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In the present work a series of N'-arylidene-2-(benzamido)-3-(naphthalen-2-yl)acrylohydrazides were synthesized by refluxing the intermediate 2-(benzamido)-3-(naphthalen-2-yl)acrylohydrazide with various substituted benzaldehyde in the presence of glacial acetic acid. The intermediate 2-(benzamido)-3-(naphthalen-2-yl)acrylohydrazide 2 was prepared by stirring 4-((naphthalen-2-yl)methylene)-2-phenyloxazol-5(4H)-one with hydrazine hydrate in the presence of absolute ethanol. The chemical structures of the compounds were established by IR, 1 H NMR and mass spectral data. All the compounds were evaluated for anti-inflammatory (in vivo, in vitro) activity and performed docking against COX-2. The compounds 3a, 3c and 3o showed good inhibition of COX-2 in in vitro studies (0.75 μM, 0.5 μM and 0.7 μM as IC50, respectively). The compounds 3c, 3e and 3f were found to be more active than standard drug phenylbutazone at equidose. Molecular docking studies showed that compound 3 m exhibited good binding affinity against COX-2 with docking score 9.328 kcal/mol, when compared to the standard celecoxib.

Background: Recent advances in genome sequencing technologies and the cost drop in high-throughput sequencing continue to give rise to a deluge of data available for downstream analyses. Among others, evolutionary biologists often make use of genomic data to uncover phenotypic diversity and adaptive evolution in protein-coding genes. Therefore, multiple sequence alignments (MSA) and phylogenetic trees (PT) need to be estimated with optimal results. However, the preparation of an initial dataset of multiple sequence file(s) (MSF) and the steps involved can be challenging when considering extensive amount of data. Thus, it becomes necessary the development of a tool that removes the potential source of error and automates the time-consuming steps of a typical workflow with high-throughput and optimal MSA and PT estimations., Results: We introduce LMAP_S (Lightweight Multigene Alignment and Phylogeny eStimation), a user-friendly command-line and interactive package, designed to handle an improved alignment and phylogeny estimation workflow: MSF preparation, MSA estimation, outlier detection, refinement, consensus, phylogeny estimation, comparison and editing, among which file and directory organization, execution, manipulation of information are automated, with minimal manual user intervention. LMAP_S was developed for the workstation multi-core environment and provides a unique advantage for processing multiple datasets. Our software, proved to be efficient throughout the workflow, including, the (unlimited) handling of more than 20 datasets., Conclusions: We have developed a simple and versatile LMAP_S package enabling researchers to effectively estimate multiple datasets MSAs and PTs in a high-throughput fashion. LMAP_S integrates more than 25 software providing overall more than 65 algorithm choices distributed in five stages. At minimum, one FASTA file is required within a single input directory. To our knowledge, no other software combines MSA and phylogeny estimation with as many alternatives and provides means to find optimal MSAs and phylogenies. Moreover, we used a case study comparing methodologies that highlighted the usefulness of our software. LMAP_S has been developed as an open-source package, allowing its integration into more complex open-source bioinformatics pipelines. LMAP_S package is released under GPLv3 license and is freely available at https://lmap-s.sourceforge.io/.

Prostaglandin endoperoxide H synthase (PGHS) is a heme-enzyme responsible for the conversion of arachidonic acid (AA) to prostaglandin H 2 (PGH 2 ). PGHS have both oxygenase (COX) and peroxidase (POX) activities and is present in two isoforms (PGHS-1 and -2) expressed in different tissues and cell conditions. It has been reported that PGHS activity is inhibited by the nitrated form of AA, nitro-arachidonic acid (NO 2 AA), which in turn could be synthesized by PGHS under nitro-oxidative conditions. Specifically, NO 2 AA inhibits COX in PGHS-1 as well as POX in both PGHS-1 and -2, in a dose and time-dependent manner. NO 2 AA inhibition involves lowering the binding stability and displacing the heme group from the active site. However, the complete mechanism remains to be understood. This review describes the interactions of PGHS with NO 2 AA, focusing on mechanisms of inhibition and nitration. In addition, using a novel approach combining EPR-spin trapping and mass spectrometry, we described possible intermediates formed during PGHS-2 catalysis and inhibition. This literature revision as well as the results presented here strongly suggest a free radical-dependent inhibitory mechanism of PGHS-2 by NO 2 AA. This is of relevance towards understanding the underlying mechanism of inhibition of PGHS by NO 2 AA and its anti-inflammatory potential., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A series of 5-oxo-5 H -furo[3,2- g ]chromene-6-carbaldehydes and their hydrazone derivatives were evaluated as potential multi-target-directed ligands in vitro against cholinesterases, β-secretase, cyclooxygenase-2, and lipoxygenase-15 (LOX-15), as well as for free radical-scavenging activities. The most active compounds against LOX-15 were also evaluated for activity against the human lipoxygenase-5 (LOX-5). Kinetic studies against AChE, BChE, and β-secretase (BACE-1) were performed on 2-(3-fluorophenyl)- ( 3b ) and 2-(4-chlorophenyl)-6-[(4-trifluoromethylphenyl)hydrazonomethyl]furo[3,2- h ]chromen-5-one ( 3e ) complemented with molecular docking (in silico) to determine plausible protein-ligand interactions on a molecular level. The docking studies revealed hydrogen and/or halogen bonding interactions between the strong electron-withdrawing fluorine atoms of the trifluoromethyl group with several residues of the enzyme targets, which are probably responsible for the observed increased biological activity of these hydrazone derivatives. The two compounds were found to moderately inhibit COX-2 and lipoxygenases (LOX-5 and LOX-15). Compounds 3b and 3e were also evaluated for cytotoxicity against the breast cancer MCF-7 cell line and Hek293-T cells.

Developments of natural inhibitors to prevent the function of cyclooxygenase-2 (COX-2) protein, responsible for a variety of inflammations and cancers, are a major challenge in the scientific community. In this study, robust QSAR classification models for predicting COX-2 inhibitor were developed, by which the self-organizing feature map neural network and random forest (RF) were adopted to improve the prediction of classification model ability. The F -score-based criterion combined with RF was used for feature selection, and good performance for COX-2 inhibitor prediction in overall accuracy was demonstrated. We used this model as a virtual screening tool for identifying the potential COX-2 inhibitor from a natural product library and found potential hit compounds. This compound further screened by applying molecular docking simulation identified five potential hits such as osthole, kavain, vanillyl acetone, myristicin, and psoralen, having a comparable binding affinity to COX-2 protein. However, in cell experiment, three hit compounds revealed COX-2 inhibitory activity in mRNA and protein level such as osthole, kavain, and psoralen.

(±)-Lucidumone ( 1 ), an enantiomeric meroterpenoid possessing an unprecedented skeleton comprising a fused 6/5/6/6/5 polycyclic system, was isolated from Ganoderma lucidum and structurally identified. The absolute configuration of (-) -1 was assigned by single-crystal X-ray crystallography. A plausible biosynthetic pathway for 1 is proposed. A chemical biology approach reveals that (-)- 1 selectively inhibits COX-2 by directly binding with an amino acid residue of Tyr385, representing a new structure scaffold of COX-2 inhibitors.

