Potent Cyclooxygenase-2 Inhibitors Research Articles

Synthesis, Characterization, DFT, and In Silico Investigation of Two Newly Synthesized β-Diketone Derivatives as Potent COX-2 Inhibitors.

Despite extensive genetic and biochemical characterization, the molecular genetic basis underlying the biosynthesis of β-diketones remains largely unexplored. β-Diketones and their complexes find broad applications as biologically active compounds. In this study, in silico molecular docking results revealed that two β-diketone derivatives, namely 2-(2-(4-fluorophenyl)hydrazono)-5,5-dimethylcyclohexane-1,3-dione and 5,5-dimethyl-2-(2-(2-(trifluoromethyl)phenyl)hydrazono)cyclohexane-1,3-dione, exhibit anti-COX-2 activities. However, recent docking results indicated that the relative anti-COX-2 activity of these two studied β-diketones was influenced by the employed docking programs. For improved design of COX-2 inhibitors from β-diketones, we conducted molecular dynamics simulations, density functional theory (DFT) calculations, Hirshfeld surface analysis, energy framework, and ADMET studies. The goal was to understand the interaction mechanisms and evaluate the inhibitory characteristics. The results indicate that 5,5-dimethyl-2-(2-(2-(trifluoromethyl)phenyl)hydrazono)cyclohexane-1,3-dione shows greater anti-COX-2 activity compared to 2-(2-(4-fluorophenyl)hydrazono)-5,5-dimethylcyclohexane-1,3-dione.

Phytochemical profiling, in vitro analysis for anti-inflammatory, immunomodulatory activities, structural elucidation and in silico evaluation of potential selective COX-2 and TNF-α inhibitor from Hydrilla verticillata (L.f.) Royle

Hydrilla verticillata (L.f.) Royle is a perennial aquatic plant, which exhibits nutritional as well as therapeutic properties. The present study has been carried out to evaluate anti-inflammatory and immunomodulatory activities along with in silico evaluation of potential selective COX-2 and TNF-α inhibitors from methanolic extract of H. verticillata (L.f.) Royle. The potential therapeutic compounds have been identified by high-resolution GC-MS analysis. Its capacity to inhibit inflammatory responses using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells has been explored. The anti-inflammatory properties of the plant extract were investigated by inhibiting inducible nitric oxide (NO) synthase and reduced NO generation driven by LPS on stimulated RAW 264.7 macrophage cells. Further investigation for the underlying molecular mechanism of the anti-inflammatory activity of plant extract has been carried out by molecular docking and molecular dynamics simulation approaches with COX-2 and TNF-α inhibitors ability against the most potent phytocompound phytol from the plant extract. To evaluate whether the extract causes any toxicity, the cytotoxicity test has been carried out with the Human embryonic kidney cell line (Hek-293), Mouse fibroblast (L929), human mesenchyme stem cells (hMSCs) and human breast epithelial cell line (MCF-10a). Ultimately, our findings suggest that the plant extract have great potential to reduce inflammation without causing any toxicity to normal cell. Communicated by Ramaswamy H. Sarma

Water dynamics on the structural properties of some NSAID’s with leucine in the picosecond region using time domain spectroscopy

Concentration-dependent dielectric response for non-steroidal anti-inflammatory drugs (NSAIDs): Aceclofenac (ACF) and Diclofenac (DCF) in the aqueous leucine solution have been reported at different concentrations and temperatures (298.15 K to 283.15 K). The time domain reflectometry technique in the frequency region of 1 GHz to 30 GHz was used for the present study. Complex permittivity (ε*), static dielectric constant (ε), dielectric relaxation time (τ), dipole moment (μ) and Kirkwood correlation factor (g) have been calculated and discussed in terms of the molecular interaction of water and the used drugs. To give more insights into the structural dynamics of drug-induced amino acids, the study includes molar enthalpy of activation (ΔH), entropy of activation (ΔS), and free energy of activation (ΔF). The overall study concludes that the drug (DCF) having a potent inhibitor of cyclooxygenase found a higher static dielectric constant (ε0) than that of the drug (ACF) having more carbon (C), hydrogen (H), and oxygen (O) in the chain, which is more efficient in controlling pain. Communicated by Ramaswamy H. Sarma

Discovering the Active Ingredients of Medicine and Food Homologous Substances for Inhibiting the Cyclooxygenase-2 Metabolic Pathway by Machine Learning Algorithms.

