Design and Synthesis of Novel Diaryl Oxo Pyrrole Derivative as Selective COX-2 Inhibitors

Inflammation is the initial defense response of the body cells and tissues to various stimuli such as pathogens, infections, irritation, chemicals, mechanical or thermal injuries.These symptoms are due to the release of some inflammatory mediators including prostaglandins (PGs). Non-steroidal anti-inflammatory drugs (NSAIDs), widely used for the treatment of pain, pyrexia, inflammation, rheumatoid arthritis and osteoarthritis, block biosynthesis of prostaglandins by inhibiting the different isoforms of cyclooxygenase enzyme (COX-1,2) . The range of activities of NSAIDs against COX-1 compared with COX-2 explains the variations in the side effects of NSAIDs at their anti-inflammatory doses. Drugs which have a high potency against COX-2 and a low COX-2/COX-1 activity ratio will have potent anti-inflammatory activity with few side effects on the stomach and kidney. The recent market withdrawal of some coxibs such as rofecoxib and valdecoxib due to their adverse cardiovascular side effects clearly delineates the need to develop alternative structures with COX-2 inhibitory activity. For this reason novel scaffolds with high selectivity for COX-2 inhibition need to be found and evaluated for their anti-inflammatory effects. Therefore in this study, novel diaryl oxo pyrrole derivatives were designed and synthesized based on the structure-activity relationship of selective COX-2 inhibitors. Target compounds were synthesized in two steps: In the first step, a solution of 4-(Methylthio)benzaldehyde, arylamine derivatives and dimethylacetylenedicarboxylate (DMAD) in the presence of para-toluenesulfonic acid (PTSA) as a catalyst, was stirred in ethanol for 72 hours. After the completion of the reaction, the resulting product was filtered off and recrystallized with ethanol. In the second step, the resulting precipitates and diethylamine were stirred in acetonitrile. Then a solution of Oxone and water was added to the mixture. After the completion of the reaction, the resulting precipitates were filtered off and recrystallized with ethanol. A series of novel diaryl oxo pyrrole derivatives were synthesized in good yields and the structure of the compounds was confirmed by FT- IR, 1HNMR and MASS spectroscopy. In this study new derivatives of diaryl oxo pyrrole was synthesized in two steps. Molecular structures of the synthesized compounds were confirmed by FT- IR, 1HNMR and MASS spectroscopy

Design and synthesis of New Methyl4-Hydroxy-1-Alkyl-2-aryl 5-Oxo 2,5-Dihydropyrrole-3-Carboxylate Derivatives as Selective COX-2 Inhibitors

The non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly medications in the world. The mechanism of action of these drugs is the inhibition of cyclooxygenase (COX) enzyme, which catalyzes the first step of the biosynthesis of PGG2 from arachidonic acid. COX isozymes exist at least in two isoforms, COX-1 and COX-2.The constitutive COX-1 isozyme is found in plateletes, kidneys, and the gastrointestinal tract and is believed to be responsible for the maintenance of physiological functions such as gastro protection and vascular homeostasis. In contrast, the COX-2 enzyme is the inducible isoform that is produced by various cell types upon exposure to cytokines, mitogens, and endotoxins released during injury and therefore molecules that inhibit its enzymatic activity would be of therapeutic value. The gastrointestinal side effects associated with NSAIDs are due to the inhibition of gastroprotective PGs synthesized through the COX-1 pathway. Thus, selective inhibition of COX-2 over COX-1 is useful for the treatment of inflammation and inflammation-associated disorders with reduced gastrointestinal toxicities when compared with NSAIDs. The recent market withdrawal of some coxibs such as rofecoxib and valdecoxib due to their adverse cardiovascular side effects clearly delineates the need to develop alternative structures with COX-2 inhibitory activity. For this reason novel scaffolds with high selectivity for COX-2 inhibition need to be found and evaluated for their anti-inflammatory effects. As a result, in this study, new methyl4-hydroxy-1-alkyl-2-aryl 5-oxo 2,5-dihydropyrrole-3-carboxylate derivatives were designed and sythesized based on the structure-activity relationship of selective COX-2 inhibitors. A mixture of 4-methylthiobenzaldehyde, arylamine derivatives and para-toluene sulfonic acid (PTSA) as a catalyst in ethanol was stirred at room temperature for 1 hour until a white precipitate appeared. Then, dimethylacetylenedicarboxylate (DMAD) was added. The reaction was stirred at room temperature until a new precipitate appeared. Finally, the resulting precipitate was recrystallized with ethanol. In the next step, a solution of Oxone in water was added to a well-stirred solution of the resulting product and diethyamine as a catalyst in acetonitrile. After the completion of the reaction, the precipitates were filtered and recrystallized with ethanol. All the target compounds were synthesized in good to high yields and the chemical structures were confirmed by IR, 1HNMR and Mass spectra. A novel series of methyl4-hydroxy-1-alkyl-2-aryl 5-oxo 2,5-dihydropyrrole-3-carboxylate derivatives was designed and synthesized as selective COX-2 inhibitors in good yields. The target compounds were characterized via IR, 1HNMR and Mass spectroscopies. The COX-2 inhibitory activity of the target compouds is under investigation