The cyclooxygenase-2 (COX-2) enzyme is considered to be an important target for developing novel anti-inflammatory agents. Selective COX-2 inhibitors offer the advantage of lower adverse effects that are commonly associated with non-selective COX inhibitors. In this work, a novel series of methyl 3-(substituted benzoyl)-7-substituted-2-phenylindolizine-1-carboxylates was synthesized and evaluated for COX-2 inhibitory activity. Compound 4e was identified as the most active compound of the series with an IC 50 of 6.71 M, which is comparable to the IC 50 of indomethacin, a marketed non-steroidal anti-inflammatory drug (NSAID). Molecular modeling and crystallographic studies were conducted to further characterize the compounds and gain better understanding of the binding interactions between the compounds and the residues at the active site of the COX-2 enzyme. The pharmacokinetic properties and potential toxic effects were predicted for all the synthesized compounds, which indicated good drug-like properties. Thus, these synthesized compounds can be considered as potential lead compounds for developing effective anti-inflammatory therapeutic agents., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

The neuroinflammatory response to peripheral nerve injury is associated with chronic pain and significant changes in the molecular expression profiles of mRNAs in neurons, glia and infiltrating immune cells. Chronic constriction injury (CCI) of the rat sciatic nerve provides an opportunity to mimic neuropathic injury and quantitatively assess behavior and differential gene expression in individual animals. Previously, we have shown that a single intravenous injection of nanoemulsion containing celecoxib (0.24 mg/kg) reduces inflammation of the sciatic nerve and relieves pain-like behavior for up to 6 days. Here, we use this targeted therapy to explore the impact on mRNA expression changes in both pain and pain-relieved states. Sciatic nerve tissue recovered from CCI animals is used to evaluate the mRNA expression profiles utilizing quantitative PCR. We observe mRNA changes consistent with the reduced recruitment of macrophages evident by a reduction in chemokine and cytokine expression. Furthermore, genes associated with adhesion of macrophages, as well as changes in the neuronal and glial mRNAs are observed. Moreover, genes associated with neuropathic pain including Maob, Grin2b/NMDAR2b, TrpV3, IL-6, Cacna1b/Ca v 2.2, Itgam/Cd11b, Scn9a/Na v 1.7, and Tac1 were all found to respond to the celecoxib loaded nanoemulsion during pain relief as compared to those animals that received drug-free vehicle. These results demonstrate that by targeting macrophage production of PGE 2 at the site of injury, pain relief includes partial reversal of the gene expression profiles associated with chronic pain.

Selective inhibition of cyclooxygenase (COX)-2 enzyme is an important achievement when looking for potent anti-inflammatory agents, with fewer gastrointestinal side effects. In this work, a new series of cinnamic acid derivatives, namely hexylamides, have been designed, synthesized and evaluated in human blood for their inhibitory activity of COX-1 and COX-2 enzymes. From this, new structure-activity relationships were built, showing that phenolic hydroxyl groups are essential for both COX-1 and COX-2 inhibition. Furthermore, the presence of bulky hydrophobic di-tert-butyl groups in the phenyl ring strongly contributes for selective COX-2 inhibition. In addition, a correlation with the theoretical log P has been carried out, showing that lipophilicity is particularly important for COX-2 inhibition. Further, a plasma protein binding (PPB) prediction has been performed revealing that PPB seems to have no influence in the activity of the studied compounds. From the whole study, effective selective inhibitors of COX-2 were found, namely compound 9 (IC 50  = 3.0 ± 0.3 μM), 10 (IC 50  = 2.4 ± 0.6 μM) and 23 (IC 50  = 1.09 ± 0.09 μM). Those can be considered starting point hit compounds for further optimization as potential non-steroidal anti-inflammatory drugs., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aspirin and Celebrex are well-known time-dependent inhibitors of the cyclooxygenases (COX). Molecular dynamics simulations suggest that Arg-513 and Leu-531 contribute to the structural mechanisms of COX inhibition. We used mutagenesis and functional analyses to characterize how substitutions at these positions influence time-dependent inhibition by aspirin and Celebrex. We show that substitutions of Leu-531 with asparagine and phenylalanine significantly attenuate time-dependent inhibition of COX-2 by these drugs. The introduction of side chain bulk, rigidity, and charge would disrupt the formation of the initial noncovalent complex, in the case of aspirin, and the "high-affinity" binding state, in the case of Celebrex. Substitution of Arg-513 with histidine (the equivalent residue in COX-1) resulted in a 2-fold potentiation of aspirin inhibition, in support of the hypothesis that the presence of histidine in COX-1 lowers the activation barrier associated with the formation of the initial noncovalent enzyme-inhibitor complex. As a corollary, we previously hypothesized that the flexibility associated with Leu-531 contributes to the binding of arachidonic acid (AA) to acetylated COX-2 to generate 15 R -hydroxyeicosatetraenoic acid (15R-HETE). We determined the X-ray crystal structure of AA bound to Co 3+ -protoporphyrin IX-reconstituted V349I murine COX-2 (muCOX-2). V349I muCOX-2 was utilized as a surrogate to trap AA in a conformation leading to 15R-HETE. AA binds in a C-shaped pose, facilitated by the rotation of the Leu-531 side chain. Ile-349 is positioned to sterically shield antarafacial oxygen addition at carbon-15 in a manner similar to that proposed for the acetylated Ser-530 side chain.

