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In the present work, we describe the synthesis of new 1,3,4-thiadiazole derivatives from natural (R)-carvone in three steps including, dichloro-cyclopropanation, a condensation with thiosemicarbazide and then a 1,3-dipolar cycloaddition reaction with various nitrilimines. the targeted compounds were structurally identified by 1 H & 13 C NMR and HRMS analyses. The cytotoxic assay demonstrated that some synthesized novel compounds were potent on certain cancer cell lines. Molecular modeling studies were undertaken to rationalize the wet lab study results. Furthermore, molecular docking was performed to unveil the binding potential of the most active derivatives, 3a and 6c, to caspase-3 and COX-2. The stabilities of the protein-compound complexes obtained from the docking were evaluated using MD simulation. Furthermore, FMO and related parameters of the active compounds and their stereoisomers were examined through DFT studies. The docking study showed compound 6c had a higher binding potential than caspase-3. However, the binding strength of 6c was found to be less than that of the standard drug, doxorubicin, as it formed lower conventional hydrogen bonds. On the other hand, compound 3a had a higher binding potential to COX-2. However, the binding potential 3a was much lower than that of the standard COX-2 inhibitor, celecoxib. The MD simulation demonstrated that the caspase-3-6c complex was less stable than the caspase-3-doxorubicin complex. In contrast, the COX-2-3a complex was stable, and 3a was anticipated to remain inside the protein's binding pocket. The DFT study showed that 3a had higher chemical stability than 6c. The electron exchange capacity, chemical stability, and molecular orbital distributions of the stereoisomers of the active compounds were also found to be alike., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Acetaminophen, a centrally-acting old analgesic drug, is a weak inhibitor of cyclooxygenase (COX) isoforms with some selectivity toward COX-2. This compound was used in this work as a precursor to create nine acetaminophen based coumarins (ACFs). To satisfy the aim of this work, which states the synthesis of acetaminophen-based coumarins as selective COX-2 inhibitors, the ACFs were subjected to two types of investigation: in vitro and in silico. Given the former type, the ACFs capacity to block COX-1 and COX-2 was investigated in lab settings. On the other hand, the in silico investigation included docking the chemical structures of ACFs into the active sites of these enzymes, predicting their anticipated toxicities, and determining the ADME characteristics. The results of the in vitro study revealed that the synthesized ACFs demonstrated good-to-excellent inhibitory properties against the enzymes under study. Also, these ACFs exhibited a high level of COX-2 selectivity, which improved as the capacity of the aromatic substitute for withdrawing electrons was enhanced. Results of docking were comparable to the in vitro investigation in case of COX-2. On the other hand, the in silico investigations indicated that the synthesized ACFs are safer than their precursor, acetaminophen, with a high potential to consider oral-administrated candidates., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Cyclooxygenase-2 (COX-2) inhibitors are nonsteroidal anti-inflammatory drugs that treat inflammation, pain and fever. This study determined the interaction mechanisms of COX-2 inhibitors and the molecular properties needed to design new drug candidates. Using machine learning and explainable AI methods, the inhibition activity of 1488 molecules was modelled, and essential properties were identified. These properties included aromatic rings, nitrogen-containing functional groups and aliphatic hydrocarbons. They affected the water solubility, hydrophobicity and binding affinity of COX-2 inhibitors. The binding mode, stability and ADME properties of 16 ligands bound to the Cyclooxygenase active site of COX-2 were investigated by molecular docking, molecular dynamics simulation and MM-GBSA analysis. The results showed that ligand 339,222 was the most stable and effective COX-2 inhibitor. It inhibited prostaglandin synthesis by disrupting the protein conformation of COX-2. It had good ADME properties and high clinical potential. This study demonstrated the potential of machine learning and bioinformatics methods in discovering COX-2 inhibitors., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Plant species from the genus Andrographis were used in Ayurveda and in other folklore medicines for treating ailments for centuries. In this study, we have hypothesized to evaluate the secondary metabolites as potent anti-inflammatory agents from the genus Andrographis. A library of secondary metabolites of the said genus was curated from the PubChem database and was subjected to energy minimization using UCSF Chimera software employing the AMBER force field. Initially, molecular docking was performed to evaluate the binding affinity of the curated library against the enzymes cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), and 5-Lipoxygenase (5-LOX) using AutoDock Vina. This resulted in shortlisting of two metabolites Echioidinin 5-O-glucoside was bound and 5,2',6'-Trihydroxy-6,7,8-trimethoxy flavone 2'-O-glucoside with high binding affinity than standard drugs Ibuprofen and Zileuton. In addition, molecular dynamic simulation studies confirm that these compounds form relatively more stable complexes than standard drugs with the above-said enzymes. The free binding energy values using MMGBSA of the above said ligands with COX-1, COX-2, and 5-LOX were found to be -49.18 kcal/mol, -38.60 kcal/mol, and -54.27 kcal/mol respectively, Whereas the standards have -21.77 kcal/mol, -9.96 kcal/mol, and -10.29 kcal/mol. Moreover, the in-silico ADMET analysis confirms the druggability of the shortlisted compounds. Later, this work will act as a base for in-vitro and in-vivo experimental studies to validate the anti-inflammatory potential of the same.Communicated by Ramaswamy H. Sarma.

In a landmark study, oleocanthal (OLC), a major phenolic in extra virgin olive oil (EVOO), was found to possess anti-inflammatory activity similar to ibuprofen, involving inhibition of cyclooxygenase (COX) enzymes. EVOO is a rich source of bioactive compounds including fatty acids and phenolics; however, the biological activities of only a small subset of compounds associated with Olea europaea have been explored. Here, the OliveNet TM library (consisting of over 600 compounds) was utilized to investigate olive-derived compounds as potential modulators of the arachidonic acid pathway. Our first aim was to perform enzymatic assays to evaluate the inhibitory activity of a selection of phenolic compounds and fatty acids against COX isoforms (COX-1 and COX-2) and 15-lipoxygenase (15-LOX). Olive compounds were found to inhibit COX isoforms, with minimal activity against 15-LOX. Subsequent molecular docking indicated that the olive compounds possess strong binding affinities for the active site of COX isoforms, and molecular dynamics (MD) simulations confirmed the stability of binding. Moreover, olive compounds were predicted to have favorable pharmacokinetic properties, including a readiness to cross biological membranes as highlighted by steered MD simulations and umbrella sampling. Importantly, olive compounds including OLC were identified as non-inhibitors of the human ether-à-go-go-related gene (hERG) channel based on patch clamp assays. Overall, this study extends our understanding of the bioactivity of Olea-europaea -derived compounds, many of which are now known to be, at least in part, accountable for the beneficial health effects of the Mediterranean diet.

Cancer is a major public health problem worldwide, and it is the second leading cause of death of humans in the world. The present study has been directed toward the preparation of methotrexate-loaded surface-modified solid lipid nanoparticles (SLNs) for potential use as a chemotherapeutic formulation for cancer therapy. A lipid (C 14 -AAP) derived from myristic acid (C 14 H 30 O 2 ) and acetaminophen (AAP) was employed as a targeting ligand for human breast and lung cancer cells that overexpress the cyclooxygenases-2 (COX-2) enzyme. The SLNs consisting of stearic acid and C 14 -AAP were characterized by several methods, including dynamic light scattering (DLS), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), ultraviolet-visible (UV-vis) spectroscopy, high-resolution transmission electron microscopy (HRTEM), and field emission scanning electron microscopy (FESEM) techniques. An in vitro cell cytotoxicity study was done by carrying out an MTT assay and flow cytometry study in the human breast cancer (MCF7) and human lung cancer cell line (A549). The expression level of COX-2 enzyme in MCF7 and A549 cell lines was examined by reverse transcription polymerase chain reaction (RT-PCR). A high level of COX-2 expression was observed in both cell lines. In vitro cell cytotoxicity study in MC7 and A549 cell lines showed the surface-modified, methotrexate-loaded SLN is more effective in cell killing and induction of apoptotic death in both the cell lines than free methotrexate in MTT, flow cytometry, clonogenic assay, and Western blot studies. The surface-modified SLN was radiolabeled with 99m Tc with %RCP greater than 95%. In vivo biodistribution study of the 99m Tc-labeled SLN in melanoma tumor-bearing C57BL6 mice showed moderate tumor uptake of the radiotracer at 3 h post injection. The SPECT/CT image aligns with the biodistribution results. This study shows that AAP-modified SLNs could be a potential chemotherapeutic formulation for cancer therapy.