Design and Synthesis of New Methyl 1,2-Diaryl-4-Hydroxy-5-oxo -2,5-Dihydro-1H-Pyrrole-3-Carboxylate Derivatives as Selective COX-2 Inhibitors

The use of non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of inflammation and pain is often accompanied by adverse gastrointestinal and renal side effects. Their anti-inflammatory activity results from inflammation of cyclooxygenase (COX), which catalyzes bioconversion of arachidonic acid to prostaglandins. Nowadays, it is well established that there are at least two COX isozymes, COX-1 and COX-2. COX-1 is responsible for the physiological production of prostaglandins while COX-2 is responsible for the elevated production of prostaglandins during inflammation. Thus, selective inhibition of COX-2 over COX-1 is useful for the treatment of inflammation and inflammation associated disorders with reduced gastrointestinal toxicities compared to NSAIDs. The withdrawal of some diaryl heterocyclic selective COX-2 inhibitors due to the adverse cardiovascular side effects delineates the need to explore and evaluate a new structural ring template possessing COX inhibitory activity. Therefore, in this study, new methyl 1,2-diaryl-4-hydroxy-5-oxo -2,5-dihydro-1H-pyrrole-3-carboxylate derivatives were designed and synthesized based on the structure-activity relationship of selective COX-2 inhibitors. Target compounds were synthesized in two steps. In the first step, 4-(methylthio)benzaldehyde, arylamine derivatives, and dimethylacetylenedicarboxylate (DMAD) in the presence of para-toluene sulfonic acid (PTSA) were stirred in ethanol for 72 hours. After the completion of the reaction, the resulting product was filtered off and recrystallized with ethanol. In the second step, a solution of Oxone and water was added to a well-stirred solution of the resulting product and diethylamine in acetonitrile. After the completion of the reaction, the resulting precipitates were filtered off and recrystallized with ethanol. In this study, new derivatives of new methyl 1,2-diaryl-4-hydroxy-5-oxo -2,5-dihydro-1H-pyrrole-3-carboxylate were designed, synthesized, and purified. The structure of the synthesized compounds was confirmed by FT- IR, 1HNMR, and MASS. We designed and synthesized some new methyl 1,2-diaryl-4-hydroxy-5-oxo -2,5-dihydro-1H-pyrrole-3-carboxylate derivatives as selective COX-2 inhibitors. The structure of synthesized compounds was confirmed by FT- IR, 1HNMR, and MASS. The COX-2 inhibitory activity of these compounds is under investigation

Evaluation of Anti-Platelet Aggregation Effect of Some Allium Species

Epidemiologic studies show that the cardiovascular diseases are associated with multiple factors such as raised serum total cholesterol, increased LDL, increased platelet aggregation, hypertension and smoking. In-vitro studies have confirmed the ability of some plants of Allium species to reduce these parameters. Therefore, we evaluated anti-platelet aggregation effect of some Allium species (Allium ampeloprasum, A. hirtifolium, A. haemanthoides, A. vavillovi, A. atroviolaceum, A. jesdianum, A. shelkovnikovii) using arachidonic acid (AA) and adenosine diphosphate (ADP) as platelet aggregation inducers. The screening results for methanolic extract of Allium species showed that the maximum effect of anti-platelet aggregation was related to A. atroviolaceum. This extract inhibited the in-vitro platelet aggregation induced by AA and ADP with IC50 values of 0.4881 (0.4826-0.4937) mg/ml and 0.4945 (0.4137-0.5911) mg/ml respectively. These results support the hypothesis that the dietary intake of Allium could be beneficial for prevention of cardiovascular diseases