Ethnopharmacological Relevance: Zi-shen pill (ZSP) is a classical Chinese herbal formula used for treatment of benign prostatic hyperplasia (BPH)., Aim of the Study: To characterize and screen cyclooxygenase-2 (COX-2) inhibitors from ZSP extract., Materials and Methods: The ZSP extract was incubated with COX-2 and the potential ligands were screened out by affinity ultrafiltration. Celecoxib and glipizide were chosen as positive control and negative control drug, respectively. Affinity ultrafiltration-ultra performance liquid chromatography-mass spectrometry (UPLC-MS) method was used. In addition, in vitro COX-2 inhibitory assay and in silico molecular docking technique were used for further validation., Results: A total of 20 components were discovered and identified from ZSP ultrafiltrate by high resolution Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS), among which 8 compounds were deduced as potential COX-2 inhibitors by their high specific binding values (>1.5). Inhibitory activities of demethyleneberberine, palmatine, berberine and timosaponin A-I were confirmed by an enzyme assay of COX-2, which validated the reliability of our approach. Molecular docking simulation investigated potential mechanism of action for these compounds., Conclusion: The results revealed that affinity ultrafiltration UPLC-MS could successfully screen out the potential COX-2 inhibitors from complex Chinese herbal formula ZSP extract, indicating that its therapeutic effect on BPH was partly based on the enzyme active ingredients., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The therapeutic efficacy of the antineoplastic drug cisplatin is limited by its nephrotoxicity, which affects particularly to proximal tubular cells (PTC). Cisplatin-induced cytotoxicity appears to be multifactorial and involves inflammation, oxidative stress as well as apoptosis. We have recently shown that the cyclo-oxygenase-2 (COX-2)/intracellular prostaglandin E 2 (iPGE 2 )/EP receptor pathway mediates the apoptotic effect of cisplatin on human proximal tubular HK-2 cells. Here, we studied the effects on HK-2 cells of apoptotic bodies (ABs) generated after treatment of HK-2 cells with cisplatin. We found that ABs inhibited cell growth, induced apoptosis and increased COX-2 expression and iPGE 2 in ABs-recipient HK-2 cells. Inhibition of the COX-2/iPGE 2 /EP receptor pathway in these cells prevented the effects of ABs without interfering with their internalization. Interestingly, 2nd generation ABs (i.e. ABs released by cells undergoing apoptosis upon treatment with ABs) did not trigger apoptosis in naïve HK-2 cells, and stimulated cell proliferation through the COX-2/iPGE 2 /EP receptor pathway. These results suggest that ABs, through iPGE 2 -dependent mechanisms, might have a relevant role in the natural history of cisplatin-induced acute kidney failure because they contribute first to the propagation of the noxious effects of cisplatin to non-injured PTC and then to the promotion of the proliferative tubular response required for proximal tubule repair. Since iPGE 2 also mediates both cisplatin-induced HK-2 cell apoptosis, intervention in the COX-2/iPGE 2 /EP receptor pathway might provide us with new therapeutic avenues in patients with cisplatin-induced acute kidney injury., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Three novel series of diarylpyrazole 10b-d and triarylpyrazole derivatives 11a-d &12a-d were synthesized through Vilsmier-Haack condition. The structures of prepared compounds were determined through IR, 1 H NMR, 13 C NMR, Mass spectral and elemental analysis. Docking of the synthesized compounds over COX-2 active site ensure their selectivity. Moreover, the target compounds were evaluated for both in vitro and in vivo inhibitory activity. All compounds were more selective for COX-2 isozyme than COX-1 isozyme and with excellent anti-inflammatory activity. Compounds 11b, 11d and 12b showed the highest anti-inflammatory activity (67.4%, 62.7%, 61.4% respectively), lower ulcerogenic liability (UI = 2.00, 2.75, 3.25 respectively) than indomethacin (UI = 14) and comparable to celecoxib (UI = 1.75) which were confirmed from the histopatholgical study., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Sphaeranthus africanus has been used in traditional Vietnamese medicine to treat sore throat, and to relieve pain and swelling. However, the anti-inflammatory activity of this plant had not yet been investigated. Previously, we isolated five carvotacetones (1-5) from this plant that displayed cytotoxicity against several cancer cell lines., Purpose: The objective of this study was to isolate further constituents from S. africanus and to investigate the anti-inflammatory activity of all constituents. Furthermore, the anti-proliferative activity of the newly isolated compounds was evaluated., Study Design and Methods: Compounds were isolated from the upper parts of S. africanus by chromatographic methods. Structures were determined using spectroscopic techniques, like NMR and MS. All nine compounds isolated from S. africanus were evaluated for inhibitory activity against COX-1 and COX-2 isoenzymes in-vitro, COX-2 mRNA expression and influence on NO production. The anti-proliferative activities of newly isolated compounds (6-9) were evaluated by XTT viability assay with four cancer cell lines, namely CCRF-CEM, MDA-MB-231, HCT-116, and U-251 cells., Results: Two diastereomeric carvotacetones (3-angeloyloxy-5-[2″S,3″R-dihydroxy-2″-methyl-butanoyloxy]-7-hydroxycarvotacetone (6) and 3-angeloyloxy-5-[2″R,3″R-dihydroxy-2″-methyl-butanoyloxy]-7-hydroxycarvotacetone (7), asperglaucide (8) and chrysoplenol D (9) were isolated from S. africanus. COX-1 and COX-2 assays of compounds 1-9 revealed that compounds 1 and 2 possess potent and selective COX-2 inhibitory activity with IC 50 values of 3.6 and 0.5 μM, respectively. COX-2 gene expression assay showed that some carvotacetones exhibited inhibitory effects on COX-2 gene expression in THP-1 macrophages. Compound 4 is the most active compound inhibiting the synthesis of COX-2 by 55% at 2.06 μM. In the iNOS assay, all seven carvotacetones inhibited NO production in BV2 and RAW cell lines with IC 50 values ranging from 0.2 to 2.9 μM. Compound 4 showed potent inhibitory activity with IC 50 values of 0.2 μM in both BV2 and RAW cell lines. Molecular docking studies revealed the binding orientations of 1 and 2 in the active sites of COX-2. XTT assay of the newly isolated compounds revealed that the two isomeric carvotacetones (6-7) exhibited considerable anti-proliferative activity against four cancer cell lines (CCRF-CEM, MDA-MB-231, HCT-116, U-251) with IC 50 values ranging from 1.23 to 8 μM., Conclusion: For the first-time, the diastereomeric carvotacetones (6-7) were isolated as separate compounds, and their anti-proliferative activity was determined. Selective COX-2 inhibitory, COX-2 mRNA expression and NO production inhibitory activities by some of the major constituents of S. africanus supports the traditional medical application of this plant for the treatment of inflammation-related disorders., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

New pyrazolo[3,4-d]pyrimidinone and pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidinone derivatives were synthesized. They have been evaluated for their anti-inflammatory activity using in vitro (COX-1/COX-2) inhibitory assay. Moreover, compounds with promising in vitro activity and COX-1/COX-2 selectivity indices were subjected for in vivo anti-inflammatory testing using formalin induced paw edema and cotton-pellet induced granuloma assays for acute and chronic models, respectively. Compounds (2c, 3i, 6a, 8 and 12) showed promising COX-2 inhibitory activity and high selectivity compared to celecoxib. Most of the compounds exhibited potential anti-inflammatory activity for both in vivo acute and chronic models. Almost all compounds displayed safe gastrointestinal profile and low ulcerogenic potential guided by histopathological examination. Furthermore, molecular docking experiments rationalized the observed in vitro anti-inflammatory activity of selected candidates. In silico predictions of the pharmacokinetic and drug-likeness properties recommended accepted profiles of the majority of compounds. In conclusion, this work provides an extension of the chemical space of pyrazolopyrimidinone and pyrazolotriazolopyrimidinone chemotypes for the anti-inflammatory activity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A potent Nonsterodial Anti-inflammatory Drug (NSAID) candidates has been conceived and built by an assembly of a hydrophilic, fluorescent and COX-2 inhibiting units in the same molecule. The isatinimino-acridinedione core (TM-7) was achieved in a simple three step synthetic procedure viz (i) a multicomponent reaction between dimedone, aldehyde and amine to furnish the nitroacridinedione (4), (ii) reduction step and (iii) schiff's-base condensation with isatin. The excellent anti-inflammatory pharmacological efficiency of the drug was established by in vivo biological experiments. Accordingly, it was found that the treatment with the synthesized isatinimino analogues (dosage: 30 mg/kg) inhibited protein expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and nuclear factor kappa B (NF-κB) as well as production of prostaglandin E2 (PGE2), nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and interleukin-6 (IL-6) levels induced by carrageenan. Further, a comparative molecular modeling analysis of TM-7 carried out with the crystal structure of aspirin acetylated human COX-2 suggested effectively binding and efficient accommodation inside the active site's gorge., (Copyright © 2019. Published by Elsevier Inc.)

Background: Arachidonic acid (AA) metabolic enzymes including cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1 (mPGES-1) and cytochrome P450 (CYP) 4A11 play important roles in glioma angiogenesis. Thus, there is an urgent need to identify the underlying mechanisms and develop strategies to overcome them., Methods: A homology model of human CYP4A11 was constructed using SYBYL-X 2.0. Structure-based virtual screening against COX-2, mPGES-1 and CYP4A11was performed using the Surflex-Dock of the SYBYL suite. The candidates were further evaluated their antiangiogenic activities in a zebrafish embryo and rabbit corneal angiogenesis model. Laser doppler analysis was used to measure tumor perfusion. The expression of CD31 and α-SMA was measured by immunofluorescence. Western blot was used to measure the expression of HIF-1, Akt and p-Akt. The gene expression of FGF-2, G-CSF, PDGF, TGF-β, Tie-2, VEGF, lncRNA NEAT1 and miR-194-5p were determined using qPCR. The production of FGF-2, TGF-β and VEGF were analyzed using ELISA. Bioinformatic analysis and luciferase reporter assays confirmed the interaction between lncRNA NEAT1 and miR-194-5p., Results: The nearly 36,043 compounds from the Traditional Chinese Medicine (TCM) database were screened against COX-2, mPGES-1 and CYP4A11 3D models, and the 17 top flavonoids were identified. In zebrafish screening, isoliquiritigenin (ISL) exhibited the most potent antiangiogenic activities with the EC 50 values of 5.9 μM. Conversely, the antiangiogenic effects of ISL in the zebrafish and rabbit corneal models were partly reversed by 20-hydroxyeicosatetraenoic acid (20-HETE) or prostaglandin E2 (PGE 2 ). ISL normalized glioma vasculature and improved the efficacy of temozolomide therapy in the rat C6 glioma model. Inhibition of COX-2, mPGES-1 and CYP4A by ISL decreased FGF-2, TGF-β and VEGF production in the C6 and U87 glioma cells with p-Akt downregulation, which was reversed by Akt overexpression. Furthermore, ISL downregulated lncRNA NEAT1 but upregulated miR-194-5p in the U87 glioma cell. Importantly, lncRNA NEAT1 overexpression reversed ISL-mediated increase in miR-194-5p expression, and thereby attenuated FGF-2, TGF-β and VEGF production., Conclusions: Reprogramming COX-2, mPGES-1 and CYP4A mediated-AA metabolism in glioma by flavonoid ISL inhibits the angiogenic Akt- FGF-2/TGF-β/VEGF signaling through ceRNA effect of miR-194-5p and lncRNA NEAT1, and may serve as a novel therapeutic strategy for human glioma.