Psychoactive substances, including morphine and methamphetamine, have been shown to interact with the classic innate immune receptor Toll-like receptor 4 (TLR4) and its partner protein myeloid differentiation protein 2 (MD2) in a nonenantioselective manner. (-)-Nicotine, the primary alkaloid in tobacco and a key component of highly addictive cigarettes, targets the TLR4/MD2, influencing TLR4 signaling pathways. Existing as two enantiomers, the stereoselective recognition of nicotine by TLR4/MD2 in the context of the innate immune response remains unclear. In this study, we synthesized (+)-nicotine and investigated its effects alongside (-)-nicotine on lipopolysaccharide (LPS)-induced TLR4 signaling. (-)-Nicotine dose-dependently inhibited proinflammatory factors such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and cyclooxygenase-2 (COX-2). In contrast, (+)-nicotine showed no such inhibitory effects. Molecular dynamics simulations revealed that (-)-nicotine exhibited a stronger affinity with the TLR4 coreceptor MD2 than (+)-nicotine. Additionally, in silico simulations revealed that both nicotine enantiomers initially attach to the entrance of the MD2 cavity, creating a metastable state before they fully enter the cavity. In the metastable state, (-)-nicotine established more stable interactions with the surrounding residues at the entrance of the MD2 cavity compared to those of (+)-nicotine. This highlights the crucial role of the MD2 cavity entrance in the chiral recognition of nicotine. These findings provide valuable insights into the distinct interactions between nicotine enantiomers and the TLR4 coreceptor MD2, underscoring the enantioselective effect of nicotine on modulating TLR4 signaling.

Cyclooxygenases 1 and 2 (COX-1/2) are enzymes renowned for inducing inflammatory responses through the production of prostaglandins. Thus, the development of COX inhibitors has been a promising approach for identifying compounds with anti-inflammatory potential. In this study, we designed 27 new compounds (1-27) based on the structure of a previously known COX inhibitor, using the Ligand Designer tool. Our aim was to improve the affinity of the compounds with COX enzymes by inducing interactions with residue Arg120 while retaining the good π-π stacking interactions of the chromene-phenyl scaffold. Through screening based on ligand-binding free energy defined by molecular docking simulations and MM/GBSA technique, compounds 9 and 10 were identified as having the highest ability to inhibit COX proteins. The binding affinities of the two compounds with COX-1/2 were superior to those of the original NAI10 compound and the reference drug indomethacin. Our virtual screening suggests that compounds 9 and 10 have a strong ability to inhibit COX-1/2 and thus could be promising candidates for further anti-inflammatory drug studies. In essence, our study underscores the pivotal role of the N-aryl iminocoumarin scaffold in shaping the future landscape of novel anti-inflammatory drug development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In the current study, we utilized molecular modeling and simulation approaches to define putative potential molecular targets for Burdock Inulin, including inflammatory proteins such as iNOS, COX-2, TNF-alpha, IL-6, and IL-1β. Molecular docking results revealed potential interactions and good binding affinity for these targets; however, IL-1β, COX-2, and iNOS were identified as the best targets for Inulin. Molecular simulation-based stability assessment demonstrated that inulin could primarily target iNOS and may also supplementarily target COX-2 and IL-1β during DSS-induced colitis to reduce the role of these inflammatory mechanisms. Furthermore, residual flexibility, hydrogen bonding, and structural packing were reported with uniform trajectories, showing no significant perturbation throughout the simulation. The protein motions within the simulation trajectories were clustered using principal component analysis (PCA). The IL-1β-Inulin complex, approximately 70% of the total motion was attributed to the first three eigenvectors, while the remaining motion was contributed by the remaining eigenvectors. In contrast, for the COX2-Inulin complex, 75% of the total motion was attributed to the eigenvectors. Furthermore, in the iNOS-Inulin complex, the first three eigenvectors contributed to 60% of the total motion. Furthermore, the iNOS-Inulin complex contributed 60% to the total motion through the first three eigenvectors. To explore thermodynamically favorable changes upon mutation, motion mode analysis was carried out. The Free Energy Landscape (FEL) results demonstrated that the IL-1β-Inulin achieved a single conformation with the lowest energy, while COX2-Inulin and iNOS-Inulin exhibited two lowest-energy conformations each. IL-1β-Inulin and COX2-Inulin displayed total binding free energies of - 27.76 kcal/mol and - 37.78 kcal/mol, respectively, while iNOS-Inulin demonstrated the best binding free energy results at - 45.89 kcal/mol. This indicates a stronger pharmacological potential of iNOS than the other two complexes. Thus, further experiments are needed to use inulin to target iNOS and reduce DSS-induced colitis and other autoimmune diseases., (© 2024. The Author(s).)

Despite the high global prevalence, rheumatoid arthritis lacks a satisfactory treatment. Hence, the present study is undertaken to design and synthesize novel anti-inflammatory compounds. For this, quinoline and anthranilic acid, two medicinally-privileged moieties, were linked by pharmacophore hybridization, and following their computational assessments, three hybrids 5a-c were synthesized in good over all yields. The in vitro and in vivo anti-inflammatory potential of these hybrids was determined by anti-denaturation and anti-proteinase, and carrageenan-induced paw edema models. The computational studies of these hybrids revealed their drug-likeness, optimum pharmacokinetics, and less toxicity. Moreover, they demonstrated high binding affinity (-9.4 to -10.6 kcal mol -1 ) and suitable binding interactions for TNF-α, FLAP, and COX-II. A three-step synthetic route resulted in the hybrids 5a-c with 83-86% yield of final step. At 50 μg mL -1 , the antiprotease and anti-denaturation activity of compound 5b was significantly higher than 5a and 5c. Furthermore, 5b significantly reduced the edema in the right paw of the rats that received carrageenan. The results of this study indicate the medicinal worth of the novel hybrids in treating inflammatory disorders such as rheumatoid arthritis.

Inflammation plays a pivotal role in various pathological processes, ranging from routine injuries and infections to cancer. Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) are two major enzymes involved in the formation of lipid mediators of inflammation, such as prostaglandins and leukotrienes, through the arachidonic acid pathway. Despite the frequent use of nonsteroidal anti-inflammatory drugs for managing inflammatory disorders by inhibiting these enzymes, there is a wide spectrum of adverse effects linked to their usage. Jeevaneeya Rasayana (JR), a polyherbal formulation traditionally used in India, is renowned for its anti-inflammatory properties. The present study aimed to identify the potential phytocompounds in JR plants against COX-2 and 5-LOX, utilizing molecular docking and dynamic simulations. Among the 429 identified phytocompounds retrieved from publicly available data sources, Terrestribisamide and 1-(9Z-octadecenoyl)-sn-glycero-3-phosphoethanolamine have shown potential binding affinity and favorable interactions with COX-2 and 5-LOX arachidonic acid binding sites. The physicochemical properties and ADMET profiles of these compounds determined their drug-likeness and pharmacokinetics features. Additional validation using molecular dynamics simulations, SASA, Rg, and MM-PBSA binding energy calculations affirmed the stability of the complex formed between those compounds with target proteins. Together, the study identified the effectual binding potential of those bioactive compounds against COX-2 and 5-LOX, providing a viable approach for the development of effective anti-inflammatory medications., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Inhibitors of COX-2 constitute a class of anti-inflammatory analgesics, showing potential against certain types of cancer. However, such inhibitors are associated with cardiovascular toxicity. Moreover, although single-target molecules possess specificity for particular targets, they often lead to poor safety, low efficacy and drug resistance due to compensatory mechanisms. A new generation of dual-target drugs that simultaneously inhibit COX-2 and another target is showing strong potential to treat cancer or reduce adverse cardiac effects. The present perspective focuses on the structure and functions of COX-2, and its role as a therapeutic target. It also explores the current state and future possibilities for dual-target strategies from a medicinal chemistry perspective.

Cyclooxygenase 2 (COX-2), the key enzyme involved in prostaglandin (PGs) production, is known to take part in inflammatory and immune responses. Though COX-2 inhibitors are therapeutically effective anti-inflammatory drugs, they deficit anti-thrombotic activity thus leading to increased cardiovascular diseases. Therefore, COX-2 inhibitors with improved therapeutic efficacy and tolerance are still needed. In recent years, traditional medicine systems have paid attention to the essential oil of genus Zingiber , particularly for the treatment of various inflammatory illnesses, with lesser side effects. Thus, the present study aims to explore the anti-inflammatory activity of Zingiber essential oil through computational-biology approaches. In this regard, virtual screening, molecular docking, and simulations were carried out on 53 compounds derived from the essential oil of Zingiber species in order to provide mechanistic insights into COX-2 inhibition and identify the most actively potent anti-inflammatory compounds. Among all the docked ligands, epi-cubenol, δ-cadinene, γ-eudesmol, cubenol, and α-terpineol were found to be powerful bioactive compounds with an increased binding affinity towards COX-2 along with favorable physiochemical properties. Additionally, MD simulation in DPPC lipid bilayers was studied to examine the intrinsic dynamics and adaptability of the chosen ligands and COX-2-complexes. The findings showed that the selected five components interacted steadily with the COX-2 active site residues throughout the simulation via different bondings. The integrative-computational approach showed that the identified natural compounds may be taken into further consideration for potential in vitro and in vivo evaluation as COX-2 inhibitors, which would lead to the development of more potent and efficient anti-inflammatory drugs.Communicated by Ramaswamy H. Sarma.

