Synthesis, characterization, molecular modelling and biological evaluation of thieno-pyrimidinone methanesulphonamide thio-derivatives as non-steroidal anti-inflammatory agents.

This study reports the synthesis, molecular docking and biological evaluation of eight (5-8 and 5a-8a) newly synthesized thieno-pyrimidinone methanesulphonamide thio-derivatives. The synthetic route used to prepare the new isomers thioaryl and thio-cycloesyl derivatives of the heterocyclic system 6-phenylthieno[3,2]pyrimidinone was economically and environmentally very advantageous and characterized by the simplicity of procedure, reduction in isolation steps, purification phases, time, costs and waste production. The study in silico for the evaluation of cyclooxygenase (COX)-1 and COX-2 selective inhibition was carried out by AutoDock Vina, an open-source program for doing molecular docking which predicts the preferred orientation of one molecule to a second when bound to each other to form a stable complex. The research in vitro for the biological evaluation was performed by using human cartilage and chondrocytes cultures treated with 10 ng/mL of interleukin-1beta as inflammation models. The anti-inflammatory activity of each new compound at the concentration of 10 µmol/L was determined by assaying COX-2, inducible nitric oxide synthetase (iNOS) and intercellular adhesion molecule 1 (ICAM 1) through Western blot. The examined derivatives showed interesting pharmacological activity, and the compound N-[2-[2,4-difluorophenyl)thio]-4-oxo-6-phenylthieno[3,2-d]pyridine-34H-yl]methanesulphonamide (7) was excellent COX-2 inhibitor. In agreement with the biological data, compound 7 was able to fit into the active site of COX-2 with highest interaction energy. These results can support the design of novel specific inhibitors of COX-2 by the comparative modelling of COX-1 and COX-2 enzymes with the available pharmacophore.

Molecular docking and fluorescence characterization of benzothieno[3,2-d]pyrimidin-4-one sulphonamide thio-derivatives, a novel class of selective cyclooxygenase-2 inhibitors.

The aims of this study were: (i) to explore the structure-activity relationship of some new anti-inflammatory benzothieno[3,2-d]pyrimidin-4-one sulphonamide thio-derivatives 1-11; and (ii) to evaluate the possibility of using the most active compounds as fluorescent probes to determine tumours or their progression. Therefore, to know the precise mechanism by which these compounds interact with cyclooxygenase (COX)-2 enzyme, a molecular docking study was carried out; to assess spectroscopic characteristics, their absorption and emission properties were determined. The results demonstrated that some derivatives of benzothieno[3,2-d] pyrimidine exhibit interesting anti-inflammatory properties related to interactions with active sites of COX-2 and are fluorescent. The antipyrine-bearing compound 4 displayed high COX-2 affinity (ΔG = -9.4) and good fluorescent properties (Φfl = 0.032). Thus, some members of this new class of anti-inflammatory may be promising for fluorescence imaging of cancer cells that express the COX-2 enzyme. Further in vitro and in vivo studies are needed to confirm this hypothesis.

Synthesis and biological evaluation of new benzo-thieno[3,2-d]pyrimidin-4-one sulphonamide thio-derivatives as potential selective cyclooxygenase-2 inhibitors.

The aim of this work was to evaluate the potential anti-inflammatory activity of eleven (5-15) new synthesized derivatives of benzo-thieno[3,2-d]pyrimidine on two cell models, namely human keratinocytes NCTC 2544 and mouse monocyte-macrophages J774. For the synthesis of test compounds an efficient approach was developed: the key isothiocyanate was prepared through a simple and ecological method using di-2-pyridyl thionocarbonate (DPT) in substitution of thiophosgene, a highly toxic agent, and the cyclization reaction of benzo-thiosemicarbazide derivates was performed through Wamhoff methods. This procedure can be a new alternative method economically and environmentally advantageous by the simplicity of procedure, reduction of isolation and purification steps, time, costs, and waste production. The potential anti-inflammatory activity of 5-15 was evaluated by determining the expression of cyclooxygenase (COX)-2, inducible NO synthase (iNOS), and intercellular adhesion molecule-1 (ICAM-1), and the release of prostaglandins (PG)E[Formula: see text] and interleukin-8 (IL-8). Our results demonstrate that the compounds 7, 10, 12, 13, 14, and 15 act as a potent inhibitor of COX-2, iNOS, ICAM-1 expression while also suppressing the production of PGE[Formula: see text] and IL-8 in human keratinocytes NCTC 2544 exposed to interferon-gamma (IFN-[Formula: see text]) and histamine and monocyte-macrophages J774 cells treated with lipopolysaccharides (LPS). In conclusion, some derivatives of benzo-thieno[3,2-d]pyrimidine could be developed as a novel class of anti-inflammatory agents.

Cement-Based Composites Containing Oxidized Graphene Nanoplatelets: Effects on the Mechanical and Electrical Properties.