The objective was to identify and characterize peptides from digested total protein (DTP) and isolated protein fractions (DPF), and their potential antioxidant, anti-inflammatory and anti-atherosclerotic effects, from chia seed (Salvia hispanica L.). Total protein and protein fractions from chia seed underwent simulated gastrointestinal digestion. The sequence, physicochemical properties, and biological potential of peptides were determined using chemical, in silico, and biochemical assays. Peptides from DTP (n = 9) and DPF albumin (n = 12), globulin (n = 11), prolamin (n = 5) and glutelin (n = 17) had interaction with cyclooxygenase-2 (COX-2), p65- nuclear factor kappa B, lipoxygenase-1 (LOX-1) and toll-like receptor 4 (p < 0.05). DTP, and digested albumin, globulin, and glutelin showed scavenging capacity for superoxide, hydrogen peroxide, nitric oxide and DPPH (1,1-diphenyl-2-picrylhydrazyl), and inhibition of 5-LOX, COX-1-2, and inducible nitric oxide synthase (iNOS) enzymes (p < 0.05). Chia seed proteins has peptides with potential beneficial health effects highlighting the importance of chia consumption., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aim: Everyday studies prove the increasing need for newer and safer agents to control cellular inflammatory response, an underlying cause for the pathophysiology of many other clinical cases. Results: Two newly designed sets of schiff 5a-h and chlacone 6a-f substituted pyrazoles were synthesized and evaluated for their in vivo/vitro anti-inflammatory activities. Most potent representatives were chosen for investigation of ulcerogenic and molecular docking properties . Conclusion: The synthesized compounds showed considerable edema inhibition percentage range if compared with celecoxib (13-93% and 58-93%, respectively) at different time intervals. Compound 6e showed the best screening results if compared with celecoxib (inhibition % = 93.62 and 93.51% at 5 h, COX-1/COX-2 selectivity index SI = 215.44 and 308.16 and ulcer index = 7.25 and 8, respectively).

Thiazoles have attracted much synthetic interest due to their wide variety of biological properties and are important members of heterocyclic compounds. In recent years, studies on the synthesis of thiazole compounds have been increasing because of the properties of this core. In particular, the hybrid structures in which the thiazole ring and the other nuclei are linked have gained popularity. Hybrid structures are formed by the combination of different groups of chemical reactivity and biological activity characteristics. In this review, we highlight recent developments related to hybrid structures containing a thiazole core, recently developed as anticancer, antibacterial, anti-inflammatory, analgesic, anti-tubercular, antialzheimer and antidiabetic compounds.

Osteosarcoma (OS) is one of the most common malignancies of bone. This study was aimed to explore the anti-metastatic effect of euxanthone on OS. Adhesion assay and Transwell assay were used to examine the effect of euxanthone on adhesion, migration and invasion of OS cells. COX-2-over-expressing plasmid was applied to transfect OS cells to assess whether COX-2 affects the anti-metastatic function of euxanthone. PDCD4 knockdown and miR-21 mimic were applied to assess whether euxanthone suppresses the transactivation of c-jun via modulating miR-21-PDCD4 signaling. The effect of euxanthone in vivo was also examined by lung metastasis assay. Euxanthone, a xanthone derivative extracted from Polygala caudata, has been found to exhibit anti-neoplastic activities. In present study, our results showed that euxanthone suppressed cell adhesion, migration, and invasion in OS cells. Our experimental data also showed that repression of COX-2 by euxanthone mediated its anti-metastatic activities. Moreover, our findings revealed that euxanthone modulated the COX-2 expression through the miR-21/PDCD4/c-jun signaling pathway. The anti-metastatic activities of euxanthone were also validated in a pulmonary metastasis model. Taken together, our results highlighted the potential of euxanthone to be used in the treatment of OS. Anat Rec, 302:1399-1408, 2019. © 2018 Wiley Periodicals, Inc., (© 2018 Wiley Periodicals, Inc.)

Santonin, a natural product, was aromatized with molecular iodine as the catalyst. The new compound was characterized as ( S)-methyl-2-(7-hydroxy-5,8-dimethylnaphthalen-2-yl) propanoate (2) based on 2D NMR spectroscopic data. Structurally, compound 2 was highly similar to the anti-inflammatory drug naproxen. The new naproxen analogue had significant potency against cyclooxygenase 1 and 2 (IC 50 = 31.0 and 66.1 μM, respectively).

Natural products play an important role in drug discovery. This work employed a natural product 1-methylhydantoin as the lead compound to develop novel dual-active drugs. 1-Methylhydantoin was isolated from Oviductus Ranae , which is a traditional Chinese medicine that has been used for tussive and inflammation treatment for a long time. An in silico study screened the more active 1-methylhydantoin derivatives. Antitussive assessment indicated that the newly synthesized agent had similar bioactivity with the natural product. An anti-inflammatory model used xylene induced ear edema model. At the same dosage (100 mg/Kg), the newly prepared agent had an inhibition rate 53.18% which was much higher than that of the lead compound (22.69%). The results might be ascribed to the cyclooxygenases-1 (COX-1) and cyclooxygenases-2 (COX-2) selectivity, and the fitness of the compound, and the binding pocket. The anti-particulate matter (PM 2.5) acute pneumonia was evaluated through an in vivo model constructed by nasal instillation with PM 2.5 suspension. The results of the above models suggested that this novel agent had remarkable antitussive, anti-inflammatory, and anti-PM 2.5 acute pneumonia activities.

A mutual prodrug (1) of ibuprofen and sulphanilamide has been synthesized with dual activity and improved toxicity profile. The synthesized compound has been characterized by elemental analysis, FT-IR, 1 HNMR, 13 CNMR and ESI-MS. The molecular geometry of the compound (1) was optimized using density functional theory (DFT/B3LYP) method with the 6-311G(d,p) basis sets in ground state. Geometric parameters (bond lengths, bond angles, torsion angles), vibrational assignments, chemical shifts and thermodynamics of the compound (1) has been calculated theoretically and compared with the experimental data. Comparative AutoDock study of compound (1) with cyclooxygenase enzymes (COX-1 and COX-2) were performed involving docking for possible selectivity of our prodrug within the two Cox enzymes. The highest binding affinities of -8.7 Kcal/mol and -8.1 Kcal/mol has been obtained for COX-1 and COX-2 enzymes respectively. Compound (1) exhibited enhanced anti-inflammatory, anti-ulcer and free radical scavenging activities as compared with the parent drugs. Based on various in vitro and in vivo tests it is suggested that the Compound (1) is more active than the parent drugs. Moreover, LD 50 of compound (1) is higher than parent drug i.e. ibuprofen and sulphanilamide suggesting that the synthesized compound is much safer than its parent analogous., (Copyright © 2019. Published by Elsevier Ltd.)

Negative image-based (NIB) screening is a rigid molecular docking methodology that can also be employed in docking rescoring. During the NIB screening, a negative image is generated based on the target protein's ligand-binding cavity by inverting its shape and electrostatics. The resulting NIB model is a drug-like entity or pseudo-ligand that is compared directly against ligand 3D conformers, as is done with a template compound in the ligand-based screening. This cavity-based rigid docking has been demonstrated to work with genuine drug targets in both benchmark testing and drug candidate/lead discovery. Firstly, the study explores in-depth the applicability of different ligand 3D conformer generation software for acquiring the best NIB screening results using cyclooxygenase-2 (COX-2) as the example system. Secondly, the entire NIB workflow from the protein structure preparation, model build-up, and ligand conformer generation to the similarity comparison is performed for COX-2. Accordingly, hands-on instructions are provided on how to employ the NIB methodology from start to finish, both with the rigid docking and docking rescoring using noncommercial software. The practical aspects of the NIB methodology, especially the effect of ligand conformers, are discussed thoroughly, thus, making the methodology accessible for new users.