Computer-based drug design is increasingly used in strategies for discovering new molecules for therapeutic purposes. The targeted drug is ketoprofen (KTP), which belongs to the family of non-steroidal anti-inflammatory drugs, which are widely used for the treatment of pain, fever, inflammation and certain types of cancers. In an attempt to rationalize the search for 72 new potential anti-inflammatory compounds on the COX-2 enzyme, we carried out an in silico protocol that successfully combines molecular docking towards COX-2 receptor (5F1A), ADMET pharmacokinetic parameters, drug-likeness rules and molecular electrostatic potential (MEP). It was found that six of the compounds analyzed satisfy with the associated values to physico-chemical properties as key evaluation parameters for the drug-likeness and demonstrate a hydrophobic character which makes their solubility in aqueous media difficult and easy in lipids. All the compounds presented good ADMET profile and they showed an interaction with the amino acids responsible for anti-inflammatory activity of the COX-2 isoenzyme. The calculation of the MEP of the six analogues reveals new preferential sites involving the formation of new bonds. Consequently, this result allowed us to understand the origin of the potential increase in the anti-inflammatory activity of the candidates. Finally, it was obtained that six compounds have a binding mode, binding energy, and stability in the active site of COX-2 like the reference drug ketoprofen, suggesting that these compounds could become a powerful candidate in the inhibition of the COX-2 enzyme.Communicated by Ramaswamy H. Sarma.

Cyclooxygenase, also known as prostaglandin H2 synthase (PGH2), is one of the most important enzymes in pharmacology because inhibition of COX is the mechanism of action of most nonsteroidal anti-inflammatory drugs. In this study, ten thiazole derivative compounds had synthesized. The analysis of the obtained compounds was performed by 1 H NMR and 13 C NMR methods. By this method, the obtained compounds could be elucidated. The inhibitory effect of the obtained compounds on cyclooxygenase (COX) enzymes was investigated. The encoded compounds 5a, 5b, and 5c were found to be the most potent compared to the reference compounds ibuprofen (IC 50  = 5.589 ± 0.278 μM), celecoxib (IC 50  = 0.132 ± 0.004 μM), and nimesulide (IC 50  = 1.692 ± 0.077 μM)against COX-2 isoenzyme. The inhibitory activity of 5a, 5b, and 5c is approximate, but the 5a derivative proved to be the most active in the series with an IC 50 value of 0.180 ± 0.002 μM. The most potent COXs inhibitor was 5a, which was further investigated for its potential binding mode by a molecular docking study. Compound 5a was found to be localized at the active site of the enzyme, like celecoxib, which has a remarkable effect on COXs enzymes., (© 2023 John Wiley & Sons Ltd.)

Background: Inflammation-provoked disorders including cancer are arbitrated by cyclooxygenase-2 (COX-2). Celecoxib and niflumic acid are among the potent and selective inhibitors of this enzyme while aspirin (acetylsalicylic acid) and sodium salicylate are its non-selective and lesser potent inhibitors. Despite these proven studies, the comparative structural study of these selective and non-selective molecules at atomistic scale in complex state with COX-2 that may answer this differential inhibitory behavior has not been accomplished spotlighting the imperative need of additional research in this area. Thus, this study was framed to provide a strong explanation for the enigma of higher inhibitory activity of celecoxib-niflumic acid duo in comparison to aspirin and sodium salicylate towards COX-2., Methods: A contemporary approach including advanced molecular docking against COX2, molecular dynamics of receptor-ligand complexes, simulation-trajectory-backed MMGBSA for different time points, radius of gyration (Rg) calculations, and e-pharmacophores approach was employed to attain a rational conclusion., Results: Our findings demonstrated the higher binding affinity of celecoxib and niflumic acid over aspirin and sodium salicylate against COX-2. Although both selective and non-selective COX-2 inhibitors manifested nearly the same stability in the active site of this enzyme but the e-pharmocophoric features found in the case of selective inhibitors scored over non-selective ones. Thus, our findings excluded the differential stability to be the cause of stronger potency of selective inhibitors but attributed their potency to greater number of complementary features present in these inhibitors against the active site of inflammation engendering COX-2., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

One-fifth of COVID-19 patients suffer a severe course of COVID-19 (SARS-CoV-2) infection; however, the specific causes remain unclear. Despite numerous papers that have been flooded in different scientific journals clear clinical picture of COVID-19 aftermath persists to remain fuzzy. The survivors of severe COVID-19infection having defeated the virus are just the starting of an uncharted recovery path. Currently, there is no drug available that is safe to consume to combat this pandemic. However, researchers still struggling to find specific therapeutic solutions. The present study employed an in silico approach to assessing the inhibitory potential of the phytochemicals obtained from GC-MS analysis of Citrus macroptera against inflammatory proteins like COX-2, NMDAR and VCAM-1 which remains in a hyperactive state even after a patient is fully cured of this deadly mRNA virus. An extensive molecular docking investigation of the phyto-compounds at the active binding pockets of the inflammatory proteins revealed the promising inhibitory potential of the phytochemicals. Reasonable physicochemical attributes of the compounds following Lipinski's rule of five, VEBER and PAINS analysis further established them as potential therapeutic candidates against aforesaid inflammatory proteins. MM-GBSA binding free energy estimation revealed that Limonene was the most promising candidate displaying the highest binding efficacy with the concerned VCAM-1 protein included in the present analysis. An interesting finding is the phytochemicals exhibited better binding energy scores with the concerned COX-2, VCAM-1 and NMDA receptor proteins than the conventional drugs that are specifically targeted against them. Our in silico results suggest that all the natural phyto-compounds derived from C. macroptera could be employed in Post covid inflammation complexities after appropriate pre-clinical and clinical trials for further scientific validation.Communicated by Ramaswamy H. Sarma.

Hypoxia induce right ventricular dysfunction in human heart, but the molecular mechanism remains limited. As known, cyclooxygenases (COX) and lipoxygenases (LOX) play a key role in the cardiovascular system under hypoxia. 3,4',5,7-Tetrahydroxyflavone (THF), which widely exists in a variety of plants and vegetables, is famous for good ability to relieve cardiac injury, but the mechanism remains to be further understood. In this study, we firstly estimated the preventive role of THF against hypoxia-induced right ventricular dysfunction. Metabolomics analysis showed there were differential metabolites involved in above process, which helped us to screen the crucial regulated enzymes of these metabolites. Molecular docking and multi-spectroscopic revealed the molecular mechanism of interaction between THF and COX/LOX. Results suggested that THF bound to COX/LOX through static quenching and these bindings were driven by hydrogen bonds. After binding with THF, the secondary structure of COX/LOX was changed. In general, this study indicated that THF inhibited COX/LOX by spontaneously forming complexes with them., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Cyclooxygenase 2 (COX-2) is a well-established target for the design of anti-inflammatory intermediates. Celecoxib was selected as a template molecule to perform ligand-based virtual screening, i.e. to search for structures with similarity in shape and electrostatic potential, with a gradual increase in accuracy through the combined fitting of several steps using eight commercial databases. The molecules ZINC408709 and ZINC2090319 reproduced values within the limits established in an initial study of absorption and distribution in the body. No alert was fired for possible toxic groups when these molecules were subjected to toxicity prediction. Molecular docking results with these compounds showed a higher binding affinity in comparison to rofecoxib for the COX-2 target. Additionally, ZINC408709 and ZINC2090319 were predicted to be potentially biologically active. In in silico prediction of endocrine disruption potential, it was established that the molecule ZINC2090319 binds strongly to the target related to cardiovascular risk in a desirable way as a non-steroidal antagonist and ZINC408709 binds strongly to the target that is associated with the treatment of inflammatory pathologies and similar to celecoxib. Metabolites generated from these compounds are less likely to have side effects. Simulations were used to evaluate the interaction of compounds with COX-1 and COX-2 during 200 ns. Despite the differences, ZINC408709 molecule showed better stability for COX-2 during molecular dynamics simulation. In the calculations of free energy MM/PBSA, the molecule ZINC408709 ΔGbind value has a higher affinity to celecoxib and rofecoxib COX-2. This demonstrates that the selected substances can be considered as promising COX-2 inhibitors. Communicated by Ramaswamy H. Sarma.

A series of 26 novel derivatives have been synthesized through structural modification of gentiopicroside, a lead COX-2 inhibitor. And their in vivo and in vitro anti-inflammatory activities have been investigated. The in vitro anti-inflammatory activities were evaluated against NO, PGE 2 , and IL-6 production in the mouse macrophage cell line RAW264.7 stimulated by LPS. Results showed that most compounds had good inhibitory activity. The in vivo inhibitory activities were further tested against xylene-induced mouse ear swelling. Results demonstrated that several compounds were more active than the parent compound gentiopicroside. The inhibition rate of the most active compound P23 (57.26%) was higher than positive control drug celecoxib (46.05%) at dose 0.28 mmol·kg -1 . Molecular docking suggested that these compounds might bind to COX-2 and iNOS. Some of them, e.g P7, P14, P16, P21, P23, and P24, had high docking scores in accordance with their potency of the anti-inflammatory activitiy, that downregulation of the inflammatory factors, NO, PGE 2 , and IL-6, was possibly associated with the suppression of iNOS and COX-2. Therefore, these gentiopicroside derivatives may represent a novel class of COX-2 and iNOS inhibitors., (Copyright © 2022 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Inflammation is a key factor linked to almost all chronic and degenerative diseases implicit with certain levels of pain. In studies, over the past few years, it has been discovered that prostaglandins are the main cause of this inflammation and therefore could be blocked. Although no steroidal medications can be effective, natural compounds may offer a safer and often an effective alternative treatment for pain relief, especially for long-term use. Hence to find out natural anti-inflammatory compounds, we have highlighted five important butenolides that are eutypoid A, B, C, D and E with structure similar to that of rofecoxib, by ADMET and druglikeness analysis, followed by molecular docking with human COX-2 enzyme. Molecular docking studies revealed the importance of hydrophobic and hydrophilic amino acid residues for the stability of the ligands and that eutypoids C and E are the best candidates for the synthetic drugs with binding energy of -10.39 kcal/mol and -9.87 kcal/mol, respectively. The resulting complexes were then subject to 50 ns molecular dynamics (MD) simulation studies with the GROMACS package to analyze the stability of docked protein-ligand complexes and to assess the fluctuation and conformational changes during protein-ligand interaction. From the RMSD, RMSF, number of hydrogen bonds, SASA, PCA and MM/PBSA binding free energy analysis, we have found that out of five selected compounds eutypoid E showed good binding free energy of -174.45 kJ/mol, which is also good in other structural analyses. This compound displayed excellent pharmacological and structural properties to be drug candidates.Communicated by Ramaswamy H. Sarma.