Cyclooxygenase-2 (COX-2) and microsomal prostaglandin E2 synthase (mPGES-1) are two key targets in anti-inflammatory therapy. Medicine and food homology (MFH) substances have both edible and medicinal properties, providing a valuable resource for the development of novel, safe, and efficient COX-2 and mPGES-1 inhibitors. In this study, we collected active ingredients from 503 MFH substances and constructed the first comprehensive MFH database containing 27,319 molecules. Subsequently, we performed Murcko scaffold analysis and K-means clustering to deeply analyze the composition of the constructed database and evaluate its structural diversity. Furthermore, we employed four supervised machine learning algorithms, including support vector machine (SVM), random forest (RF), deep neural networks (DNNs), and eXtreme Gradient Boosting (XGBoost), as well as ensemble learning, to establish 640 classification models and 160 regression models for COX-2 and mPGES-1 inhibitors. Among them, ModelA_ensemble_RF_1 emerged as the optimal classification model for COX-2 inhibitors, achieving predicted Matthews correlation coefficient (MCC) values of 0.802 and 0.603 on the test set and external validation set, respectively. ModelC_RDKIT_SVM_2 was identified as the best regression model based on COX-2 inhibitors, with root mean squared error (RMSE) values of 0.419 and 0.513 on the test set and external validation set, respectively. ModelD_ECFP_SVM_4 stood out as the top classification model for mPGES-1 inhibitors, attaining MCC values of 0.832 and 0.584 on the test set and external validation set, respectively. The optimal regression model for mPGES-1 inhibitors, ModelF_3D_SVM_1, exhibited predictive RMSE values of 0.253 and 0.35 on the test set and external validation set, respectively. Finally, we proposed a ligand-based cascade virtual screening strategy, which integrated the well-performing supervised machine learning models with unsupervised learning: the self-organized map (SOM) and molecular scaffold analysis. Using this virtual screening workflow, we discovered 10 potential COX-2 inhibitors and 15 potential mPGES-1 inhibitors from the MFH database. We further verified candidates by molecular docking, investigated the interaction of the candidate molecules upon binding to COX-2 or mPGES-1. The constructed comprehensive MFH database has laid a solid foundation for the further research and utilization of the MFH substances. The series of well-performing machine learning models can be employed to predict the COX-2 and mPGES-1 inhibitory capabilities of unknown compounds, thereby aiding in the discovery of anti-inflammatory medications. The COX-2 and mPGES-1 potential inhibitor molecules identified through the cascade virtual screening approach provide insights and references for the design of highly effective and safe novel anti-inflammatory drugs.

Triazole tethered organosilane based fluorescent sensor as a logic gate operation for selective detection of Sn2+ ions: A potent Cyclooxygenase-2 inhibitor

In recent years, the development of a probe for tin ions has gained significant attention due to their relevance in environmental, industrial, and biological contexts. To address this, an imidazole-based fluorescent sensor called BO was designed and synthesized using the click methodology. The characterization of BO was carried out using NMR spectroscopy and mass spectrometry techniques. The fluorescence of BO exhibits remarkable selectivity and sensitivity towards Sn2+ ions, even in the presence of other metal ions. This increase in fluorescence is attributed to the suppression of the PET process upon interaction with Sn2+ ions. Notably, the detection limits for Sn2+ ions using BO in this study are much lower than the drinking water recommendations set by the WHO. Furthermore, it was observed that compound BO displays reversible behaviour towards Sn2+ ions through the formation of the sodium salt of CH3COO–, suggesting its potential application in the construction of a molecular logic gate. Additionally, molecular docking experiments with the Cyclooxygenase-2 (COX-2) protein provided further insights into the potential of BO in this regard.