The rate-limiting enzyme cyclooxygenase-2 (COX-2) is considered as an insightful prognostic target for non-small cell lung cancer (NSCLC) therapy. Now, administration and prolonged utilization of selective COX-2 inhibitors (COXIBs) towards moderating the NSCLC has been associated with different side effects. In the present study, we focused on the structure-based drug repositioning approaches for predicting therapeutic potential de novo candidates for human COX-2. Due to discrepancies in the eminence of x-ray diffraction structures, creates a big barrier in drug discovery approach. Hence, the adaptable COX-2 structure was investigated using multi-template modeling method. Next, a dataset of twenty-six celebrex-associated optimized scaffolds were screened from ZINC database. Comparative docking approaches were then utilized to identify five compounds as best binders to the active site of COX-2 structures and strongly agree with enormous experimental consequences. MD simulations of regarded protein-ligand complexes reveals that lead molecules were stabilized dynamically in inside the cyclooxygenase site by forming potential salt bridges with Tyr 348 , Tyr 385 and Ser 530 residues. These significant results revealed that, identified druggables could prevent the tyrosyl radicals and prostaglandin production that reduces NSCLC progression. Furthermore, pharmacokinetics assets of respected ligands were analyzed, which incorporates similarity ensemble approach, druglikeness and ADMET properties. Finally, the identified novel candidates could serve as COX-2 inhibitors for NSCLC therapy, and coxibs are the best choices for designing new scaffolds to treat cyclooxygenases regard disorders.

Many indomethacin amides and esters are cyclooxygenase-2 (COX-2)-selective inhibitors, providing a framework for the design of COX-2-targeted imaging and cancer chemotherapeutic agents. Although previous studies have suggested that the amide or ester moiety of these inhibitors binds in the lobby region, a spacious alcove within the enzyme's membrane-binding domain, structural details have been lacking. Here, we present observations on the crystal complexes of COX-2 with two indomethacin-dansyl conjugates (compounds 1 and 2) at 2.22-Å resolution. Both compounds are COX-2-selective inhibitors with IC 50 values of 0.76 and 0.17 μm, respectively. Our results confirmed that the dansyl moiety is localized in and establishes hydrophobic interactions and several hydrogen bonds with the lobby of the membrane-binding domain. We noted that in both crystal structures, the linker tethering indomethacin to the dansyl moiety passes through the constriction at the mouth of the COX-2 active site, resulting in displacement and disorder of Arg-120, located at the opening to the active site. Both compounds exhibited higher inhibitory potency against a COX-2 R120A variant than against the WT enzyme. Inhibition kinetics of compound 2 were similar to those of the indomethacin parent compound against WT COX-2, and the R120A substitution reduced the time dependence of COX inhibition. These results provide a structural basis for the further design and optimization of conjugated COX reagents for imaging of malignant or inflammatory tissues containing high COX-2 levels.

Inflammation is a consequence of an array of biological reactions that occur in response to pain sensation, local injury, and cell damage. A large number of studies have demonstrated that quercetin and other flavonoids show anti-inflammatory effects; thus, in the present work, we evaluated a triazine-phenol derivative (TP derivative) compound as a possible drug candidate with anti-inflammatory activity. This compound was studied as a possible anti-inflammatory drug using synthesis and characterization by Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and mass spectrometry (MS). The derivative of melamine was evaluated for its antioxidant activity and exhibited good DPPH and FRAP antioxidant activity. Additionally, we evaluated the putative effect of the molecule on the COX-2 enzyme through molecular dynamic simulation (MDS), and the result suggested that the TP derivative is a potential anti-inflammatory agent that can interact with the COX-2 enzyme because of the high number of protein-ligand interactions observed with MDS. Finally, the study of theoretical physicochemical properties, the observation of low toxicity (hemolysis assay), and the evaluation of oral bioavailability of the TP derivative showed that it is a possible anti-inflammatory drug candidate.

Aims: Spontaneously hypertensive rats (SHR) exhibit impaired endothelial vasodilation and enhanced vasoconstriction. The phosphodiesterase 5 (PDE5) inhibitor sildenafil (Sild) potentiates the nitric oxide (NO)-mediated effects exerting antioxidative and anti-inflammatory actions. In the present study, we hypothesized that Sild could improve endothelial function in SHR., Materials and Methods: Male rats were treated daily for 60 days by oral gavage with Sild (45 mg/kg) before the onset of the hypertensive state (pre-hypertensive protocol). The aortic relaxation to acetylcholine (ACh), sodium nitroprusside (SNP) and the phenylephrine (Phe)-induced contraction was evaluated in SHR. Protein expression of eNOS, p-eNOS, caveolin, COX-1, COX-2, ERK and p-ERK was measured by Western blot., Key Findings: Resting blood pressure was not modified by Sild administration. Treatment with Sild did not alter the relaxation response to SNP but improved the ACh-induced relaxation and reduced Phe-induced contraction in aortic rings from SHR. This protective effect of Sild could be attributed to reduced superoxide anions (O 2 - ) generation, cyclooxygenase type 2 (COX-2) protein downregulation and increased NO bioavailability., Significance: Sild improves endothelial function in SHR aorta without affecting resting blood pressure values. These results indicate that PDE5 inhibition has a potential role in the improvement of vascular function and could be an adjuvant in the treatment of essential hypertension., (Copyright © 2019. Published by Elsevier Inc.)

A series of bi-functional 7-hydroxycoumarin platinum(IV) complexes were synthesized, characterized, and evaluated for antitumor activities. The 7-hydroxycoumarin platinum(IV) complexes display moderate to effective antitumor activities toward the tested cell lines and show much potential in overcoming drug resistance of platinum(II) drugs. In reducing microenvironment, the title compounds could be reduced to platinum(II) complex accompanied with two equivalents of coumarin units. By a unique mechanism, the 7-hydroxycoumarin platinum(IV) complex attacks DNA via the released platinum(II) compound, meanwhile it also inhibits the activities of cyclooxygenase by coumarin fragment. This action mechanism might be of much benefit for reducing tumor-related inflammation in the progress of inhibiting tumor proliferation and overcoming cisplatin resistance. The incorporation of 7-hydroxycoumarin leads to significantly enhanced platinum accumulation in both whole tumor cells and DNA. The HSA interaction investigation reveals that the tested coumarin platinum(IV) compound could effectively combine with HSA via van der Waals force and hydrogen bond., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