In this study, 5 sterols were isolated and purified from Laminaria japonica, commonly known as edible brown seaweed, and their structures were identified based on detailed chemical methods and spectroscopic analyses. Spectroscopic analyses characterized 5 sterols as 29-Hydroperoxy-stigmasta-5,24(28)-dien-3β-ol, saringosterol (24-vinyl-cholest-5-ene-3β,24-diol), 24-methylenecholesterol, fucosterol (stigmasta-5,24-diene-3β-ol), and 24-Hydroperoxy-24-vinyl-cholesterol. The bioactivities of these sterols were tested using lipid peroxidation (LPO) and cyclooxygenase (COX-1 and -2) enzyme inhibitory assays. Fucosterol exhibited the highest COX-1 and -2 enzyme inhibitory activities at 59 and 47%, respectively. Saringosterol, 24-methylenecholesterol and fucosterol showed higher LPO inhibitory activity at >50% than the other compounds. In addition, the results of molecular docking revealed that the 5 sterols were located in different pocket of COX-1 and -2 and fucosterol with tetracyclic skeletons and olefin methine achieved the highest binding energy (-7.85 and -9.02 kcal/mol) through hydrophobic interactions and hydrogen bond. Our results confirm the presence of 5 sterols in L. japonica and its significant anti-inflammatory and antioxidant activity., Competing Interests: The authors have declared that no competing interests exist.

Organic extract of the brown seaweed Turbinaria conoides (Sargassaceae) was chromatographically fractionated to yield an undescribed furanyl-substituted isochromanyl metabolite, named as turbinochromanone, which was characterized as methyl 4-[(3S)-8-{[(3R)-4-ethyl-2,3-dihydrofuran-3-yl]methyl}-1-oxo-3,4-dihydro-1H-2-benzopyran-3-yl]butanoate. The isochromanyl derivative possessed comparable attenuation potential against 5-lipoxygenase (IC 50 3.70 μM) with standard 5-lipoxygenase inhibitor drug zileuton (IC 50 2.41 μM). Noticeably, the index of anti-inflammatory selectivity of turbinochromanone (∼1.7) was considerably greater than that exhibited by the standard agent diclofenac (1.06). Antioxidant properties of turbinochromanone against oxidants (IC 50 ∼24 μM) further supported its potential anti-inflammatory property. Greater electronic properties (topological polar surface area of 61.8) along with comparatively lesser docking parameters of the studied compound with aminoacyl residues of targeted enzymes (cyclooxygenase-2 and 5-lipoxygenase) (binding energy of -11.05 and -9.40 kcal mol -1 , respectively) recognized its prospective anti-inflammatory potential. In an aim to develop seaweed-based natural anti-inflammatory leads, the present study isolated turbinochromanone as promising 5-lipoxygenase and cyclooxygenase-2 inhibitor, which could be used for pharmaceutical and biotechnological applications., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.)

In recent years, inflammatory mediators have been considered a possible key for nonsteroidal anti-inflammatory drugs (NSAID's). NSAID's have been known as most promising medication against inflammation and its mediated pain. Inflammation could be recognize as a systemic adaptive stimulation triggered by detrimental stimuli as pathogenic attack and endogenous signals mediated injury inside the cells. In addition, there has been an inflammatory key mechanism involved in disease state. NSAIDs have been compromisingly recommended for targeting specific proteins and/or inflammatory-mediated enzymes including cyclooxygenases (COX). This subsequently inhibits the prostaglandins at the site of inflammation. For the past decades, two forms of the COX enzyme have been implicated as COX-1 expressed in cells and tissues and other COX-2 selectively triggered via proinflammatory cytokines at the site of inflammation and/or injury. In addition, NSAID's have also been implicated for the inhibition of NF-κB pathways, and other relevant proteins considered potent candidates for these drugs. NF-κB has been identified a classical proinflammatory signaling pathway. It has been recognized as a primary target for novel anti-inflammatory drugs. In our results, reports are being confirmed via the probable effects of NSAID's on inflammatory-mediated switches. Several studies were considered to enquire the possible interactions of NSAID's and inflammatory hub. Nevertheless, the exact mechanism is still debatable. In our study, NSAID's and their targeted proteins or molecules caused a convincing pattern. For improvised perception, the binding affinity of NSAID's with inflammatory-mediated proteins was quantified using a molecular docking tool. In addition, we have depicted the complex juncture of hydrogen bonding in targeted proteins with NSAID's. Our in silico investigations have revealed NSAID's as the powerful armor against COX-2- and NF-κB-mediated inflammation., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ethnopharmacological Relevance: Consumable herbs play a basic part in sustenance and human health. Traditionally, Colocasia gigantea Hook (Araceae) is used to treat fever, infection, wounds healing, drowsiness, tuberculosis, stomach problems etc. AIM OF THE STUDY: The study aspired to identify bioactive compounds, to evaluate anti-inflammatory and analgesic potentials of edible herb C. gigantea, and to molecular docking study against anti-inflammatory enzyme Cyclooxygenase-2 (COX-2)., Materials and Methods: Chemical components of C. gigantea were discerned by HPLC and GCMS assays. In vitro anti-inflammatory activity was appraised by heat-induced, hypotonicity, and hydrogen peroxide-induced hemolysis assays and in vivo by formalin-induced paw edema assay. In vivo analgesic activity was evaluated by acetic acid-induced pain modulation assay. Also, molecular docking of the identified compounds was explored against the anti-inflammatory enzyme cyclooxygenase-2., Results: HPLC-DAD analysis divulged the presence of trans-cinnamic acid along with (-)-epicatechin as a prime component. Also, 9, 12-Octadecadienoic acid (37.86%) and n-Hexadecanoic acid (25.89%) as the major as well as 24 other compounds were confirmed through GCMS in the extract. In in vitro anti-inflammatory study, C. gigantea extract indicated prominent erythrocyte membrane stabilization activity with good percentage aegis in all experimental assays. In addition to, formalin-induced in vivo anti-inflammatory assay revealed the maximum (42.37% and 48.72%) suppression of edema at the fourth hour at 250 and 500 mg/kg body weight, respectively. Moreover, an in-vivo pain modulation assay exposed significant (p < 0.05) activity at experimental doses. Furthermore, in the docking study, (-)-epicatechin was more active rather than other identified compounds with strong binding affinity to COX-2 protein., Conclusions: The extract evinced remarkable anti-inflammatory and analgesic activities. Identified bioactive components along with other components of the extract might play a pivotal role in the observed bioactivity and the results vindicate the use of edible herb C. gigantea in ancestral medicine., (Copyright © 2021 Elsevier B.V. All rights reserved.)

It has been previously reported that targeting and retaining antigens in the endoplasmic reticulum (ER) can induce an ER stress response. In this study, we evaluated the antitumor effect of E7 antigen fused to an ERresident protein, cyclooxygenase-2, which possesses a 19-aminoacid cassette that directs it to the endoplasmic reticulum-associated protein degradation (ERAD) pathway. The featured DNA constructs, COX2-E7 and COX2-E7ΔERAD, with a deletion in the 19-aminoacid cassette, were used to evaluate the importance of this sequence. In vitro analysis of protein expression and ER localisation were verified. We observed that both constructs induced an ER stress response. This finding correlated with the antitumor effect in mice injected with TC-1 cells and treated with different DNA constructs by biolistic vaccination. Immunisation with COX2-E7 and COX2-E7ΔERAD DNA constructs induced a significant antitumor effect in mice, without a significant difference between them, although the COX2-E7 construct induced a significant E7-specific immune response. These results demonstrate that targeting the E7 antigen to the ERAD pathway promotes a potent therapeutic antitumor effect. This strategy could be useful for the design of other antigen-specific therapies.