Chondroitin Sulphate-Chitosan polyelectrolyte complexes for etorocoxib transdermal delivery: in silico, in vitro and in vivo studies

Rheumatoid arthritis (RA) is a chronic autoimmune disease which affects around 1% globally leading to joint inflammation and disability. Etorocoxib (ETR) is a potent COX-2 inhibitor traditionally used orally to alleviate RA induced inflammation, yet it causes hepatic side effects on prolonged use. This study aims for in silico optimization of ETR polyelectrolyte complex (PEC) utilizing chondroitin sulphate (CS) and chitosan (CH) for transdermal delivery to RA-inflamed joints with a synergistic anti-inflammatory action owing to CS. An artificial neural network (ANN) combined with 22 factorial design was used to optimize the PEC formula according to particle size (PS) and entrapment efficiency (%EE) by varying CS and CH concentrations. The optimum ETR PEC was incorporated in a gel and examined for its in vitro release, ex vivo permeation, in vivo inflammatory biomarkers, and histopathological evaluation in rats. The optimized formula (F3) with 0.1 CH% w/w and 0.5 CS %w/w showed a PS of 214.98 ± 17.24 nm, %EE 75.31 ± 1.67%, and enhanced in vitro release profile, ex vivo permeation and in vivo anti-inflammatory effect compared to ETR gel via suppressing the expression of IL-6, TNF-α, and TGF-β pro-inflammatory cytokines as well as the additional anti-inflammatory effect of CS. In conclusion, ETR-PEC gel holds promise as transdermal therapy for managing RA-induced inflammation.

Synthesis, Biological, Spectroscopic and Computational Investigations of Novel N-Acylhydrazone Derivatives of Pyrrolo[3,4-d]pyridazinone as Dual COX/LOX Inhibitors.

Secure and efficient treatment of diverse pain and inflammatory disorders is continually challenging. Although NSAIDs and other painkillers are well-known and commonly available, they are sometimes insufficient and can cause dangerous adverse effects. As yet reported, derivatives of pyrrolo[3,4-d]pyridazinone are potent COX-2 inhibitors with a COX-2/COX-1 selectivity index better than meloxicam. Considering that N-acylhydrazone (NAH) moiety is a privileged structure occurring in many promising drug candidates, we decided to introduce this pharmacophore into new series of pyrrolo[3,4-d]pyridazinone derivatives. The current paper presents the synthesis and in vitro, spectroscopic, and in silico studies evaluating the biological and physicochemical properties of NAH derivatives of pyrrolo[3,4-d]pyridazinone. Novel compounds 5a-c-7a-c were received with high purity and good yields and did not show cytotoxicity in the MTT assay. Their COX-1, COX-2, and 15-LOX inhibitory activities were estimated using enzymatic tests and molecular docking studies. The title N-acylhydrazones appeared to be promising dual COX/LOX inhibitors. Moreover, spectroscopic and computational methods revealed that new compounds form stable complexes with the most abundant plasma proteins-AAG and HSA, but do not destabilize their secondary structure. Additionally, predicted pharmacokinetic and drug-likeness properties of investigated molecules suggest their potentially good membrane permeability and satisfactory bioavailability.

Protective Effects of Long-Term Usage of Cyclo-Oxygenase-2 Inhibitors on Colorectal Cancer in Genetically Predisposed Individuals and Their Overall Effect on Prognosis: A Systematic Review.

Colorectal cancer (CRC) is a major global health concern, accounting for significant cancer-related morbidity and mortality worldwide. Despite advancements in early detection and treatment modalities, the prevention of CRC remains a critical goal. Cyclo-oxygenase-2 (COX-2) is an inducible enzyme involved in the production of pro-inflammatory prostaglandins, which play a crucial role in various cellular processes, including inflammation, cell proliferation, apoptosis, and angiogenesis. Elevated COX-2 expression has been consistently observed in colorectal tumors, indicating their role in the pathogenesis of cancer. COX-2 inhibitors, such as celecoxib and rofecoxib, have been studied as potentiallyeffective treatment modalities due to their ability to decrease prostaglandin levels, which are generally higher in cancer patients.Aberrant prostaglandin production is linked to the adenoma-carcinoma sequence, during which adenomas turn dysplastic and accumulate enough damage to become malignant. COX-2 inhibitors have also been shown to modulate various signaling pathways involved in CRC development, such as wingless-related integration site/β-catenin (Wnt/β-catenin), mitogen-activated protein kinase (MAPK), and phosphoinositide-3-kinase-protein kinase B/Akt (PI3K/Akt) pathways. This systematic review aimed to evaluate the protective effects of long-term usage of COX-2 inhibitors on CRC in genetically predisposed individuals and their overall effect on the prognosis of the disease. The researchers conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines and collected data from several databases, including PubMed, PubMed Central, Cochrane Library, and Web of Science. The search strategy combined keywords related to CRC, COX-2 inhibitors, protective effects, and prognosis. They identified 1189 articles and shortlisted 26 full-text articles that met the eligibility criteria. Quality assessment tools, such as the Assessment of Multiple Systematic Review (AMSTAR) for systematic reviews, the Cochrane bias assessment tool for randomized control trials, the scale for the assessment of narrative review articles(SANRA) checklist for narrative reviews, and the Joanna Briggs Institute (JBI) tool for cross-sectional studies and case reports, are used. This review's conclusions will assist in determining the effectiveness of COX-2 inhibitors to prevent CRC. This review may also contribute to developing guidelines for clinicians to manage genetically predisposed individuals with CRC. Furthermore, the results of this review will shed light on the potential of COX-2 inhibitors as a preventive measure against CRC in genetically predisposed individuals.