We have synthesized a fluorinated analogue of indomethacin bearing a 3,3,3-trifluoroprop-1-enyl group at its 2-position and evaluated its inhibitory activity towards the COX-1 and COX-2 enzymes in vitro. The results revealed that this fluorinated analogue exhibited much greater inhibitory activity and selectivity towards COX-2 than indomethacin. The increased affinity between the fluorinated analogue and COX-2 was attributed to a significant increase in van der Waals contacts (i.e. van der Waals contributions in ΔG were -13.80 kcal/mol for COX-1 and -18.46 kcal/mol for COX-2), explaining an effect of the fluorine substituent in enzyme selectivity. This newly synthesized fluorinated analogue therefore represents a potent and selective COX-2 inhibitor., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Osteoarthritis (OA) is one of the main locomotor disorders in horses. Although nonsteroidal anti-inflammatory drugs are the first-line treatment for OA, opioids could also be used. In previous studies, opioids showed promising anti-inflammatory and analgesic effects. In this study, we aimed to investigate the effects of two opioids (morphine and methadone) against inflammation in lipopolysaccharide (LPS)-stimulated synoviocytes by analyzing microsomal prostaglandin E synthase-1 (mPGES-1) and prostaglandin-endoperoxide synthase 2 (PTGS2) expression. Synoviocytes were obtained from the joints at the distal limbs of dead animals. The cytotoxic effects of LPS, morphine, and methadone were investigated by using a cell viability assay with crystal violet dye. Synoviocytes were treated with LPS, LPS plus morphine, or LPS plus methadone for 3, 6, and 12 h, and mPGES-1 and PTGS2 expression was measured using real-time polymerase chain reaction. LPS, and morphine did not affect the viability of synoviocytes, even at high concentrations. LPS treatment increased mPGES-1 and PTGS2 expression, whereas morphine inhibited the increase in mPGES-1 and PTGS2 expression in LPS-stimulated synoviocytes. Methadone did not inhibit mPGES-1 or PTGS2 expression. These results suggest that morphine may exhibit anti-inflammatory effect; therefore, it might be beneficial for the treatment of OA., (Copyright © 2019 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Inflammation is a complex reaction involving cellular and molecular components and an unspecific response to a specific aggression. The use of scientific and technological innovations as a research tool combining multidisciplinary knowledge in informatics, biotechnology, chemistry and biology are essential for optimizing time and reducing costs in the drug design. Thus, the integration of these in silico techniques makes it possible to search for new anti-inflammatory drugs with better pharmacokinetic and toxicological profiles compared to commercially used drugs. This in silico study evaluated the anti-inflammatory potential of two benzoylpropionic acid derivatives (MBPA and DHBPA) using molecular docking and their thermodynamic profiles by molecular dynamics, in addition to predicting oral bioavailability, bioactivity and toxicity. In accordance to our predictions the derivatives proposed here had the potential capacity for COX-2 inhibition in the human and mice enzyme, due to containing similar interactions with the control compound (ibuprofen). Ibuprofen showed toxic predictions of hepatotoxicity (in human, mouse and rat; toxicophoric group 2-arylacetic or 3-arylpropionic acid) and irritation of the gastrointestinal tract (in human, mouse and rat; toxicophoric group alpha-substituted propionic acid or ester) confirming the literature data, as well as the efficiency of the DEREK 10.0.2 program. Moreover, the proposed compounds are predicted to have a good oral bioavailability profile and low toxicity (LD 50 < 700 mg/kg) and safety when compared to the commercial compound. Therefore, future studies are necessary to confirm the anti-inflammatory potential of these compounds.

Background: Raspberry and strawberry are high value-added food products that can contribute to human health due to the abundance of polyphenols that they contain. Polyphenols are secondary metabolites and therefore devoted to improve plant adaptation, these polyphenol profile can be induced applying different stimuli, such as certain bacteria. The aim of this study was twofold: (i) to evaluate the ability of two bacterial strains to modulate secondary metabolisms in strawberry and raspberry, and (ii) to explore the ability of plant extracts to modify enzyme activities related to metabolic syndrome., Results: Total phenolic and anthocyanin content was higher in strawberries than in raspberries, despite similar antioxidant capacities. Strawberry extracts performed better on the tested enzymes, except on α-glucosidase inhibition capacity. Bacillus amyloliquefaciens stabilized the effects of extracts at different points in time, and Pseudomonas fluorescens modified plant metabolism after more inoculations (spring) in both species, improving the effects of raspberry extracts on α-glucosidase, COX1, and COX2, and of strawberry on α-amylase and COX1., Conclusion: It is good to include these two fruits in the diet because they improve the activity of metabolic syndrome-related enzymes. Applying either strain during plant growth modifies the bioactive profile of the plants, improving the effects of the fruit extracts on human health. © 2018 Society of Chemical Industry., (© 2018 Society of Chemical Industry.)

New thiophene and annulated thiophene pyrazole hybrids were synthesized and screened for their in vitro COX-1/COX-2 enzymatic inhibition and in vivo anti-inflammatory activities. All compounds were more COX-2 selective inhibitors than COX-1 with compound 13 exhibiting the highest COX-2 selectivity index. Compounds 3, 6a, 9 and 11 were the most promising in the acute anti-inflammatory assay while compounds 3, 5, 6a, 6c, 9, 10, 11 and 13 exerted promising anti-inflammatory activity in the sub-acute anti-inflammatory assay. Compounds 3, 6a, 6c, 9, 10 and 11 were evaluated for their ED 50 values and were more potent than diclofenac sodium while compounds 6a, 6c and 9 were of greater potency than celecoxib with compound 6a being the most potent showing ED 50  = 0.033 mmol/kg. These compounds were non-toxic and proved to be gastrointestinal safe compared to indomethacin, diclofenac sodium and celecoxib. Docking studies into COX-2 active site (PDB code 3LN1) revealed that compounds 3, 6a, 6c, 9, 10, 11 and 13 had binding modes and energies comparable to that of celecoxib. Compounds 3, 9, 10 and 11 complied with Lipinski's RO5 while compounds 6a and 6c showed one violation whereas compound 13 deviated by 2 violations. Compounds 6a, 6c and 13 showed 100% plasma protein binding (PPB) and showed no aqueous solubility while compounds 3, 10 and 11 demonstrated the best drug likeness model scores. Therefore, the thiophene analog 3 and the thienopyrimidine derivatives 10 and 11 are promising anti-inflammatory candidates that exert moderate selective COX-2 inhibition with acceptable physicochemical properties., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The antioxidant and anti-inflammatory mechanisms of action of flavonoids in lotus plumule were systematically analyzed using radical scavenging assays and ELISA kits. By this means, flavonoids displayed significant antioxidant activity by donating electron, H atom as well as capturing DPPH and ABTS + free radicals, and anti-inflammatory effect by inhibiting the production of the inflammatory mediators (NO radicals, PGE 2 and TNF-α) and pro-inflammatory cytokines (IL-1β and IL-6). Meanwhile, the bioactive components against inflammation targeting COX-2 were also revealed using ultrafiltration coupled to LC-MS (UF-LC/MS). In this way, 12 components showing specific binding to COX-2 were screened out and identified. The structure-activity relationships suggested that flavonoids O-glycosides displayed comparable binding affinities to COX-2 compared with flavonoids C-glycosides and could be considered as the main active components. This study will provide valuable information for the further exploration of lotus plumule as functional foods or in pharmaceutical industries in the near future., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Triterpenes possess anti-inflammatory and anti-nociceptive effects. In this study anti-inflammatory activities of Asparacosin A were evaluated' using in-vitro cyclooxygenases 1 and 2 (COX-1/2) inhibition assays. Moreover, anti-nociceptive activities were assessed in-vivo by carrageenan-induced paw edema test, xylene-induced ear edema tests, and acetic acid-induced writhing and formalin tests. Additionally molecular docking was conducted to elucidate the binding mechanism of the compound and to correlate the in-vitro findings with the in-silico data. Oral administration of Asparacosin A at the doses of 10, 20, and 40 mg/kg induced significant anti-inflammatory effects ( * p < 0.05, ** p < 0.01, and *** p < 0.001) in a dose-dependent manner in both models. Asparacosin A also inhibited the human recombinant COX-2 enzyme and caused a dose-dependent decrease in the levels of TNF-α, IL-1β, and PGE2 in the carrageenan-induced paws. Moreover, Asparacosin A displayed significant anti-nociceptive effects ( * p < 0.05, ** p < 0.01, *** p < 0.001) at the doses of 10, 20, and 40 mg/kg in acetic-acid induced writhing test. However, in formalin test, Asparacosin A (10-40 mg/kg, p.o) produced anti-nociceptive effects only in the late phase, similar to the effect observed with the reference drug celecoxib (50 mg/kg, p.o). Molecular docking was carried out on both COX-1 and COX-2 structures which revealed that Asparacosin A targets allosteric binding site similar to the binding mode of the selective COX inhibitor. In conclusion, Asparacosin A exhibits anti-inflammatory and peripheral anti-nociceptive activities which are likely mediated via inhibition of COX-2 enzyme and inflammatory cytokines. Furthermore, Asparacosin A can serve as a model to obtain new and more selective potent anti-inflammatory and anti-nociceptive drugs.

