Synthesis,molecular docking,and pharmacological evaluation of N‐(2‐(3,5‐dimethoxyphenyl)benzoxazole‐5‐yl)benzamide derivatives as selective COX‐2 inhibitors and anti‐inflammatory agents

A series of N‐(2‐(3,5‐dimethoxyphenyl)benzoxazole‐5‐yl)benzamide derivatives ( 3am ) was synthesized and evaluated for their in vitro inhibitory activity against COX‐1 and COX‐2. The compounds with considerable in vitro activity (IC₅₀ < 1 μM) were evaluated in vivo for their anti‐inflammatory potential by the carrageenan‐induced rat paw edema method. Out of 13 newly synthesized compounds, 3a , 3b , 3d , 3g , 3j , and 3k were found to be the most potent COX‐2 inhibitors in the in vitro enzymatic assay, with IC₅₀ values in the range of 0.06–0.71 μM. The in vivo anti‐inflammatory activity of these six compounds ( 3a , 3b , 3d , 3g , 3j , and 3k ) was assessed by the carrageenan‐induced rat paw edema method. Compounds 3d (84.09%), 3g (79.54%), and 3a (70.45%) demonstrated significant anti‐inflammatory activity compared to the standard drug ibuprofen (65.90%) and were also found to be safer than ibuprofen, by ulcerogenic studies. A docking study was done using the crystal structure of human COX‐2, to understand the binding mechanism of these inhibitors to the active site of COX‐2.

     

Pyrimidine‐based pyrazoles as cyclin‐dependent kinase 2 inhibitors: Design,synthesis, and biological evaluation

A series of new pyrimidine‐pyrazole hybrid molecules were designed as inhibitors of cyclin‐dependent kinase 2. Designed compounds were docked using Glide and the compounds showing good score values and encouraging interactions with the residues were selected for synthesis. They were then evaluated using CDK2‐CyclinA2 enzyme inhibition by a luminescent ADP detection assay. We show that of the 26 compounds synthesized and evaluated, at least 5 compounds were found to be highly potent (IC₅₀ < 20 nm ); which can be further optimized to have selectivity over other kinase isoforms.     

Synthesis of 18F‐labeled cyclooxygenase‐2 (COX‐2) inhibitor as a potential PET imaging agent

A new PET tracer for COX‐2 imaging, the 6‐ethoxy‐3‐(4‐methanesulfonylphenyl)‐4‐(4‐[¹⁸F]fluorophenyl)pyran‐2‐one ([¹⁸F]EFMP), was synthesized. For F‐18 radiolabeling, a trimethylammonium precursor and a brominated precursor were synthesized from 1,1,2,3‐tetrachlorocycloprop‐2‐ene in 6 steps. The radiolabeling was achieved through nucleophilic substitution using no‐carrier‐added (n.c.a.) fluorine‐18. Solid‐phase extraction and semi‐preparative‐HPLC purification produced [¹⁸F]EFMP in 14.6±3.3% (n =4) decay corrected radiochemical yield with a specific activity of 487±85.1 (n =4) Ci/mmol and greater than 98% radiochemical purity. Copyright © 2006 John Wiley & Sons, Ltd.     

Design and synthesis of new 1,3-benzdiazinan-4-one derivatives as selective cyclooxygenase (COX-2) inhibitors

A new group of regioisomeric 2,3-diaryl-1,3-benzdiazinan-4-ones, possessing a methyl sulfonyl pharmacophore, were synthesized and their biological activities were tested for cyclooxygenase-2 (COX-2) inhibitory activity. In vitro COX-1/COX-2 inhibition studies identified 3-(p-fluorophenyl)-2-(4-methylsulfonylphenyl)-1,3-benzdiazinane-4-one (2b) as a potent and highly selective (IC(50) = 0.07 μM; selectivity index = 572.8) COX-2 inhibitor.     

Phthalate plasticizer di(2‐ethyl‐hexyl) phthalate induces cyclooxygenase‐2 expression in gastric adenocarcinoma cells