Purpose: The enzyme Cyclooxygenases (COX-1 and COX-2) catalyze the formation of prostaglandin, a mediator of the inflammatory pathway. Inflammation related pathological conditions may be alleviated by targeting the Cox enzymes.COX-2 inhibitors that are currently available in the market causes undesirable side effects. Our present study focuses on the in-silico inhibition of COX -2 enzyme by the phytocompounds from Albizia amara and Phyla nodiflora., Methods: The phytochemicals present in Albizia amara and Phyla nodiflora were analyzed for their COX-2 inhibition potential. Eight compounds from Albizia amara and eleven compounds from Phyla nodiflora obtained from GC-MS analysis was used for the current study. Molecular docking was performed using AutoDock vina. The crystal structure of COX-2 (PDB ID: 5IKR) was obtained from Protein data bank. PyMol was used to remove any solvent, organic and inorganic molecules. Energy minimization of the protein was carried out using SPDBV software. Geometrical optimizations of the ligands were performed using Avogadro software. Celecoxib was used as the positive control. ADMET properties of the compounds were analyzed using SwissADME and ProtoxII online servers. Molecular mechanics/generalized born surface area (MM/GBSA) calculations were performed to evaluate the binding efficiency. Molecular dynamics of the protein and protein-ligand complex was studied for about 100 ns using Desmond package of Schrodinger suite., Results: Among the eighteen compounds, Squalene present in both the plants showed a better binding energy of -7.7 kcal/mol, when compare to other phytocompounds present in the extract. The control celecoxib showed a binding energy of about - 9.4 kcal/mol. The toxicity and ADMET properties of squalene indicated that it is non-toxic and followed Lipinski's rule. Molecular Dynamics (MD) analysis showed that the binding of squalene to the enzyme was stable., Conclusion: Squalene could potentially inhibit COX2 and o wing to its properties, squalene can be formulated in gels/creams and could be possibly used for external edema and inflammation., (© 2021. Springer Nature Switzerland AG.)

Series of piperidone-salicylate conjugates were synthesized through the reaction of 3E,5E-bis(arylidene)-4-piperidones with the appropriate acid chloride of acetylsalicylate in the presence of triethylamine. All the synthesized conjugates reveal antiproliferative properties against A431 (squamous skin) cancer cell line with potency higher than that of 5-fluorouracil. Many of the synthesized agents also exhibit promising antiproliferative properties against HCT116 (colon) cancer cell line, of which 5o and 5c are the most effective with 12.9, 9.8 folds potency compared with Sunitinib. Promising activity is also shown against MCF7 (breast) cancer cell line with 1.19, 1.12 folds relative to 5-fluorouracil. PI-flow cytometry of compound 5c supports the arrest of cell cycle at G1-phase. However, compound 5o and Sunitinib arrest the cell cycle at S-phase. The synthesized conjugates can be considered as multi-targeted tyrosine kinase inhibitors due to the promising properties against VEGFR-2 and EGFR in MCF7 and HCT116. CDOCKER studies support the EGFR inhibitory properties. Compounds 5p and 5i possessing thienylidene heterocycle are anti-SARS-CoV-2 with high therapeutic indices. Many of the synthesized agents show enhanced COX-1/2 properties than aspirin with better selectivity index towards COX-2 relative to COX-1. The possible applicability of the potent candidates discovered as antitumor and anti-SARS-CoV-2 is supported by the safe profile against normal (non-cancer, RPE1 and VERO-E6) cells., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Addressing the global need for the development of safe and potent NSAIDs, new series of oxadiazolo and thiadiazolo fused pyrmidinones were synthesized and initially tested for their analgesic activity. All tested compounds showed promising analgesic activity compared with the reference standard indomethacin. Moreover, anti-inflammatory activity evaluation, ulcerogenic liability, and in vitro COX-1, COX-2 enzyme inhibition assays were also performed for the most active derivatives. The methoxyphenyl piperazinyl derivative 3d showed analgesic activity surpassing indomethacin with protection of 100%, and 83%; respectively. Also 3d showed good anti-inflammatory activity with relatively lower ulcer index compared with other tested compounds, and potent COX-1 and COX-2 inhibitory activity with IC 50  = 0.140, 0.007 μm, respectively, and with a selectivity index of 20.00 which was better than the reference standards and the other tested congeners. Additionally, compounds 3b, 3g and 3h revealed moderate selectivity (SI = 3.53, 3.70 and 5.87, respectively). Moreover, in silico physicochemical parameters revealed that the new fused pyrimidinones demonstrated promising pharmacokinetic properties. Furthermore, computational studies in form of 2D-quantitative structure-activity relationship (2D-QSAR) and 3D-pharmacophore confirmed the potential analgesic properties of the new target compounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Regarding that the chronic use of commonly available non-steroidal and anti-inflammatory drugs (NSAIDs) is often restricted by their adverse effects, there is still a current need to search for and develop new, safe and effective anti-inflammatory agents. As a continuation of our previous work, we designed and synthesized a series of 18 novel N -substituted-1,2,4-triazole-based derivatives of pyrrolo[3,4- d ]pyridazinone 4a-c-9a-c . The target compounds were afforded via a convenient way of synthesis, with good yields. The executed cell viability assay revealed that molecules 4a-7a , 9a , 4b-7b , 4c-7c do not exert a cytotoxic effect and were qualified for further investigations. According to the performed in vitro test, compounds 4a-7a , 9a , 4b , 7b , 4c show significant cyclooxygenase-2 (COX-2) inhibitory activity and a promising COX-2/COX-1 selectivity ratio. These findings are supported by a molecular docking study which demonstrates that new derivatives take position in the active site of COX-2 very similar to Meloxicam . Moreover, in the carried out in vitro evaluation within cells, the title molecules increase the viability of cells pre-incubated with the pro-inflammatory lipopolysaccharide and reduce the level of reactive oxygen and nitrogen species (RONS) in induced oxidative stress. The spectroscopic and molecular modeling study discloses that new compounds bind favorably to site II(m) of bovine serum albumin. Finally, we have also performed some in silico pharmacokinetic and drug-likeness predictions. Taking all of the results into consideration, the molecules belonging to series a ( 4a-7a , 9a ) show the most promising biological profile.

Colorectal cancer (CRC) is the second cause of cancer death worldwide. Inhibitors of COX-2, 5-LOX and PIM-1 kinase were very effective in the treatment and prevention of CRC in mouse models in vivo. Furthermore, thymol was confirmed to inhibit CRC cell proliferation in cancer cell lines and inhibitory activity against COX-2 and 5-LOX. On the other hand, 4-thiazolidinone pharmacophore was incorporated in the structures of various reported COX-2, 5-LOX and PIM kinase inhibitors. Consequently, the aim of the present investigation was to combat CRC by synthesis and biological evaluation of new thymol - 4-thiazolidinone hybrids as multitarget anticancer agents that could inhibit the key COX-2, 5-LOX and PIM-1 kinase enzymes simultaneously. Compounds 5a-d and 5g displayed inhibitory activity against COX-2 nearly equal to Celecoxib with high selectivity index (SI). Moreover, compounds 5b-e showed 5-LOX inhibitory activity nearly equal to the reference Quercetin while compounds 5a, 5f and 5g elicited inhibitory activity slightly lower than Quercetin. Furthermore, in vivo formalin-induced paw edema test revealed that, compounds 5a, 5c, 5f and 5g showed higher % inhibition than Celecoxib and compounds 5a, 5f and 5g showed higher % inhibition than Diclofenac sodium. In addition, compounds 5a-c, 5e-g showed in vivo superior gastrointestinal safety profile as Celecoxib in fasted rats. Besides, compounds 5d, 5e and 5g exhibited the highest activity against human CRC cell lines (Caco-2 and HCT-116) at doses less than their EC 100 on normal human cells. Furthermore, compounds 5e and 5g induced apoptosis-dependent death by above 50% in the treated CRC cell lines. Moreover, compounds 5e and 5g induced caspase activation by >50% in human CRC. Also, compounds 5d, 5e and 5g showed in vitro inhibitory activity against both PIM-1\2 kinases comparable to the reference Staurosporine. In silico docking studies were concordant with the biological results. In conclusion, compound 5g, of simple chemical structure, achieved the target goal of inhibiting three targets leading to inhibition of human CRC cell proliferation. It inhibited the target key enzymes COX-2, 5-LOX and PIM-1\2 kinase in vitro. Besides, it revealed in vitro inhibition of cell proliferation in cancer cell lines via activation of caspase 3\7 dependent-apoptosis in human CRC cell lines. In addition, it elicited in vivo anti-inflammatory activity in formalin-induced paw edema test and in vivo oral safety in gastric ulcerogenic activity test., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Leucas vestita Wall. ex. Benth., is an endemic species restricted to Western Ghats, India. In this study, the carrageenan-induced anti-inflammatory model was used to evaluate the influence of L. vestita ethanol extract on inflammation. The Ethanol extract was tested for its anti-inflammatory property at a dose of 200mg/kg po. and 400mg/kg po. The paw volume was reduced gradually, three hours after administration of the extract. The extract showed a dosage dependant activity. The compounds present in the ethanol extract were identified by using HPLC and the binding affinity of these compounds against Cyclo-oxygenase-2 (COX-2, the enzyme involved in the perception of pain) was analyzed by using FlexX molecular docking suite., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Since long-term use of classic NSAIDs can cause severe side effects related mainly to the gastroduodenal tract, discovery of novel cyclooxygenase inhibitors with a safe gastric profile still remains a crucial challenge. Based on the most recent literature data and previous own studies, we decided to modify the structure of already reported 1,3,4-oxadiazole based derivatives of pyrrolo[3,4- d ]pyridazinone in order to obtain effective COX inhibitors. Herein we present the synthesis, biological evaluation and molecular docking studies of 12 novel compounds with disubstituted arylpiperazine pharmacophore linked in a different way with 1,3,4-oxadiazole ring. None of the obtained molecules show cytotoxicity on NHDF and THP-1 cell lines and, therefore, all were qualified for further investigation. In vitro cyclooxygenase inhibition assay revealed almost equal activity of new derivatives towards both COX-1 and COX-2 isoenzymes. Moreover, all compounds inhibit COX-2 isoform better than Meloxicam which was used as reference. Anti-inflammatory activity was confirmed in biological assays according to which title molecules are able to reduce induced inflammation within cells. Molecular docking studies were performed to describe the binding mode of new structures to cyclooxygenase. Investigated derivatives take place in the active site of COX, very similar to Meloxicam. For some compounds, promising druglikeness was calculated using in silico predictions.