A new series of benzimidazothiazole derivatives has been synthesized. The structure of the products was confirmed by spectroscopic techniques such as IR, NMR and mass spectroscopy. The tested compounds were evaluated for their anti-inflammatory activity either in vitro through the COX enzyme inhibition assay, or in vivo through carrageenan paw edema technique. Results revealed that compound 25 and 29 represented the most active ones among the entire series with % inhibition 72.19, 72.07 for COX-1, and 87.46, 87.38 for COX-2, respectively. Interestingly, all synthesized compounds exhibited IC 50 values less than both reference drugs celecoxib and naproxen, indicating their superior potency. For compound 25, it showed about 340 and 198 times more potent than celecoxib and naproxen respectively as COX-1 inhibitor (IC 50 value 0.044 vs. 15.000 and 8.700 µM), and 10 and 115 times more potent than the same drugs as COX-2 inhibitor (IC 50 value 4.52 vs. 40.00 and 520.00 nM). The antitumor activity of the products was also evaluated and the results obtained are consistent with those obtained by the anti-inflammatory screening where compounds 25 and 29 proved to be the most active ones among the other compounds with %GI ranging from 31.5 to 62.5% and they exhibited the lowest IC 50 values as well. The ADMET analysis of the tested compounds was also performed in addition to the molecular modeling studies that included flexible alignment, surface and electrostatic maps in addition to the Lipinisk's rule of five., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Trimellitimides 6-21 were prepared and investigated in vivo for anti-inflammatory and ulcerogenic effects and in vitro for cytotoxicity. They were subjected to in vitro cyclooxygenase (COX-1/2) and carbonic anhydrase inhibition protocols. Compounds 6-11 and 18 exhibited anti-inflammatory activities and had median effective doses (ED 50 ) of 34.3-49.8 mg kg -1 and 63.6-86.6% edema inhibition relative to the reference drug celecoxib (ED 50 : 33.9 mg kg -1 and 85.2% edema inhibition). Compounds 6-11 and 18 were weakly cytotoxic at 10 μM against 59 cell lines compared with the reference standard 5-fluorouracil (5-FU). Compounds 6-11 had optimal selectivity against COX-2. The selectivity index (SI) range was >200-490 and was comparable to that for celecoxib [COX-2 (SI) > 416.7]. In contrast, compounds 12, 13, and 16-18 were nonselective COX inhibitors with a selectivity index range of 0.92-0.25. The carbonic anhydrase inhibition assay showed that sulfonamide incorporating trimellitimides 6-11 inhibited the cytosolic isoforms hCA I and hCA II, and tumor-associated isoform hCA IX. They were relatively more susceptible to inhibition by compounds 8, 9, and 11. The K I ranges were 54.1-81.9 nM for hCA I, 25.9-55.1 nM for hCA II, and 46.0-348.3 nM for hCA IX. © 2018 Elsevier Science. All rights reserved., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The aim of this work was to compare the anti-inflammatory activity of compounds prepared from terpenes and the synthetic drugs ibuprofen and naproxen. The anti-inflammatory activity of the hybrid compounds was compared with the activity of the parent compounds. This was accomplished using in vitro inhibition of lipoxygenases (LOX) and COX-2, and in silico docking studies in 15-LOX and COX-2. The synthesized hybrids showed an inhibition of COX-2 and LOX between 9.8%-57.4% and 0.0%-97.7%, respectively. None of the hybrids showed an improvement in the inhibitory effect toward these pro-inflammatory enzymes, compared to the parent terpenes and non-steroidal anti-inflammatory drugs. The docking studies allowed us to predict the potential binding modes of hybrids 6-15 within COX-2 and 15-LOX active sites. The relative affinity of the compounds inside the binding sites could be explained by forming non-covalent interactions with most important and known amino acids reported for those enzymes. A good correlation (r 2  = 0.745) between docking energies and inhibition percentages against COX-2 was found. The high inhibition obtained for compound 10 against COX-2 was explained by hydrogen bond interactions at the enzyme binding site. New synthetic possibilities could be obtained from our in silico models, improving the potency of these hybrid compounds., (© 2018 John Wiley & Sons A/S.)

Nowadays, diabetes and its associated inflammatory complications are important public health problems worldwide. Market limitations of drugs with dual actions as anti-inflammatory (AI) and anti-diabetic have been led to a temptation for focusing on the discovery and development of new compounds with potential AI and anti-diabetic activities. Herein, we synthesized two new series containing pyrazole ring with vicinal diaryl rings as selective COX-2 moiety and thiazolidindione (series 12a-f) or thiazolidinone (series 13a-f) as anti-diabetic moiety and the two moieties were linked together with methylene or methylenehydrazone functionality. The two series were evaluated for their COX inhibition, AI activity and ulcerogenic liability and for the anti-diabetic activity; 12a-f and 13a-f were assessed in vitro against α-glucosidase, β- glucosidase, in vivo hypoglycemic activity (one day and 15 days studies) in addition to PPARγ activation study. Four compounds (12c, 12f, 13b and 13f) had higher COX-2 S.I. (8.69-9.26) than the COX-2 selective drug celecoxib (COX-2 S.I. = 8.60) and showed the highest AI activities and the lowest ulcerogenicity than other derivatives. Also, two thiazolidindione derivatives 12e and 12f and two thiazolidinone derivatives 13b and 13c showed higher inhibitory activities against α- and β-glucosidase (% inhibitory activity = 62.15, 55.30, 65.37, 59.08 for α-glucosidase and 57.42, 60.07, 58.19, 66.90 for β-glucosidase respectively) than reference compounds (acarbose with % inhibitory activity = 49.50 for α-glucosidase and d-saccharic acid 1,4-lactone monohydrate with % inhibitory activity = 53.42 for β-glucosidase) and also showed good PPAR-γ activation and good hypoglycemic effect in comparison to pioglitazone and rosiglitazone. Moreover, Shape comparison and docking studies were carried out to understand their interaction and similarity with standard drugs., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: In past few decades, computational chemistry has seen significant advancements in design and development of novel therapeutics. Benzimidazole derivatives showed promising anti-inflammatory activity through the inhibition of COX-2 enzyme., Objective: The structural features necessary for COX-2 inhibitory activity for a series of oxadiazole substituted benzimidazoles were explored through 3D-QSAR, combinatorial library generation (Combi Lab) and molecular docking., Methods: 3D-QSAR (using kNN-MFA (SW-FB) and PLSR (GA) methods) and Combi Lab studies were performed by using VLife MDS Molecular Design Suite. The molecular docking study was performed by using AutoDockVina., Results: Significant QSAR models generated by PLSR exhibited r2 = 0.79, q2 = 0.68 and pred&#95;r2 = 0. 84 values whereas kNN showed q2 = 0.71 and pred&#95;r2 = 0.84. External validation of developed models by various parameters assures their reliability and predictive efficacy. A library of 72 compounds was generated by combinatorial technique in which 11 compounds (A1-A5 and B1-B6) showed better predicted biological activity than the most active compound 27 (pIC50 = 7.22) from the dataset. These compounds showed proximal interaction with amino acid residues like TYR355 and/or ARG120 on COX-2(PDB ID: 4RS0)., Conclusion: The present work resulted in the design of more potent benzimidazoles as COX-2 inhibitors with good interaction as compared to reference ligand. The results of the study may be helpful in the development of novel COX-2 inhibitors for inflammatory disorders., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Copper complexes are hopeful anticancer drugs due to their multifacet biological properties and high biocompatibility. Inflammatory environment plays an important role in tumor progression and affects the body response to chemotherapeutic agents. A copper(II) complex CuLA with a phenanthroline derivative N-(1,10-phenanthrolin-5-yl)-nonanamide (L) and two aspirin anions (A) as the ligands was synthesized. CuLA effectively induces mitochondrial dysfunction and promotes early-apoptosis in SKOV-3 cells; moreover, it suppresses the expression of cyclooxygenase-2, a key enzyme involved in inflammatory response, in lipopolysaccharide stimulated RAW 264.7 cells. By contrast, the analogue complex CuL without aspirin ligand shows similar influences on cellular redox homeostasis and cell cycle progression but relatively low cytotoxic activity due to its mild effect on mitochondrial function; more importantly, it lacks inhibition to cyclooxygenase-2. The results demonstrate that CuLA inhibits cancer cells through dual pathways involving DNA damage and mitochondrial dysfunction. The introduction of aspirin not only enhances the antitumour efficacy but also reduces the inflammatory threat. Copper complexes with both antitumor and anti-inflammatory activities may represent a new type of multifunctional metal complexes in hope to be developed into novel metallodrugs., (Copyright © 2018. Published by Elsevier Inc.)