In silico screening, synthesis, characterization and biological evaluation of novel anticancer agents as potential COX-2 inhibitors.

Cyclooxygenase enzyme is frequently overexpressed in various types of cancer and found to play a crucial role in poor prognosis in cancer patients. In current research, we have reported the new COX-2 inhibitors for cancer treatment using computer-aided drug design and experimental validation. A total of 12,795 compounds from the different databases were used to screen against the COX-2 enzyme. It perceived three new compounds with better binding affinity to the enzyme. Afterwards, physicochemical properties and in silico bioactivity were assessed for efficacy, safety, and structural features required for binding. The molecules were synthesized and confirmed by spectroscopic techniques. Later on, molecules were evaluated for their anti-cancer activity using MCF-7, MDA-MB-231 and SiHa cancer cell lines. Compound ZINC5921547 and ZINC48442590 (4a, and 4b) reduced the MCF-7, MDA-MB-231, and SiHa cells proliferation potently than parent compounds. The PG-E2 estimation shown, both compounds act through the COX-2 PGE2 axis. Compound 4a and 4b block the cell cycle at G1-S phase and induce cancer cell death. We concluded that compounds 4a and 4b effectively promotes cancer cell death via COX-2 PGE2 axis, and further in vivo studies can be evaluated for development in both compounds as anticancer agents. The compilation of this information will help us to generate better outcome through robust computational methods. The high-quality experimental results may pave the way for identifying effective drug candidates for cancer treatment.

Synthesis of New Compounds Bearing Methyl Sulfonyl Pharmacophore As Selective COX-2 Inhibitor.

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 investigated. The encoded compounds 5a, 5b, and 5c were found to be the most potent compared to the reference compounds ibuprofen (IC50 =5.589±0.278 μM), celecoxib (IC50 =0.132±0.004 μM), and nimesulide (IC50 =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 IC50 value of 0.180 ± 0.002 μM The most potent COXs inhibitor was 5a, which further investigated for its potential binding mode by molecular docking study. Compound 5a found to be localized at the active site of the enzyme, like celecoxib, which has a remarkable effect on COXs enzymes. This article is protected by copyright. All rights reserved.

Molecular Docking Analysis for Screening of Cyclooxygenase-2 Inhibitors from Secondary Metabolite Compounds of Lactococcus lactis subsp. lactis (Lac3)

Inflammatory response plays important roles in both tumorigenesis and carcinogenesis. In this study, secondary metabolite compounds from Lactococcus lactis subsp. lactis (Lac3) were analyzed by LC-MS and the potential inhibition activity against the COX-2 receptor was screened through molecular docking and molecular dynamics (MD) analysis. Anti-inflammatory agents, mofezolac and ibuprofen, were used as positive control ligands. The result indicates a potential COX-2 inhibitor of 5-[(4-Amino-6-morpholin-4-yl-1,3,5-triazin-2-yl)amino]-2- methylbenzenesulfonate, which has a hydrogen bond on the active site Tyr385 of COX-2 with affinity energy of –9.0 kcal/mol. Moreover, another candidate of COX-2 inhibitor, designated as 3-Indolepropionic acid binds hydrogen on the important residue Ser530 of COX-2, with an affinity energy of –6.9 kcal/mol. To confirm the binding specificity, molecular docking analysis was also performed against COX-1. The binding stability and flexibility were confirmed using MD simulations. In addition, the toxicity and solubility of the potential ligands were predicted according to Lipinski’s rules and BOILED-Egg modeling. The 5-[(4-Amino-6-morpholin-4-yl- 1,3,5-triazin-2-yl)amino]-2-methylbenzenesulfonate shows the propensity for passive absorption through the gastrointestinal tract, whereas 3-Indolepropionic acid shows a high probability of blood-brain barrier penetration. In conclusion, this study identified potential compounds through molecular docking analysis which can be developed as COX-2 inhibitors.