Idiopathic pulmonary fibrosis (IPF) is a devastating and fatal interstitial lung disease due to various challenges in diagnosis and treatment. Due to its complicated pathogenesis and difficulty in early diagnosis, there is no effective cure. Cyclooxygenase-2 (COX-2) is inextricably associated with pulmonary fibrosis. The abnormal level of COX-2 leads to extremely exacerbated pulmonary fibrosis. Therefore, we reported a near-infrared fluorescent probe Cy-COX to detect the fluctuation of COX-2 levels during pulmonary fibrosis and explain its important protective effect. The probe Cy-COX showed a significant enhancement of fluorescence signal to COX-2 with excellent selectivity and sensitivity. In order to clarify the relationship between COX-2 and pulmonary fibrosis, we used the probe Cy-COX to detect COX-2 fluctuation in organisms with pulmonary fibrosis. The results showed that the COX-2 level increased in the early stage and decreased in the late stage with the aggravation of pulmonary fibrosis. Furthermore, up-regulation of COX-2 levels can effectively alleviate the severity of pulmonary fibrosis. Therefore, Cy-COX is a fast and convenient imaging tool with great potential to predict the early stage of pulmonary fibrosis and evaluate the therapeutic effects.

Four biogenic β-sitosterol analogues were identified from methanolic extract of the leaves of loop-root mangrove Rhizophora mucronata. These were characterized as 4, 14, 23-trimethyl-3β-sitosterol (1), 7-ethyl-3β-sitosterol (2), sitosteryl-3β-(3 3 E)-pent-3 3 -enoate (3) and 12α-hydroxy-3β-sitosterol (4) based on comprehensive spectroscopic techniques. Anti-inflammatory activities of β-sitosterol 4 against pro-inflammatory enzymes 5-lipoxygenase and cyclooxygenase-2 were found to be significantly higher (IC 50 1.85 and 1.92 mM, respectively) compared to those demonstrated by compounds of 1-3 (p < 0.05). These β-sitosterol analogues disclosed superior selectivity indices (1.43-2.07) with regard to inducible cyclooxygenase-2 than its constitutive isoform cyclooxygenase-1, when compared to the standard, ibuprofen (0.44). Antioxidant properties of 12α-hydroxy-β-sitosterol (4) were found to be significantly greater (IC 50 1.43-1.67 mM) than those of other sitosterol analogues. Structure-activity correlation analyses put forward that the bioactive potencies of the titled β-sitosterols were positively correlated to their electronic parameters. Molecular docking simulations were carried out in the active sites of 5-lipoxygenase/cyclooxygenase-2, and the docking scores and binding energies of the studied β-sitosterol analogues were positively correlated with their attenuation properties against 5-lipoxygenase and cyclooxygenase-2., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The intestinal barrier dysfunction is crucial for the development of liver fibrosis but can be disturbed by intestinal chronic inflammation characterized with cyclooxygenase-2 (COX-2) expression. This study focused on the unknown mechanism by which COX-2 regulates intestinal epithelial homeostasis in liver fibrosis. The animal models of liver fibrosis induced with TAA were established in rats and in intestinal epithelial-specific COX-2 knockout mice. The impacts of COX-2 on intestinal epithelial homeostasis via suppressing β-catenin signalling pathway were verified pharmacologically and genetically in vivo. A similar assumption was tested in Ls174T cells with goblet cell phenotype in vitro. Firstly, disruption of intestinal epithelial homeostasis in cirrhotic rats was ameliorated by celecoxib, a selective COX-2 inhibitor. Then, β-catenin signalling pathway in cirrhotic rats was associated with the activation of COX-2. Furthermore, intestinal epithelial-specific COX-2 knockout could suppress β-catenin signalling pathway and restore the disruption of ileal epithelial homeostasis in cirrhotic mice. Moreover, the effect of COX-2/PGE2 was dependent on the β-catenin signalling pathway in Ls174T cells. Therefore, inhibition of COX-2 may enhance intestinal epithelial homeostasis via suppression of the β-catenin signalling pathway in liver fibrosis., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Two pregnane-type of steroid derivatives characterized as 5α-pregna-3β-methyl pent-3-enoate-12β, 16β diol-20-one (clathroid A) and 12β,15β- dihydroxypregna-4,6-diene-3,20-dione (clathroid B) were purified from the crude extract of the marine sponge, Clathria (Thalysias) vulpina (family Microcionidae) by extensive chromatographic fractionation. Spectroscopic methods including nuclear magnetic resonance spectroscopy were employed to characterize the purified clathroids A-B. The studied compounds exhibited duel inhibitory potentials against pro-inflammatory cyclooxygenase-2 and 5-lipoxygenase (median inhibitory concentration, IC 50  < 1 mM), whereas the attenuation property of clathroid A against 5-lipoxygenase (IC 50 0.85 mM) was greater than the standard anti-inflammatory ibuprofen (IC 50 4.51 mM, p < 0.05). Greater selectivity index (anti cyclooxygense-2/anti cyclooxygense-1) of the studied clathroids (>1) than ibuprofen (0.43) attributed the greater selective attenuation properties towards pro-inflammatory inducible cyclooxygenase-2 than its constitutive isoenzyme cyclooxygenase-1. The antioxidant potentials of clathroid A against 2, 2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (IC 50 0.80 mM) and diphenyl-1-picrylhydrazyl (IC 50 0.83 mM) free radicals were greater than those of clathroid B (IC 50 0.86-0.96 mM). Structure-activity analyses showed that the bioactivities of the clathroids were directly related to their electronic parameters coupled with permissible hydrophobic properties. Clathroid A exhibited grater electronic parameter (topological polar surface area tPSA, 83.83) than clathroid B (74.60) and ibuprofen (37.30), which were found to be in agreement with the prospective anti-inflammatory profile of clathroid A. Clathroid A exhibited higher number of hydrogen bonding interactions with 5-lipoxygenase active site and lesser docking values, such as docking score (DS -12.90 kcal mol -1 ) and inhibition constant (Ki 1.11 nM) than those recorded by clathroid B (DS -10.49 kcal mol -1 ; Ki 13.88 nM). The molecular binding properties of clathroid A with 5-lipoxidase inferred that its docking score/ binding energy were positively correlated with their in vitro bioactivie potentilas. A putative biosynthetic pathway of the studied clathroids was proposed from a pregnenolone precursor. The present study recognized the potential of clathroid A isolated from C. (Thalysias) vulpina as prospective anti-inflammatory lead that could find its use in medicinal applications., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Based on the observed pharmacophoric structural features for the reported dual COX/15-LOX inhibitors and inspired by the abundance of COX/LOX inhibitory activities reported for the 1,2,4-triazine and quinoline scaffolds, we designed and synthesized novel 1,2,4-triazine-quinoline hybrids (8a-n). The synthesized hybrids were evaluated in vitro as dual COXs/15-LOX inhibitors. The new triazine-quinoline hybrids (8a-n) exhibited potent COX-2 inhibitory profiles (IC 50  = 0.047-0.32 μM, SI ∼ 20.6-265.9) compared to celecoxib (IC 50  = 0.045 μM, SI ∼ 326). Moreover, they revealed potent inhibitory activities against 15-LOX enzyme compared to reference quercetin (IC 50  = 1.81-3.60 vs. 3.34 μM). Hybrid 8e was the most potent and selective dual COX-2/15-LOX inhibitor (COX-2 IC 50  = 0.047 μM, SI = 265.9, 15-LOX IC 50  = 1.81 μM). These hybrids were further challenged by their ability to inhibit NO, ROS, TNF-α, IL-6 inflammatory mediators, and 15-LOX product, 15-HETE, production in LPS-activated RAW 264.7 macrophages cells. Compound 8e was the most potent hybrid in reducing ROS and 15-HETE levels showing IC 50 values of 1.02 μM (11-fold more potent than that of celecoxib, IC 50  = 11.75 μM) and 0.17 μM (about 43 times more potent than celecoxib, IC 50  = 7.46 μM), respectively. Hybrid 8h exhibited an outstanding TNF-α inhibition with IC 50 value of 0.40 μM which was about 25 times more potent than that of celecoxib and diclofenac (IC 50  = 10.69 and 10.27 μM, respectively). Docking study of the synthesized hybrids into the active sites of COX-2 and 15-LOX enzymes ensures their favored binding affinity. To our knowledge, herein we reported the first 1,2,4-triazine-quinoline hybrids as dual COX/15-LOX inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no financial, conflict of interest, or personal relationships that may appear to hinder or affect this work., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

