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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]

A series of new 1,3,4-oxadiazole/oxime hybrids were synthesized and designed as potent COX inhibitors. The prepared compounds were evaluated for their anti-inflammatory, antioxidant and ulcerogenic activities. The results indicated that the prepared compounds exhibited remarkable anti-inflammatory activity with (69.60–109.60% of indomethacin activity) after 4 h. In vitro COX inhibitory assay showed that compounds 6d and 7h are potent COX inhibitors with IC 50 of (1.10–0.94) and (2.30–5.00) µM on both COX-1 and COX-2 respectively. Compound 7h was found to inhibit both COXs non-competitively with K i values of 73 µM and 89 µM. Most of the tested compounds showed ulcer-free stomachs compared to indomethacin. [ABSTRACT FROM AUTHOR]

A new series of 1,3,5-triaryl-4,5-dihydro-1 H -pyrazole 10a – l was designed and synthesized via cyclization of chalcones 8a – f with 4-amino/methanesulfonylphenylhydrazine hydrochloride 9a – b . All the synthesized compounds were evaluated for their cyclooxygenase (COX) inhibition, anti-inflammatory activity, ulcerogenic liability and analgesic activity. All compounds were more COX-2 inhibitors than COX-1. While most compounds showed good anti-inflammatory activity, the trimethoxy derivatives ( 10a , 10b, 10g and 10h ) were the most potent derivatives (ED 50 = 55.78, 53.99, 67.65 and 69.20 μmol/kg respectively) in comparison with celecoxib (ED 50 = 82.15 μmol/kg). Compounds 10a , 10b, 10g and 10h (ulcer index = 2.68, 1.20, 2.63 and 2.66 respectively) showed less ulceration effect than celecoxib (ulcer index = 2.90). Also, Compounds 10a , 10b, 10g and 10h showed analgesic activity higher than celecoxib and comparable to that of ibuprofen. In addition, molecular docking studies were performed for compounds 10a , 10b, 10g and 10h and the results were in agreement with that obtained from the in vitro COX inhibition assays. [ABSTRACT FROM AUTHOR]

[Display omitted] • Summative view of tail-approach based selective as well as potent hCA IX and XII inhibitors reported in the last decade. • Listing of the most promising molecules in terms of selectivity and potency from the available 181 research papers. • One stop solution to tailor the tail-approach based rational design of novel libraries of carbonic anhydrase inhibitors. Human carbonic anhydrase (hCA) isoforms hCA IX and hCA XII are well established anticancer drug targets and their selective inhibition is highly desired for the proper treatment of cancer. Lack of isoform-selectivity in current clinically used CA inhibitors (CAIs) is a major concern as it leads to undesired side effects, associated with off-target inhibition. Thus, there is need to explore alternative approaches for the design of isoform-selective inhibitors and the leading promising approach for the design of isoform-selective CAIs is "the tail-approach". Virtually, most drug design studies in the last decade were done by considering the tail-approach reported in 1999. The past decade of 2010–2020 witnessed progressive maturation of this approach as a large number of CAIs have been designed and synthesised based on it, many of which turned out to be effective as well as selective hCA IX and hCA XII inhibitors. This review covers the past decade (2010–2020) research, considering selective as well as potent inhibitors of tumor associated isoforms, hCA IX and hCA XII, which include newer generation inhibitors containing sulfonamides or their bioisosteres, non-classical inhibitors (including carboxylic acid/ester, coumarin and sulfocoumarin classes) and various other novel classes of inhibitors belonging to newly identified chemotypes/scaffolds. [ABSTRACT FROM AUTHOR]