Discovery of andrographolide hit analog as a potent cyclooxygenase-2 inhibitor through consensus MD-simulation, electrostatic potential energy simulation and ligand efficiency metrics

Cyclooxygenase-2 (COX-2) is the key enzyme responsible for the conversion of arachidonic acid to prostaglandins that display pro-inflammatory properties and thus, it is a potential target protein to develop anti-inflammatory drugs. In this study, chemical and bio-informatics approaches have been employed to find a novel potent andrographolide (AGP) analog as a COX-2 inhibitor having better pharmacological properties than aspirin and rofecoxib (controls). The full amino acid sequenced human Alpha fold (AF) COX-2 protein (604AA) was selected and validated for its accuracy against the reported COX-2 protein structures (PDB ID: 5F19, 5KIR, 5F1A, 5IKQ and 1V0X) followed by multiple sequence alignment analysis to establish the sequence conservation. The systematic virtual screening of 237 AGP analogs against AF-COX-2 protein yielded 22 lead compounds based on the binding energy score (< − 8.0 kcal/mol). These were further screened out to 7 analogs by molecular docking analysis and investigated further for ADMET prediction, ligand efficiency metrics calculations, quantum mechanical analysis, MD simulation, electrostatic potential energy (EPE) docking simulation, and MM/GBSA. In-depth analysis revealed that AGP analog A3 (3-[2-[(1R,4aR,5R,6R,8aR)-6-hydroxy-5,6,8a-trimethyl-2-methylidene-3,4,4a,5,7,8-hexahydro-1H-naphthalen-1-yl]ethylidene]-4-hydroxyoxolan-2-one) forms the most stable complex with the AF-COX-2 showing the least RMSD value (0.37 ± 0.03 nm), a good number of hydrogen bonds (protein–ligand H-bond = 11, and protein H-bond = 525), minimum EPE score (− 53.81 kcal/mol), and lowest MM-GBSA before and after simulation (− 55.37 and − 56.25 kcal/mol, respectively) value compared to other analogs and controls. Thus, we suggest that the identified A3 AGP analog could be developed as a promising plant-based anti-inflammatory drug by inhibiting COX-2.

In Vitro and In Silico Investigation of Polyacetylenes from Launaea capitata (Spreng.) Dandy as Potential COX-2, 5-LOX, and BchE Inhibitors.

Diverse secondary metabolites are biosynthesized by plants via various enzymatic cascades. These have the capacity to interact with various human receptors, particularly enzymes implicated in the etiology of several diseases. The n-hexane fraction of the whole plant extract of the wild edible plant, Launaea capitata (Spreng.) Dandy was purified by column chromatography. Five polyacetylene derivatives were identified, including (3S,8E)-deca-8-en-4,6-diyne-1,3-diol (1A), (3S)-deca-4,6,8-triyne-1,3-diol (1B), (3S)-(6E,12E)-tetradecadiene-8,10-diyne-1,3-diol (2), bidensyneoside (3), and (3S)-(6E,12E)-tetradecadiene-8,10-diyne-1-ol-3-O-β-D-glucopyranoside (4). These compounds were investigated for their in vitro inhibitory activity against enzymes involved in neuroinflammatory disorders, including cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), and butyrylcholinesterase (BchE) enzymes. All isolates recorded weak-moderate activities against COX-2. However, the polyacetylene glycoside (4) showed dual inhibition against BchE (IC50 14.77 ± 1.55 μM) and 5-LOX (IC50 34.59 ± 4.26 μM). Molecular docking experiments were conducted to explain these results, which showed that compound 4 exhibited greater binding affinity to 5-LOX (-8.132 kcal/mol) compared to the cocrystallized ligand (-6.218 kcal/mol). Similarly, 4 showed a good binding affinity to BchE (-7.305 kcal/mol), which was comparable to the cocrystallized ligand (-8.049 kcal/mol). Simultaneous docking was used to study the combinatorial affinity of the unresolved mixture 1A/1B to the active sites of the tested enzymes. Generally, the individual molecules showed lower docking scores against all the investigated targets compared to their combination, which was consistent with the in vitro results. This study demonstrated that the presence of a sugar moiety (in 3 and 4) resulted in dual inhibition of 5-LOX and BchE enzymes compared to their free polyacetylenes analogs. Thus, polyacetylene glycosides could be suggested as potential leads for developing new inhibitors against the enzymes involved in neuroinflammation.