The synthesis of a novel cyclohexanone derivative (CHD; Ethyl 6-(4-metohxyphenyl)-2-oxo-4-phenylcyclohexe-3-enecarboxylate) was described and the subsequent aim was to perform an in vitro, in vivo and in silico pharmacological evaluation as a putative anti-nociceptive and anti-inflammatory agent in mice. Initial in vitro studies revealed that CHD inhibited both cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) enzymes and it also reduced mRNA expression of COX-2 and the pro-inflammatory cytokines TNF-α and IL-1β. It was then shown that CHD dose dependently inhibited chemically induced tonic nociception in the abdominal constriction assay and also phasic thermal nociception (i.e. anti-nociception) in the hot plate and tail immersion tests in comparison with aspirin and tramadol respectively. The thermal test outcomes indicated a possible moderate centrally mediated anti-nociception which, in the case of the hot plate test, was pentylenetetrazole (PTZ) and naloxone reversible, implicating GABAergic and opioidergic mechanisms. CHD was also effective against both the neurogenic and inflammatory mediator phases induced in the formalin test and it also disclosed anti-inflammatory activity against the phlogistic agents, carrageenan, serotonin, histamine and xylene compared with standard drugs in edema volume tests. In silico studies indicated that CHD possessed preferential affinity for GABA A , opioid and COX-2 target sites and this was supported by molecular dynamic simulations where computation of free energy of binding also favored the formation of stable complexes with these sites. These findings suggest that CHD has prospective anti-nociceptive and anti-inflammatory properties, probably mediated through GABAergic and opioidergic interactions supplemented by COX-2 and 5-LOX enzyme inhibition in addition to reducing pro-inflammatory cytokine expression. CHD may therefore possess potentially beneficial therapeutic effectiveness in the management of inflammation and pain., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Chitosan (Cs) was cross-linked with four various quantities of 4,4'-(5,5'‑carbonylbis(1,3-dioxoisoindoline-5,2-diyl))dibenzoyl isothiocyanate. Elemental analysis, FTIR and 1 H NMR spectroscopy assured that the amino groups of chitosan reacted with the isothiocyanate groups of the cross-linker producing four new hydrogels namely as BBTU-Cs-1, BBTU-Cs-2, BBTU-Cs-3, and BBTU-Cs-4 according to the increment of their cross-linking content, respectively. SEM showed their porous structures and XRD indicated their amorphous nature. Their swell ability increased with decreasing the medium pH value and with increasing cross-linking density. In comparison with the popular COX inhibitor Celecoxib, these hydrogels showed an inhibition activity towards COX enzymes with selective inhibition towards COX-2. Their inhibition activity could be arranged as follows: Celecoxib > BBTU-Cs-4 > BBTU-Cs-3 > BBTU-Cs-2 > BBTU-Cs-1. BBTU-CS-4 hydrogel exhibited a potent inhibition against COX-2 (IC 50 0.42 μg/ml) compared with that observed for the standard Celecoxib (IC 50 0.26 μg/ml). BBTU-Cs-4 is more potent against H. pylori compared to the other hydrogels. BBTU-Cs-4 at a concentration of 7.81 μg/ml is able to kill 100% of the H. pylori and exhibits a preferential ability to inhibit 89.35% of COX-2 than COX-1 (0%). These findings make BBTU-Cs-4 a promising anti-H. pylori and selective anti-inflammatory agent., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Starting from indomethacin (IND), one of the most prescribed non-steroidal anti-inflammatory drugs (NSAIDs), new nitric oxide-releasing indomethacin derivatives with 1,3,4-oxadiazole-2-thiol scaffold (NO-IND-OXDs, 8a-p ) have been developed as a safer and more efficient multitarget therapeutic strategy. The successful synthesis of designed compounds (intermediaries and finals) was proved by complete spectroscopic analyses. In order to study the in silico interaction of NO-IND-OXDs with cyclooxygenase isoenzymes, a molecular docking study, using AutoDock 4.2.6 software, was performed. Moreover, their biological characterization, based on in vitro assays, in terms of thermal denaturation of serum proteins, antioxidant effects and the NO releasing capacity, was also performed. Based on docking results, 8k, 8l and 8m proved to be the best interaction for the COX-2 (cyclooxygense-2) target site, with an improved docking score compared with celecoxib. Referring to the thermal denaturation of serum proteins and antioxidant effects, all the tested compounds were more active than IND and aspirin, used as references. In addition, the compounds 8c , 8h , 8i , 8m , 8n and 8o showed increased capacity to release NO, which means they are safer in terms of gastrointestinal side effects.

Lusianthridin is a phenanthrene derivative isolated from Dendrobium venustum . Some phenanthrene compounds have antiplatelet aggregation activities via undefined pathways. This study aims to determine the inhibitory effects and potential mechanisms of lusianthridin on platelet aggregation. The results indicated that lusianthridin inhibited arachidonic acid, collagen, and adenosine diphosphate (ADP)-stimulated platelet aggregation (IC 50 of 0.02 ± 0.001 mM, 0.14 ± 0.018 mM, and 0.22 ± 0.046 mM, respectively). Lusianthridin also increased the delaying time of arachidonic acid-stimulated and the lag time of collagen-stimulated and showed a more selective effect on the secondary wave of ADP-stimulated aggregations. Molecular docking studies revealed that lusianthridin bound to the entrance site of the cyclooxygenase-1 (COX-1) enzyme and probably the active region of the cyclooxygenase-2 (COX-2) enzyme. In addition, lusianthridin showed inhibitory effects on both COX-1 and COX-2 enzymatic activities (IC 50 value of 10.81 ± 1.12 µM and 0.17 ± 1.62 µM, respectively). Furthermore, lusianthridin significantly inhibited ADP-induced suppression of cAMP formation in platelets at 0.4 mM concentration ( p < 0.05). These findings suggested that possible mechanisms of lusianthridin on the antiplatelet effects might act via arachidonic acid-thromboxane and adenylate cyclase pathways.

Earlier we have shown that certain flavonoids (e.g., quercetin) are high-affinity reducing cosubstrates for cyclooxygenase (COX) 1 and 2. These compounds can bind inside the peroxidase active sites of COXs and donate an electron from one of their B-ring hydroxyl groups to hematin. Based on these earlier findings, it is postulated that some of the natural flavonoids such as galangin that are structural analogs of quercetin but lack the proper B-ring hydroxyl groups might function as novel inhibitors of COXs by blocking the effect of the reducing cosubstrates. This idea is tested in the present study. Computational docking analysis together with quantum chemistry calculation shows that galangin can bind inside the peroxidase active sites of COX-1 and COX-2 in a similar manner as quercetin, but it has little ability to effectively donate its electrons, thereby blocking the effect of the reducing cosubstrates like quercetin. Further experimental studies confirm that galangin can inhibit, both in vitro and in vivo, quercetin-mediated activation of the peroxidase activity of the COX-1/2 enzymes. The results of the present study demonstrate that galangin is a novel naturally-occurring inhibitor of COX-1 and COX-2, acting by blocking the function of the reducing cosubstrates at the peroxidase sites., (Copyright © 2021. Published by Elsevier B.V.)