The phthalate plasticizer, di(2‐ethyl‐hexyl) phthalate (DEHP), and its derived metabolites are common anthropogenic environmental toxins, which are known to act as endocrine disruptors. Numerous studies have associated DEHP with disruption of sex hormones, abnormal development of reproductive organs, allergies, and inflammation. Its role in promoting inflammation has been reported by both human epidemiological and animal studies. In stomach tissue, chronic inflammation is known to accompany mucosal damage, and pave the way to gastritis, stomach ulcers, and ultimately gastric cancer. Eastern Asian populations possess the highest gastric cancer incidences in the world. Coincidentally, East Asia is one of the world's major sites for plastics manufacture and export. Thus, possible correlations between DEHP, a common plasticizer, and gastric cancer are of great interest. Our study revealed several critical findings. First, even at very low dosage, mimicking the residual plasticizer exposure, detrimental effects of DEHP on gastric cells can be detected. Second, gastric cells treated with DEHP increased cyclooxygenase‐2 (COX‐2) in a time‐dependent manner. Third, promoter deletion studies revealed a critical role of nuclear factor‐kappa B (NF‐κB) for COX‐2 gene responses. Finally, our results indicated that a low concentration of DEHP is able to trigger COX‐2 activation via the extracellular signal–regulated kinase (ERK1/2) and NF‐κB signaling pathway. Taken together, we demonstrate that very low doses of DEHP enhance the expression of the prototypical inflammatory gene, COX‐2, in gastric cancer cells via ERK1/2 and NF‐κB activation. This study provides important insights into the inflammatory process and damages associated with phthalate plasticizers exposure.     

Antiproliferative Diarylpyrazole Derivatives as Dual Inhibitors of the ERK Pathway and COX‐2

A series of 3,4‐diarylpyrazole‐1‐carboxamide derivatives was designed and synthesized. A selected group of the target compounds was tested for in vitro antiproliferative activities over a panel of 60 cancer cell lines at the National Cancer Institute (NCI, Bethesda, MD, USA) at a single‐dose concentration of 10 μm , and the four most active compounds 9a , 9l , 9n , and 10o were further tested in a five‐dose testing mode to determine their IC₅₀ values over the 60 cell lines. In addition, a selected group of target compounds were tested for inhibitory effect over cyclooxygenase isozymes. Compounds 9a , 9l , 9n , and 10o were also tested for MEK and ERK kinase inhibitory activity using Western blot assay. Compound 10o was selective toward melanoma cell line subpanel, and its antiproliferative activity may be attributed to selective cyclooxygenase‐2 inhibition and ERK pathway inhibition.     

Synthesis and evaluation of [123I]‐indomethacin derivatives as COX‐2 targeted imaging agents

A novel series of iodinated indomethacin derivatives was synthesized, and evaluated as selective inhibitors of COX‐2. Two candidate compounds N‐(p‐iodobenzyl)‐2‐(1‐(p‐chlorobenzoyl)‐5‐methoxy‐2‐methyl‐1H‐indol‐3‐yl)acetamide (3) and 1‐(p‐iodobenzyl)‐5‐methoxy‐2‐methyl‐3‐indoleacetic acid (9) possessed optimum properties suitable for potential in vivo imaging. Arylstannane precursors for radioiododestannylation were synthesized in 70–85% yield from the iodo compounds by reaction with hexabutylditin and tetrakis(triphenylphosphine)palladium(0) in refluxing dioxane. Radioiododestannylation was conducted by reaction with carrier‐added Na[¹²³I] in the presence of Chloramine‐T in an EtOAc/H₂O binary system under acidic conditions (pH 3.5), allowing direct isolation of the labeled products by separation of the organic phase. Radioiodinated products [¹²³I]3 and [¹²³I]9 were recovered in a decay‐corrected radiochemical yield of 86–87% and radiochemical purity of 98–99%. Copyright © 2009 John Wiley & Sons, Ltd.     

QSAR analysis of some fused pyrazoles as selective cyclooxygenase-2 inhibitors: a Hansch approach

Quantitative structure activity relationships (QSAR) for two unique series of centrally fused pyrazole ring systems have been studied for selective cyclooxygenase-2 inhibitory activity. Several statistically significant QSAR models were developed and suggest that hydrophobicity of entire molecules and a fluorine atom substitution at position 8 of the non benzene sulphonyl ring fused with central pyrazole core of series 1 compounds is crucial for improved COX-2 selectivity. Various structural and physicochemical stipulations to improve the inhibitory activities of the enzymes among individual series of compounds are also discussed. The conclusions derived may serve as an example to advance the design of new selective COX-2 inhibitors.     

Pyrazolo[3,4‐d]pyrimidine Derivatives as COX‐2 Selective Inhibitors: Synthesis and Molecular Modelling Studies

The pyrazolo[3,4‐d]pyrimidine system shows a multitude of interesting pharmacological properties. Owing to the potential anti‐inflammatory activity of 5‐benzamido‐pyrazolo[3,4‐d]pyrimidin‐4‐one derivatives and considering the easy synthesis of this class of compounds, a set of new 5‐benzamido‐1H‐pyrazolo[3,4‐d]pyrimidin‐4‐ones has been prepared in 42‐80% yields by reacting 5‐aminopyrazole‐4(N‐benzoyl)carbohydrazide derivatives and the opportune triethylorthoesters. Compounds 8a , b , 10a – d , and 11a , b revealed a superior inhibitory profile against COX‐2, when compared to that of reference standards NS398 and indomethacin. Molecular modelling studies confirmed the obtained biological results.