Synthesis, Evaluation of Enzyme Inhibition and Redox Properties of Potential Dual COX-2 and 5-LOX Inhibitors.

Various dual inhibitors of COX-2 and 5-LOX enzymes have been developed so far in order to obtain more effective and safer anti-inflammatory drugs. The aim of this study was to design and synthesize new dual COX-2 and 5-LOX inhibitors, and to evaluate their enzyme inhibition potential and redox properties. Thirteen compounds (1-13) were designed taking into account structural requirements for dual COX-2 and 5-LOX inhibition and antioxidant activity, synthesized, and structurally characterized. These compounds can be classified as N-hydroxyurea derivatives (1, 2 and 3), 3,5-di-tert-butylphenol derivatives (4, 5, 6, 7 and 13), urea derivatives (8, 9 and 10) and "type B hydroxamic acids" (11 and 12). COX-1, COX-2 and 5-LOX inhibitory activities were evaluated using fluorometric inhibitor screening kits. The evaluation of the redox activity of newly synthesized compounds was performed in vitro in the human serum pool using redox status tests. The prooxidative score, the antioxidative score and the oxy-score were calculated. Seven out of thirteen synthesized compounds (1, 2, 3, 5, 6, 11 and 12) proved to be dual COX-2 and 5-LOX inhibitors. These compounds expressed good COX-2/COX-1 selectivity. Moreover, dual inhibitors 1, 3, 5, 11 and 12 showed good antioxidant properties.

Design, synthesis, and biological evaluation of new 2-(4-(methylsulfonyl)phenyl)-N-phenylimidazo[1,2-a]pyridin-3-amine as selective COX-2 inhibitors.

Cyclooxygenase (COX), which plays a role in converting arachidonic acid to inflammatory mediators, could be inhibited by non-steroidal anti-inflammatory drugs (NSAIDs). Although potent NSAIDs are available for the treatment of pain, fever, and inflammation, some side effects, such as gastrointestinal ulcers, limit the use of these medications. In recent years, selective COX-2 inhibitors with a lower incidence of adverse effects attained an important position in medicinal chemistry. In order to introduce some new potent COX-2 inhibitors, a new series of 2-(4-(methylsulfonyl)phenyl)-N-phenylimidazo[1,2-a]pyridin-3-amines was designed, synthesized, and evaluated. The docking studies performed by AutoDock Vina demonstrated that docked molecules were positioned as well as a crystallographic ligand in the COX-2 active site, and SO2Me pharmacophore was inserted into the secondary pocket of COX-2 and formed hydrogen bonds with the active site. The designed compounds were synthesized through two-step reactions. In the first step, different 1-(4-(methylsulfonyl)phenyl)-2-(phenylamino)ethan-1-one derivatives were obtained by the reaction of aniline derivatives and α-bromo-4-(methylsulfonyl)acetophenone. Then, condensation of intermediates with different 2-aminopyridines gave final compounds. Enzyme inhibition assay and formalin test were performed to evaluate the activity of these compounds. Among these compounds, 8-methyl-2-(4-(methylsulfonyl)phenyl)-N-(p-tolyl)imidazo[1,2-a]pyridin-3-amine (5n) exhibited the highest potency (IC50 = 0.07 µM) and selectivity (selectivity index = 508.6) against COX-2 enzyme (selectivity index: COX-1 IC50/COX-2 IC50). The antinociceptive activity assessment via the formalin test showed that nine derivatives (5a, 5d, 5h, 5i, 5k, 5q, 5r, 5s, and 5t) possessed significant activity compared with the control group with a p value less than 0.05.