Ethnopharmacological Relevance: The flower buds of Sophora japonica L. are a major traditional medicine in China, Japan, and Korea and are used to stop bleeding and 'cool the blood'. Accordingly, they are used to treat bleeding haemorrhoids, hypertension, and pyoderma. In addition, it was recently found that the flower buds of S. japonica (SJ) have cosmetic whitening properties., Materials and Methods: Compounds in SJ and their targets and related diseases were investigated using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and analysis platform. Target gene information was obtained from the UniProt database. Network construction was carried out using Cytoscape 3.72. Contact dermatitis (CD)-related gene searching was performed using the Cytoscape string App. Docking analysis was conducted using AutoDock Vina. Six-week-old Balb/c male mice with DNFB (1-fluoro-2,4-dinitrofluorobenzene)-induced CD were treated with a methanol extract of the flower buds of S. japonica (MESJ), and its effects on skin colour, lesions, and immune cell infiltration, and on histopathological abnormalities such as epidermal hyperplasia were investigated., Results: Eleven compounds targeted 13 CD-related genes, that is, serum albumin (ALB), prostaglandin G/H synthase (COX) 2, C-X-C motif chemokine (CXCL) 2, CXCL10, ICAM1, IFN-γ, IL-10, IL-1α, IL-1β, IL-2, IL-6, E-selectin, and TNF. In the murine DNFB model, MESJ significantly suppressed scaling, erythema, and skin thickening as compared with DNFB controls and epithelial hyperplasia and immune cell infiltrations induced by repeated DNFB application., Conclusions: Our animal study showed that the mode of action of MESJ was closely related to the prevention of epithelial hyperplasia and immune cell infiltration. The results obtained demonstrated that the flower buds of S. japonica offer a potential means of treating CD, and suggest that the therapeutic mechanism of CD is explained by relations between 11 major components of SJ, including kaempferol and quercetin, and 13 CD-related genes., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Saussurea laniceps Hand.-Mazz. (Compositae) is a representative "snow lotus" herb well known in Chinese folk medicine to treat inflammation-related diseases such as arthritis. S. laniceps (SL) shows anti-inflammatory and analgesic potencies and contains various constituents potentially with cyclooxygenase-2 (COX-2) selective inhibition. The herb is a valuable source of natural alternatives to synthetic COX-2 selective nonsteroidal anti-inflammatory drugs, a common medication for rheumatoid arthritis (RA) and osteoarthritis (OA) reported with serious cardiovascular side effects., Aim of the Study: Based on an innovative drug screening platform, this study aimed to discover safe, effective COX-2 selective inhibitors from SL., Materials and Methods: An enzyme-anchored nanomagnetic fishing assay was developed to separate COX-2 ligands from SL. Cell and animal models of cardiomyocytes, lipopolysaccharide-stimulated macrophages, rat adjuvant-induced arthritis, and anterior cruciate ligament transection-induced OA rats, were adopted to screen the single/combined ligands regarding toxicity and bioactivity levels. Molecular docking was employed to unravel binding mechanisms of the ligands towards COX-1 and COX-2., Results: Four COX-2 selective compounds were separated from SL using optimized COX-2-functionalized magnetic nanoparticles. All the four ligands were proved with evidently lower cardiotoxicity both in vitro and in vivo than celecoxib, a known COX-2 selective inhibitor. Two ligands, scopoletin and syringin, exhibited potent anti-arthritic activities in rat models of RA and OA by alleviating clinical statuses, immune responses, and joint pathological features; their optimum combination ratio was discovered with stronger remedial effects on rat OA than single administrations. The COX-1/2 binding modes of the two phytochemicals contributed to explain their cardiac safety and therapeutic performances., Conclusions: The screened chemicals are promising to be developed as COX-2 selective inhibitors as part of treating RA and OA. The hybrid strategy for discovering therapeutic agents from SL is shown here to be efficient; it should be equally valuable for finding other active chemicals in other natural sources., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Pulicaria incisa sub. candolleana E. Gamal-Eldin (Asteraceae) was traditionally used by Bedouins as a refreshing tea and as hypoglycemic, in gastrointestinal ailments, sinusitis and headache. Recently a great correlation has been established between liver cirrhosis and gastrointestinal dysfunction reflected by abdominal bloating, pain, diarrhea, constipation, besides decreased food intake. So far, the hepatoprotective effect of P. incisa sub. candolleana E. Gamal-Eldin was not studied before although other Pulicaria species have previously shown hepatoprotective and antioxidant effects., Aim of the Study: In this study, we aimed to identify the phytochemical constituents of the P. incisa sub. candolleana E. Gamal-Eldin hydroethanolic extract (PICE), as well as to evaluate the hepatoprotective, anti-inflammatory and antioxidant activities in methotrexate (MTX)- intoxicated rats. Besides, the molecular interaction between the isolated compounds and cyclooxygenase-2 (COX-2) and phospholipase 2 (PLA-2) were assessed by in-silico screening., Material and Methods: The main phytoconstituents were characterized using liquid chromatography-tandem mass spectrometry (LC-MS-MS). Vacuum liquid chromatography (VLC) aided by preparative high-performance liquid chromatography (HPLC) were also used to isolate the major phenolics from the hydroethanolic extract. Their structures were elucidated using different spectroscopic analysis methods, including 1D and 2D nuclear magnetic resonance (NMR) and electrospray ionization mass spectrometry (ESI/MS). The hepatoprotective activity of three doses (100, 250, 500 mg/kg) of PICE in MTX-intoxicated rats was assessed and compared to silymarin as a standard. Additionally, in silico docking study on cyclooxygenase-2 (COX-2) and phospholipase 2 (PLA-2) was performed to justify the anti-inflammatory activity of the isolated compounds., Results: Thirteen compounds were tentatively identified, including flavonoids and phenolic acids. Four main isolated compounds were identified as, eugenol-1-O-β-glucoside, 5-O-caffeoylquinic acid, 3, 5-di-O-caffeoylquinic acid and quercetin-3-O-β-glucoside. Treatment of MTX-intoxicated rats with the 250 mg/kg extract reversed the altered levels of biochemical markers of liver damage, ameliorated the oxidant status and reduced the inflammatory mediators, similar to treatment with silymarin. Quercetin-3-O-β-glucoside showed the best docking energy score of -19.12 kcal/mol against COX-2, forming four binding interactions with residues Leu 353, Arg 121, Tyr 356 and Ala 528, followed by 3,5-di-O-caffeoylquinic acid (-18.01 kcal/mol)., Conclusion: This study reveals P. incisa sub. candolleana as a rich source of phenolics including flavonoids, supporting its anti-inflammatory and hepatoprotective effects and suggesting its usage as a promising candidate in inflammatory conditions., (Copyright © 2020 Elsevier B.V. All rights reserved.)

An automatic methodology based on micro sequential injection analysis coupled to a lab-on-valve system (termed μSIA-LOV) was developed and used to determine the ability of metal-based anticancer compounds to inhibit cyclooxygenase 2 (COX-2) activity. COX-2 may be involved in pathogenesis of cancer and it is overexpressed in several types of solid tumors. Since platinum-based compounds are extensively used in the treatment of cancer, and ruthenium compounds are considered as promising candidates for next generation of non-targeted anticancer drugs, it is interesting to establish whether COX-2 inhibition is relevant to their mode of action. The μSIA-LOV system was optimized and the IC 50 values of each compound were calculated. All the results present RSD values less than 2.5%. IC 50 values of 9.7 ± 0.6 μM to 207 ± 3 μM were obtained, with the most active inhibitor for COX-2 being rofecoxib with the metal compounds exhibiting IC 50 values in the range 13.7 ± 1.6 to 207 ± 3. The results obtained in this work provide significant information about the mechanism of the studied compounds, mostly ruthenium-based compounds, and the role of COX-2 in their mode of action. Moreover, this work confirmed the potential of the μSIA-LOV system as a simple, versatile, robust, and rapid analytical tool for automating the determination of IC 50 values of metal-based compounds., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The aim of the present study was to determine the impact of Saskatoon powder addition on phytochemical parameters, biological activity, and nutritional value of wheat bread. Supplementation increased phenolics content up to 72% in the bread with 6% powder content. This increase was reflected in the improved antioxidative properties of breads, especially after their supplementation with the microencapsulated additives (an increase by 93% in the bread enriched with 6% of powder covered with maltodextrin). The in vitro digestion released the antioxidative compounds, leading to higher bioaccessibility of the breads enriched with the microencapsulated powders. The highest inhibition of activities of cyclooxygenase 1 and -2, as well as amylase and glucosidase was recorded for the breads enriched with the additive microencapsulated with maltodextrin and inulin. Thus, Saskatoon berry powders, especially the microencapsulated ones, may be used as functional components in designing innovative bakery products., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The fabrication, characterization of butyl methyl imidazolium silica sulfate [BMIm]SS as a novel nano hybrid catalyst and its application in synthesis of new ibuprofen (IBP) 1,2-diol mono esters were described. [BMIm]SS catalyzed the reaction of IBP with epoxides to afford the new IBP 1,2-diol mono esters in good to excellent yields. The products were tested in vivo for the analgesic properties on female mice using formalin test. The test results revealed that most compounds, in particular compounds 1h, 1k and 1o displayed potent analgesic activity compare to IBP as a reference drug. No mortality was observed due to the toxicity of the synthesized compounds. The docking analysis was conducted that confirmed the strong binding affinity of active compounds to active site of murine cyclooxygenase-2 (COX-2) enzyme compare to IBP. The in silico pharmacokinetic profile, drug likeness and toxicity predictions were carried out for all compounds which determined that 1h can be suggested as an appropriate future drug candidate., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Two novel series derived from nicotinic acid were synthesized and evaluated for their inhibitory activity against cyclooxygenases COX-1 and COX-2, and their selectivity indices were determined. Celecoxib, diclofenac and indomethacin were used as reference drugs. All compounds showed highly potent COX-2 inhibitory activity and higher selectivity towards COX-2 inhibition compared to indomethacin. In addition, these compounds except 3a showed clear preferential COX-2 over COX-1 inhibition compared to diclofenac. Compounds 3b, 3e, 4c and 4f showed COX-2 inhibitory activity equipotent to celecoxib. Compounds 4c and 4f demonstrated selectivity indices 1.8-1.9 fold higher than celecoxib. These two most potent and COX-2 selective compounds were further tested in vivo for anti-inflammatory activity by means of carrageenan induced rat paw edema method. Ulcerogenic activity with histopathological studies were performed. The results showed no ulceration, which implies their safe gastric profile. Compound 4f exhibited the most potent in vivo anti-inflammatory activity comparable to all reference drugs. Further, compounds 4c and 4f were investigated for their influence on certain inflammatory cytokines TNF-α and IL-1β in addition to PEG2. The findings revealed that these candidates could be identified as promising potent anti-inflammatory agents. Molecular docking of 4c and 4f in the COX-2 active site was performed to rationalize their COX-2 inhibitory potency. The results were found to be in line with the biological findings as they exerted more favorable interactions compared to that of celecoxib, explaining their remarkable COX-2 inhibitory activity., (Copyright © 2021 Elsevier Inc. All rights reserved.)