, 0.28, 0.28, 0.1, 0.28 and 0.27 µM, respectively). The results revealed that binding to 15-LOX and COX is sensitive to the bulkiness of the substituents at the 5 positions. 15-LOX bind better with small substituents, while COXs bind better with bulky substituents. Compounds 3a , 4r and 4q showed comparable in vivo anti-inflammatory activity to the reference drug (celecoxib). The ulcer liability test showed no sign of ulceration which ensures the safe gastric profile. Docking study was performed to explore the possible mode of interaction of the new compounds with the active site of human 15-LOX and COX-2. This study discloses some structural features for binding to 15-LOX and COX, thus pave the way to design anti-inflammatory agents with balanced dual inhibition of these enzymes. [ABSTRACT FROM AUTHOR]