New NSAID Conjugates as Potent and Selective COX-2 Inhibitors: Synthesis, Molecular Modeling and Biological Investigation.

New sets of ibuprofen and indomethacin conjugates comprising triazolyl heterocycle were synthesized via click chemistry, adopting an optimized protocol through the molecular hybridization approach affording the targeted agents in good yields. The new non-steroidal anti-inflammatory drug (NSAID) conjugates were designed and synthesized and could be considered as potential drug candidates for the treatment of pain and inflammation. The anti-inflammatory properties were investigated for all the synthesized conjugates. Among 14 synthesized conjugates, four (5a, 5b, 5d, and 5e) were found to have significant anti-inflammatory properties potency 117.6%, 116.5%, 93.8%, and 109.1% in comparison to reference drugs ibuprofen (97.2%) and indomethacin (100%) in the rat paw edema carrageenan test without any ulcerogenic liability. The suppression effect of cytokines IL-6, TNF-α, and iNOS in addition to NO in the LPS-induced RAW264.7 cells supports the promising anti-inflammatory properties observed in the ibuprofen conjugates. In addition, several conjugates showed promising peripheral and central analgesic activity. The selectivity index (SI) of compound 5a (23.096) indicates the significant efficacy and selectivity for COX-2 over COX-1. Molecular modeling (docking and QSAR) studies described the observed biological properties.

Green synthesis of ferrocenyl chalcones against triple negative breast cancer

Without using any solvents, a green and highly efficient protocol for the preparation of ferrocenyl chalcones has been achieved by grinding between acetylferrocene and aldehyde. In addition, their in vitro antiproliferative activity against two breast cancer cell lines MCF-7 (estrogen receptor-positive) and MDA-MB-231 (triple negative breast cancer, TNBC) was also evaluated. Most of them exhibited excellent antiproliferative activity against MDA-MB-231 cells. The structure-activity relationship (SAR) study indicated that the aldehydes unit of ferrocenyl chalcones with halogens or dimethyl substitutions were favorable for anti-TNBC activity. Among them, compound 1d (IC50 = 2.4 ± 0.1 µM) exhibited the best anti-tumor effect on MDA-MB-231 cells. An enzymatic assay indicated that compound 1d (IC50 = 2.4 µM) was a potent COX-2 inhibitor. Molecular docking suggested 1d adopted an optimal binding pose in the COX-2 active-site pocket, and the carbonyl group of 1d formed the key hydrogen bond with the Y355 residue of COX-2

Abortitristoside A and desrhamnosylverbanscoside: the potential COX-2 inhibitor from the leaves of Nyctanthes arbor-tristis as anti-inflammatory agents based on the in vitro assay, molecular docking and ADMET prediction

The plant Nyctanthes arbor-tristis belongs to the genus Nyctanthes (Oleaceae family) which is used in the treatment of many diseases like diabetes, cancer, inflammation, intestinal problem and tuberculosis in many countries of Asia. In this analysis, we have investigated the anti-inflammatory activity of various extracts of leaves of Nyctanthes arbor-tristis by the in vitro method as the cyclooxygenase inhibitory potential. The reported phytochemical constituent of the plant was in silico screened to find the cyclooxygenase inhibitory potential by molecular docking method. The molecular docking study of pre-isolated phytochemicals from the leaves of plants shows that compounds possess a great inhibition potential against COX-1 and COX-2 therefore, an in vitro comparative study is required to conclude the selective and potential COX-2 inhibitor for the development of new anti-inflammatory drug without causing any gastrointestinal ulcer. Here, we deliver a new strategy to design a selective COX-2 inhibitor from the plant origin natural compound by using molecular docking technique and in vitro screening of plant extract. In the other part of the paper, abortitristoside A (1) and abortitristoside B (2) were isolated from the leaves part of the plant. The isolated compound possesses good activity against COX-2 and COX-1 (IC50 value 7.91–8.00 μM against COX-2) which is also established by structure–activity relationship analysis.