Simultaneous measurement of lead and cadmium in the milk distributed in Tehran’s schools by differential-pulse anodic stripping voltammetry

Milk is one of the most important foods in the dietary regimen of children which can be contaminated with toxic elements such as lead (Pb) and cadmium (Cd). In this study, the concentrations of Cd and Pb were determined in the milk distributed among school-aged children in Tehran. Differential-pulse anodic stripping voltammetry (DPASV) method using hanging mercury drop electrode (HMDE) was performed.The obtained limit of detection (LOD) and limit of quantification (LOQ) were 0.31 ppb and 1.03 ppb for Pb and 0.09 ppb and 0.32 ppb for Cd, respectively. The concentration of Pb and Cd in the examined milk was 3.34 ± 0.63, and 0.42 ± 0.47 ppb, with recovery range between 85-109% and 91-112%, respectively.The results demonstrated that the levels of Pb and Cd were considerably less than the maximum residue limit (MRL), mentioned by the regulatory organizations

Identification of (Z)-2,3-Diphenylacrylonitrile as Anti-Cancer Molecule in Persian Gulf Sea Cucumber Holothuria parva

Hepatocellular carcinoma (HCC), also named cancerous hepatoma, is the most common type of malignant neoplasia of the liver. In this research, we screened the Persian Gulf sea cucumber Holothuria parva (H. parva) methanolic sub-fractions for the possible existence of selective toxicity on liver mitochondria isolated from an animal model of HCC. Next, we purified the most active fraction. Thus the structure of the active molecule was identified. HCC was induced by diethylnitrosamine (DEN) and 2-acetylaminofluorene (2-AAF) protocol. Rat liver mitochondria for evaluation of the selective cytotoxic effects of sub-fractions of H. parva were isolated and then mitochondrial parameters were determined. Our results showed that C1 sub-fraction of methanolic extract of H. parva considerably increased reactive oxygen species (ROS) generation, collapse of mitochondrial membrane potential (MMP), swelling in mitochondria and cytochrome c release only on HCC liver mitochondria. Furthermore, the methanolic extract of H. parva was investigated furthermore and the active fraction was extracted. In this fraction, (Z)-2,3-diphenylacrylonitrile molecule, which is also known as α-cyanostilbene, was identified by mass analysis. This molecule increased ROS generation, collapse of MMP, swelling in mitochondria and finally cytochrome c release only on HCC liver mitochondria. The derivatives of (Z)-2,3-diphenylacrylonitrile in other natural products were also reported as an anti-cancer agent. These results suggest the eligibility of the (Z)-2,3-diphenylacrylonitrile as a complementary therapeutic agent for patients with HCC

Electrosynthesis, in Silico Ligand-Protein Interaction and Pharmacokinetic Studies of Some Aryl Sulfone Derivatives as Potential Acetylcholinesterase Inhibitors: Synthesis of aryl sulfones as acetylcholinesterase inhibitors

Acetylcholinesterase (AChE) is an enzyme that catalyzes the hydrolysis of acetylcholine. Acetylcholine plays an essential role in learning and memory. Since acetylcholine deficiency is related to the pathogenesis of Alzheimer's disease, obtaining acetylcholinesterase inhibitors is of great interest. Here, a group of aryl sulfone derivatives with a catechol ring was synthesized by the electrochemical method. The structure of compounds was confirmed by 1HNMR and ESI-MS. Molecular docking studies of the synthesized compounds with AChE were performed and the results showed that all of the compounds have good theoretical affinities for the target enzyme, AChE. Moreover, the physicochemical properties and ADME parameters of synthesized compounds were predicted, which revealed that they have acceptable features as drug candidates. HIGHLIGHTS Aryl sulfone derivatives with catechol rings were synthesized by electrochemical method. Molecular docking studies of the compounds revealed good binding affinities against acetylcholinesterase. All of the synthesized compounds obey Lipinski’s rule of five which suggests them as good oral drug candidates

Green Synthesis of Nalidixic Acid by Ionic Liquid: Using ionic liquid for drug synthesis