Graphene nanoplatelets can improve the electrical and mechanical properties of cement matrix composites. The dispersion and interaction of graphene in the cement matrix appears to be difficult due to its hydrophobic nature. By introducing polar groups, graphene oxidation improves the level of dispersion and interaction with the cement. In this work, graphene oxidation using sulfonitric acid for 10, 20, 40, and 60 min was studied. Thermogravimetric Analysis (TGA) and Raman spectroscopy were employed to analyze the graphene before and after the oxidation. The mechanical properties of the final composites showed an improvement of 52% in the flexural strength, 4% in the fracture energy, and 8% in the compressive strength in the case of 60 min of oxidation. In addition, the samples showed a reduction of at least one order of magnitude in electrical resistivity when compared with pure cement.

Inhibition of iNOS and COX-2 in human whole blood ex vivo and monocyte-macrophage J774 cells by a new group of aminothiopyrimidone derivatives.

We tested a series of 11 new aminothiopyrimidones on the activity of inducible nitric oxide synthase (iNOS) and prostaglandin G/H synthase-1 and 2 (COX-1 and COX-2) in the whole human blood and monocyte-macrophage J774 cell line. To induce COX-2 and iNOS, blood samples and J774 cells were stimulated with bacterial lipopolysaccharide (LPS) in the absence or presence of the test compounds. After incubation, the plasma and the supernatants of culture media were collected for the measurement of TxB(2) and PGE(2) by a specific enzyme-immunoassay and determination of nitrite by a colorimetric assay. Several phenylthieno derivatives of substituted pyrimidone inhibited formation of both COX-2 and iNOS derived products with one of the compounds (compound 11, N-[2-[(2,4-dinitrophenyl)thio]-4-oxo-6-phenylthieno[2,3-d]pyrimidin-3(4H)-y]methanesulfonamide) showing a complete inhibition of LPS-stimulated formation of NO and PGE(2).

Synthesis and biological evaluation of sulfonilamidothienopyrimidinone derivatives as novel anti-inflammatory agents.

Eight new sulfonilamidothienopyrimidinone derivatives (1-8) were synthesized and evaluated for their antiinflammatory activity on the human keratinocyte line NCTC 2544. The potential anti-inflammatory activity of the derivatives (1-8) was evaluated by determining, through Western blot, the expression of cyclooxygenase (COX)-2, inducible NO synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1), and the release of prostaglandins (PG)E2 and interleukin- 8 (IL-8). Moreover, through ELISA assay, the release of monocyte chemoattractant protein-1 (MCP-1), and interleukin- 8 (IL-8) was analyzed. Our results demonstrated that the derivatives 3, 5, 6 and 8 act as excellent inhibitors of inflammatory markers: iNOS, COX-2, ICAM-1, MCP-1, and IL-8. These findings could be useful for the development of new drugs for the treatment of various inflammatory pathologies.

Sulfonilamidothiopyrimidone and thiopyrimidone derivatives as selective COX-2 inhibitors: synthesis, biological evaluation, and docking studies.

Newly synthesized sulfonilamidothiopyrimidone derivatives and a subset of 14 sulfonilamidothiopyrimidones and thiopyrimidones selected by an MTT assays cell viability guided selection from an in house collection were evaluated to determine the inhibitory effect on the PGE(2) formation in human peripheral blood lymphocytes (PBLs) using commercial ELISA. The newly synthesized sulfonilamidothiopyrimidone derivatives showed interesting pharmacological activities. Preliminary in vitro assays showed that compounds 2-5 are endowed with very high activity. Compound 2 was the most active as hCOX-2 inhibitor. The observed effects were not due to an inhibition of cell proliferation as proved by the BrdU assay. Western blot of COX-2 confirmed the inhibition on the PGE(2) secretion. Further evidence on the inhibitory potential and selectivity as COX-2 inhibitors of the selected compounds came from the in vitro screening. In order to better rationalize the action and the binding mode of these compounds, docking studies were carried out. These studies were in agreement with the biological data. Compounds 2-5 were able to fit into the active site of COX-2 with highest scores and interaction energies. Furthermore, compound 2, which showed an inhibition of around 50% on PGE(2) production, was the best scored in all the docking calculations carried out.

Synthesis and effects on the COX-1 and COX-2 activity in human whole blood ex vivo of derivatives containing the [1]benzothienol-[3, 2-d]pyrimidin-4-one heterocyclic system.

Methyl and phenyl derivatives containing the [1]Benzothieno [3, 2-d]pyrimidin-4-one system have been synthesized and tested as inhibitors of COX-1 and COX-2 activities in human whole blood (HWB) ex vivo; all compounds turned out to be weak inhibitors of COX-1 activity, as deduced from the TXB(2) (thromboxane B) generation; the acid phenyl derivative 11 b was an interesting inhibitor of COX-2 activity, as deduced from the PGE(2) (prostaglandine E) generation.

Synthesis and activity of phenyl derivatives containing 5,6-dimethylthieno[2,3-d]pyrimidin-4(1H)-one or 4H-pyrimido[5,4-b]indol-4-one heterocyclic system as potential nonsteroidal anti-inflammatory drugs.

The synthesis, the analgesic and anti-inflammatory activities of two series of phenyl derivatives containing 5,6-dimethyl-thieno[2,3-d]pyrimidin-4(1H)-one and 4H-pyrimido[5,4-b]indol-4-one system, respectively, are reported. Two of these derivatives, 6A and 9B, showed interesting activities. The results of the pharmacological assays are discussed.