Computational Screening for Finding New Potent COX-2 Inhibitors as Anticancer Agents

Background: Breast cancer ranks first in women and the second most common type of cancer overall. It is the most important barrier to the rise of life expectancy, globally affecting disease modalities. Cyclooxygenase-2 (COX-2) has become a prominent hallmark as inhibition target for breast cancer, and this therapeutic target for anti-inflammatory drugs regulates cell proliferation, angiogenesis, tumor growth and apoptosis. There is a need to explore new anti-cancerous drugs for searching the best possible hit candidates for cancer treatment. The computer-aided drug design approach was conducted to discover the new alternative COX-2 inhibitors. Objective: The research framework of this study is to identify new potent inhibitors for the COX-2 using computer-aided drug design. Methods: In the present investigation, an in-silico approach was used to screen with the best established three biological databases (Zinc15, ChemSpider and BindingDB) and docked against the COX-2 protein structure (PDB ID: 5IKR). Molecular docking was carried out using the Schrodinger Maestro suite. The compounds were filtered out based on their physicochemical, ADMET, and other drug-like properties. Several computational approaches such as molecular docking, binding free energy calculation, ADMET analysis, protein-ligand interaction and MD simulation were performed to determine the suitability of correct ligands for selected COX-2 target. Results: The two ligands showed relatively better binding affinities (-10.028 kcal/mol for compound A and -10.007 kcal/mol for ZINC000048442590) than the standard (-9.751 kcal/mol). These compounds followed Lipinski’s rule and drug-likeness index, which exhibited a good predicted therapeutic druggability profile. The interaction of the protein-ligand complex correlates with the COX-2. The MD simulation of the protein-ligand complex showed good stability in the time period of 10ns. Conclusion: It is the first study in which two new compounds ZINC000048442590 and compound A were found to be highly promising and have active potential in inhibiting cyclooxygenase-2 enzyme and could be effective as the potential drug candidates for breast cancer against COX-2 protein. Hopefully, in the future, these compounds as anti-inflammatory drug molecules could be used as new templates for the development of anticancer agents.

Design, Synthesis, Docking Studies, Enzyme Inhibitory and Antiplatelet Aggregation Activities of New 1,3-Diphenyl-3-(Phenylthio)Propan-1-One Derivatives as Selective COX-2 Inhibitors.

Cancer is the second leading cause of death worldwide after heart disease. A vast number of studies indicated that selective cyclooxygenase-2 (COX-2) inhibitors could be chemopreventive against different types of cancer because the expression of COX-2 is increased. Therefore, to develop new therapeutics for cancer, the design and synthesis of new COX-2 inhibitors with few side effects seem attractive as anti-cancer agents. Some of the well-known drugs that have been widely used for some time have been removed from the market due to the cardiac side effects they cause, so there is a need to introduce a scaffold that can inhibit COX-2 with high potency and low side effects. This study aimed to introduce a new COX-2 inhibitor structure. A new series of β-aryl-β-mercapto ketones possessing a methylsulfonyl pharmacophore was synthesized and evaluated as selective COX-2 inhibitors. In-vitro COX-1 and COX-2 inhibition effects of these compounds were evaluated, and molecular modeling was examined. Also, the antiplatelet aggregation activity of the synthesized compounds was tested. In-vitro COX-1 and COX-2 inhibition assays indicated that almost all newly synthesized compounds showed selectivity for COX-2 with IC50 values in the 0.07-0.22 μM range and COX-2 selectivity indexes in the 170 to 703.7 range. Among the tested compounds 1-(4-(methylsulfonyl)phenyl)-3-phenyl-3-(phenylthio)propan-1-one (4a), 3-(3,4- dimethoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-3-(phenylthio)propan-1-one (4g) and 3-(4-fluorophenyl)-1-(4-(methyl sulfonyl)phenyl)-3-(phenylthio)propan-1-one (4h) were the most potent COX-2 inhibitors and 3-(3,4- dimethoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-3-(phenylthio)propan-1-one had the highest selectivity index for COX-2 enzyme inhibitory activity. The Anti-platelet aggregation activity results indicated that the compound 1-(4- (methylsulfonyl)phenyl)-3-(phenylthio)-3-(p-tolyl)propan-1-one (4b) possesses the strong anti-platelet activity. Our molecular modeling studies also indicated that the methylsulfonyl pharmacophore group is placed into the adjunct pocket in the COX-2 active site and forms hydrogen bond interactions with NH of Arg513 and NH of His90. In brief, all designed and synthesized compounds showed moderate to good COX-2 inhibitory effects and showed good anti-platelet activity. Therefore, these compounds have the potential for further research into developing anti-cancer agents.