In this study, a green process was applied for the preparation of nalidixic acid by the assistance of an ionic liquid. Nalidixic acid was prepared by reaction of 6-methylpyridin-2-amine, ethyl formate and diethyl malonate in tris-(2-hydroxyethyl) ammonium acetate solution as ionic liquid (IL) which was provided by reaction of triethanolamine and acetic acid. The 1HNMR, 13CNMR, FTIR, mass spectroscopy and melting point were used to characterize the structure of the synthesized compounds. The ionic liquid was recovered and reused for four runs. This method introduces a novel idea for synthesis of nalidixic acid with high yield (86%) and the least damage to the environment. This IL can be used as a green solvent in synthesis of compounds instead of using harmful solvents

Synthesis and Labeling of Two Fibrin-Targeted Peptides (HYNICGPRPILE, HYNIC-GPKGAAD) Using Technetium-99m and In Vitro Evaluation of Fibrin Binding and Platelet Aggregation: Fibrin-targeted peptides for molecular imaging of thrombus

Early detection of thrombus and its location in the body are critical factors for the treatment of thrombosis related diseases. Fibrin is the main component of thrombus, abundant in all thrombi, and is not found in non-pathological conditions. The presence of fibrin in all types of thrombi and its low concentration in blood makes it a sensitive and specific target for imaging studies of thrombus. Fibrin also accumulates in malignant tumors. Thus, fibrin imaging can be used in oncology, atherosclerosis, and thrombosis-related pathologies such as pulmonary emboli and deep vein thrombosis. Different compounds such as antibodies, nanoparticles, and peptides have been studied for fibrin imaging. Among them, peptides are more attractive because of better pharmacokinetics, simple and cheap preparation, and better radiolabeling methods. In this study, two peptides (HYNIC-GPRPILE, HYNIC-GPKGAAD) designed to target fibrin were synthesized.  The peptides were identified by LC-MS. The stability and platelet aggregation of peptides were determined. Peptides were radiolabeled with 99mTc using HYNIC as chelating agent. The release of 99mTc and fibrin binding of radiopeptides were evaluated. Based on the results, peptides were stable in human plasma for at least 6 h and had no effect on platelet aggregation. Peptides were radiolabeled with pertechnetate at 80°C in 30 min. Radiochemical purity was over 95%. Radiopeptides were stable in human plasma and there was less than 5% release of 99mTc. The fibrin binding of radiopeptides was 70%>. Since peptides had no platelet binding activity, it can be concluded that binding of radiopeptides to fibrin is specific. HIGHLIGHTS Molecular imaging of fibrin used in oncology, atherosclerosis, and thrombosis related pathologies. Invasive early detection of thrombus using radiolabeled fibrin targeted peptides. Radiolabeling of peptides with 99mTc using HYNIC as chelating agent and EDDA and tricine as co-ligand. &nbsp

Synthesis, Radiolabeling and Stability Studies of Peptide HYNIC-LIKKP-Pyr-F with 99mTc as an Apoptosis Imaging Agent : Radiolabeling of an apoptosis imaging agent

A non-invasive method for detecting phosphatidylserine (PS) exposure on the outer surface of plasma membranes, such as nuclear imaging, could aid in the diagnosis and treatment of diseases associated with apoptosis. Annexin V has been the most researched imaging agent for apoptosis to date. Due to Annexin V's limitations, additional agents, such as small peptides and molecules, have been introduced, including LIKKPF developed by Burtea et al. In this study, HYNIC-LIKKP-pyr-F, a derivative of LIKKPF was prepared using the 9-fluoroenylmethoxycarbonyl (fmoc) method, radiolabeled with Technetium-99m (99mTc) with the use of Stannous chloride (SnCl2) as a reducing agent and ethylenediamine diacetate (EDDA) and tricine as co-ligands. Radiochemical purity, labeling efficiency, and stability of radiopeptide in normal saline and human plasma were determined using thin layer chromatography (TLC). The partition coefficient of radiolabeled peptide was measured in a combination of PBS (pH 7.4) and n-octanol. Specific activity was also measured. LC-MS was used to examine the synthesized peptide. Peptide was stable in human serum for at least 4 hr. Peptide was radiolabeled with 99mTc with radiochemical purity and labeling efficiency over 95% and 90%, respectively. Radiopeptide was stable in saline and human serum for at least 4 hours. The radiolabeled peptide has a great deal of potential as an apoptosis imaging agent for in vitro and in vivo experiments. HIGHLIGHTS A noninvasive method for apoptosis imaging is the usage of radiolabeled affinity ligands. A new derivative of LIKKPF with affinity for phosphatidyl serine was synthesized. The LIKKPF peptide was radiolabeled with 99