Background: Formally belonging to the non-steroidal anti-inflammatory drug class pyrazolones have long been used in medical practices., Objective: Our goal is to synthesize N-methylated 1-aryl-3-polyfluoroalkylpyrazolones as fluorinated analogs of antipyrine, their isomeric O-methylated derivatives resembling celecoxib structure and evaluate biological activities of obtained compounds., Methods: In vitro (permeability) and in vivo (anti-inflammatory and analgesic activities, acute toxicity, hyperalgesia, antipyretic activity, "open field" test) experiments. To suggest the mechanism of biological activity, molecular docking of the synthesized compounds was carried out into the tyrosine site of COX-1/2., Results: We developed the convenient methods for regioselective methylation of 1-aryl-3- polyfluoroalkylpyrazol-5-ols leading to the synthesis N-methylpyrazolones and O-methylpyrazoles as antipyrine and celecoxib analogs respectively. For the first time, the biological properties of new derivatives were investigated in vitro and in vivo., Conclusion: The trifluoromethyl antipyrine represents a valuable starting point in design of the lead series for discovery new antipyretic analgesics with anti-inflammatory properties., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Previous studies have demonstrated that the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib shows efficacy against multiple cancers, including hepatocellular carcinoma. However, whether celecoxib is effective in alleviating steatosis during hepatocarcinogenesis is unknown. In a rapid hepatocellular carcinoma (HCC) mouse model established via hydrodynamic transfection of activated forms of AKT and c-Met proto-oncogenes, we investigated the antisteatotic and anticarcinogenic efficacy of celecoxib in vivo. Multiple HCC cell lines were employed for in vitro evaluation. Additionally, immunoblotting, immunohistochemistry, hematoxylin and eosin staining and Oil Red O staining were applied for mechanistic investigation. The results revealed that if celecoxib was administered in the early stage of AKT/c-Met-induced HCC, it resulted in disease stabilization. Moreover, celecoxib could alleviate lipid accumulation in the HCC mice and in an oleic acid-induced in vitro hepatic steatosis model. Further evidence at the molecular level indicated that celecoxib down-regulated the expression of phospho-ERK (Thr202/Tyr204) and proliferating cell nuclear antigen (PCNA) in the HCC mice. In addition, celecoxib efficiently repressed the phosphor-Akt (Thr308)/fatty acid synthase (FASN) axis both in vivo and in vitro. Altogether, this study suggests that celecoxib exerts its antilipogenic efficacy by targeting a COX-2/AKT/FASN cascade, which contributes to its ability to delay hepatocarcinogenesis., (© 2018 Wiley Periodicals, Inc.)

The benefits associated with resveratrol (Resv; 3,4',5-trihydroxy-trans-stilbene) are known for a long time. The therapeutic properties of Resv are observed in diseases like cancer, neurological disorders, atherosclerosis, aging, inflammation, etc. Multiple studies suggest that the beneficial properties of Resv are due to its binding to targets in multiple pathways. The same has been reflected in inflammation, where Resv has been shown to inhibit nuclear factor κ light-chain enhancer of activated B cells in the toll-like receptor 4 (TLR4) pathway. There are multiple cellular targets which bind to Resv, however the mode and the key interactions involved remain elusive for many of them. In the current work, we have investigated the structural insights of Resv with three of its binding partners involved in the inflammatory TLR4 signaling pathway. Through a structure-based modelling and molecular dynamics study, we have unraveled the molecular and atomic interactions involved in the Resv-binary complexes of inhibitor of κB kinase, cyclooxygeanse-2, and tank-binding kinase I, all three of which are key players in TLR4 inflammatory signaling. This study is the latest addition to the investigations of the structural partners of Resv and its molecular interactions., (© 2018 Wiley Periodicals, Inc.)

Sulfonamide derivatives have been used in pharmaceutics for decades. Here we report a new approach to release sulfonamides efficiently using a bioorthogonal reaction of sulfonyl sydnonimines and dibenzoazacyclooctyne (DIBAC). The second-order rate constant of the cycloaddition reaction can be up to 0.62 M-1 s-1, and the reactants are highly stable under physiological conditions. Most significantly, we also discovered the mutual orthogonality between the sydnonimine-DIBAC and benzonorbornadiene-tetrazine cycloaddition pairs, which can be used for selective and simultaneous liberation of sulfonamide and primary amine drugs.

Doxorubicin (DXR) is one of the most important chemotherapeutic agent. However, nephrotoxicity reduces its clinical utility in humans. The aim of the study was to investigate protective effects of curcumin (CMN) against DXR-induced nephrotoxicity. Rats were subjected to oral treatment of CMN (100 and 200 mg/kg body weight) for 7 days. Nephrotoxicity was induced by single intra peritoneal injection of DXR (40 mg/kg body weight) on the fifth day and then the experiment was terminated on the eighth day. Nephroprotective effects of CMN were associated with decrease in serum toxicity markers and increase in antioxidant enzyme activities. CMN was able to reduced the levels of inflammatory markers such as TNF-α, NF-κB, IL-1β, iNOS and COX-2 in the rats. It also reduced the expressions of apoptotic marker including caspase-3, and oxidative DNA damage marker including 8-OHdG. Collectively, these findings indicated that CMN protect against DXR-induced nephrotoxicity.

Treatment with intrauterine devices (IUD) prolongs luteal phases in mares, but the mechanism for this has not been fully elucidated. The aims of the present study were to examine how IUDs affect the uterus to induce longer luteal phases, particularly the role of cyclooxygenase-2 (COX-2) in the maintenance of the corpus luteum (CL). Twenty-seven reproductively normal mares were included: 12 were inseminated (AI), and 15 were fitted with IUDs. Blood samples for progesterone were obtained on Days 0, 3, 5, 7, 9, 11, 13, 14, and 15 (relative to day of ovulation). The groups were further divided into non-pregnant (AI-N, n = 4), pregnant (AI-P, n = 8), normal (IUD-N, n = 8) and prolonged luteal phase (IUD-P, n = 7) based on ultrasonic examinations and serum progesterone concentrations on Days 14 and 15. Blood sampling to quantify the PGF 2α metabolite (PGFM) was performed through a catheter hourly from 15:00 to 20:00 h on Day 14, and from 6:00 until 13:00 h on Day 15. On Day 15, a low-volume uterine lavage followed by an endometrial biopsy was performed. Estradiol concentration in the Day 15 serum and lavage fluid was determined, while the abundance of COX-2 was evaluated in the biopsy specimens using western blotting (WB) and immunohistochemistry (IHC). All pregnant mares were negative for COX-2 in IHC samples and 5 of 8 were negative in WB samples while all mares of the IUD-N group were positive for COX-2. Of the seven mares in the IUD-P group, five and four were negative for COX-2 with the IHC and WB samples, respectively. The results from this study indicate that IUDs, when effective, suppress COX-2, leading to the inhibition of PGF2α release and maintenance of CL., (Copyright © 2018 Elsevier B.V. All rights reserved.)