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medications as analgesics and antipyretics. Currently, there is a growing interest in their antitumor activity and their ability to reduce the risk and mortality of several cancers. While several studies revealed the ability of NSAIDs to induce apoptosis and inhibit angiogenesis in cancer cells, their exact anticancer mechanism is not fully understood. However, both cyclooxygenase (COX)-dependent and -independent pathways were reported to have a role. In an attempt to develop new anticancer agents, a series of diphenylthiazole substituted thiazolidinone derivatives was synthesized and evaluated for their anticancer activity against a panel of cancer cell lines. Additionally, the inhibitory activity of the synthesized derivatives against COX enzymes was investigated as a potential mechanism for the anticancer activity. Cytotoxicity assay results showed that compounds 15b and 16b were the most potent anticancer agents with half maximal inhibitory concentrations (IC 50 ) between 8.88 and 19.25 μM against five different human cancer cell lines. Interestingly, COX inhibition assay results were in agreement with that of the cytotoxicity assays where the most potent anticancer compounds showed good COX-2 inhibition comparable to that of celecoxib. Further support to our results were gained by the docking studies which suggested the ability of compound 15b to bind into COX-2 enzyme with low energy scores. Collectively, these results demonstrated the promising activity of the newly designed compounds as leads for subsequent development into potential anticancer agents. [ABSTRACT FROM AUTHOR]

• A novel class of trisubstituted pyrazolines as PDE5 inhibitors was discovered. • The compounds were developed inspired by the off-target activity of celecoxib against PDE5. • The developed compounds showed promising selectivity profile. • The developed compounds could increase intracellular cGMP levels in HEK293 cells. Celecoxib, is a selective cyclooxygenase-2 (COX2) inhibitor with a 1,5-diaryl pyrazole scaffold. Celecoxib has a better safety profile compared to other COX2 inhibitors having side effects of systemic hypertension and thromboembolic complications. This may be partly attributed to an off-target activity involving phosphodiesterase 5 (PDE5) inhibition and the potentiation of NO/cGMP signalling allowing coronary vasodilation and aortic relaxation. Inspired by the structure of celecoxib, we synthesized a chemically diverse series of compounds containing a 1,3,5-trisubstituted pyrazoline scaffold to improve PDE5 inhibitory potency, while eliminating COX2 inhibitory activity. SAR studies for PDE5 inhibition revealed an essential role for a carboxylic acid functionality at the 1-phenyl and the importance of the non-planar pyrazoline core over the planar pyrazole with the 5-phenyl moiety tolerating a range of substituents. These modifications led to new PDE5 inhibitors with approximately 20-fold improved potency to inhibit PDE5 and no COX-2 inhibitory activity compared with celecoxib. PDE isozyme profiling of compound 11 revealed a favorable selectivity profile. These results suggest that trisubstituted pyrazolines provide a promising scaffold for further chemical optimization to identify novel PDE5 inhibitors with potential for less side effects compared with available PDE5 inhibitors used for the treatment of penile erectile dysfunction and pulmonary hypertension. [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]

• The investigational drug IND has been patented with USPTO. • Plasma protein binding has a major role in drug therapy specifically the pharmacokinetics and pharmacodynamics. • The interaction between IND and BSA has been investigated by using spectroscopic methods. • Molecular docking studies suggested that IND binds mainly to the subdomain IIA of BSA. • The experimental results will be helpful in preclinical drug development of IND. The indole derivative 2-(5-methoxy-2-methyl-1H-indol-3-yl)-N'-[(E)-(3-nitrophenyl) methylidene]acetohydrazide (IND) was synthesized for its therapeutic potential to inhibit cyclooxygenase (COX)-II. Binding if IND to bovine serum albumin (BSA) was investigated was because most drugs bind to serum albumin in -vivo. Fluorescence, UV–vis spectrophotometry and molecular modeling methodologies were employed for studying the interaction mechanism. The intrinsic fluorescence of BSA was quenched by BSA and the quenching mechanism involved was static quenching. The binding constants between IND and BSA at the three studied temperatures (298, 301 and 306 K) were 1.09 × 105, 4.36 × 104 and 1.23 × 104 L mol−1 respectively. The most likely site for binding IND to BSA was Site I (subdomain IIA). The analysis of thermodynamic parameter revealed the involvement of hydrogen bonding and van der Waals forces in the IND-BSA interaction. Synchronous fluorescence spectroscopic (SFS) and UV–vis spectrophotometric studies suggested conformational change in BSA molecule post interaction to IND. Molecular docking and the experimental results corroborated one another. The study can prove as an insight for future IND drug development. [ABSTRACT FROM AUTHOR]