Selective Cyclooxygenase-2 Inhibitor Research Articles

Hybrids of selective COX-2 inhibitors and active derivatives of edaravone as COX-2 selective NSAIDs with free radical scavenging activity: Design, synthesis and biological activities

Novel hybrids of selective COX-2 inhibitors (coxibs) and active derivatives of free radical scavenger edaravone were designed to overcome the risk of cardiovascular events and stroke increased by NSAIDs (nonsteroidal anti-inflammatory drugs) in this study. All the hybrids were assayed for the COX-2 inhibitory and DPPH (2, 2-diphenyl-1-picrylhydrazyl) free radical scavenging activities in vitro. Finally, we found a series of hybrids with good inhibitory activity and selectivity of COX-2 and excellent free radical scavenging activity in vitro. The most promising compound 6a (WYZ90) exhibited very potent COX-2 inhibitory activity (COX-2, IC50 = 75 nM), weak COX-1 inhibitory activity (COX-1, IC50 = 5734 nM), better free radical scavenging activity (DPPH, IC50 = 19.9 μM) than edaravone, moderate drug-likeness and ADME properties in silico, acceptable pharmacokinetic properties (T1/2 = 4.16 h, 10 mg/kg, o.p.) and oral bioavailability (F% = 36.03 %) in mice. In addition, compound WYZ90 showed similar analgesic activity to the selective COX-2 inhibitor celecoxib in acetic acid-induced mice and better antioxidant activity in Fe2+-induced lipid peroxidation in mouse liver tissue homogenate than edaravone. In conclusion, this study provided a novel class of coxibs containing edaravone moiety as COX-2 selective NSAIDs with free radical scavenging activity and the candidate compound WYZ90 showed not only similar selective COX-2 inhibitory and analgesic activity to celecoxib but also better free radical scavenging and antioxidant activity than edaravone.

Plasma Proteomic Analysis Based on 4D-DIA Evaluates the Clinical Response to Imrecoxib in the Early Treatment of Osteoarthritis.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the primary treatment for osteoarthritis (OA), but prolonged use has adverse effects and varying efficacy. Among NSAIDs, imrecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, reduces side effects yet remains ineffective for half of the patient population. This study aims to identify biomarkers for early evaluation of imrecoxib efficacy in OA for personalized therapy optimization. From September 2021 to January 2022, imrecoxib was administered to patients with OA at Nanjing Drum Tower Hospital. Plasma samples from these patients underwent proteomic analysis through the four-dimensional data-independent acquisition (4D-DIA) method, followed by bioinformatics analysis. Potential differentially expressed proteins (DEPs) were validated using enzyme-linked immunosorbent assays (ELISA). Sixty-six patients with knee OA were included and divided into responders (n = 35) and non-responders (n = 31). Proteomic analysis was conducted on 15 patients from each group, with ELISA validation for every patient. We found 140 DEPs between the two groups after imrecoxib treatment, characterized by 29 proteins showing upregulation and 111 displaying downregulation (P < 0.05, fold change > ± 1.2). Galectin-1 (LGALS1), galectin-3 (LGALS3), and cluster of differentiation 44 (CD44) were identified as potential markers for evaluating clinical response to imrecoxib in OA following ELISA validation. This study successfully identified biomarkers for evaluating imrecoxib's clinical response in patients with OA using 4D-DIA technology. These biomarkers may play a vital role in future personalized OA treatment strategies, pending further confirmation.

A further pocket or conformational plasticity by mapping COX-1 catalytic site through modified-mofezolac structure-inhibitory activity relationships and their antiplatelet behavior

Cyclooxygenase enzymes have distinct roles in cardiovascular, neurological, and neurodegenerative disease. They are differently expressed in different type of cancers. Specific and selective COXs inhibitors are needed to be used alone or in combo-therapies. Fully understand the differences at the catalytic site of the two cyclooxygenase (COX) isoforms is still opened to investigation. Thus, two series of novel compounds were designed and synthesized in fair to good yields using the highly selective COX-1 inhibitor mofezolac as the lead compound to explore a COX-1 zone formed by the polar residues Q192, S353, H90 and Y355, as well as hydrophobic amino acids I523, F518 and L352. According to the structure of the COX-1:mofezolac complex, hydrophobic amino acids appear to have free volume eventually accessible to the more sterically hindering groups than the methoxy linked to the phenyl groups of mofezolac, in particular the methoxyphenyl at C4-mofezolac isoxazole. Mofezolac bears two methoxyphenyl groups linked to C3 and C4 of the isoxazole core ring. Thus, in the novel compounds, one or both methoxy groups were replaced by the higher homologous ethoxy, normal and isopropyl, normal and tertiary butyl, and phenyl and benzyl. Furthermore, a major difference between the two sets of compounds is the presence of either a methyl or acetic moiety at the C5 of the isoxazole. Among the C5-methyl series, 12 (direct precursor of mofezolac) (COX-1 IC50 = 0.076 μM and COX-2 IC50 = 0.35 μM) and 15a (ethoxy replacing the two methoxy groups in 12; COX-1 IC50 = 0.23 μM and COX-2 IC50 > 50 μM) were still active and with a Selectivity Index (SI = COX-2 IC50/COX-1 IC50) = 5 and 217, respectively. The other symmetrically substituted alkoxyphenyl moietis were inactive at 50 μM final concentration. Among the asymmetrically substituted, only the 16a (methoxyphenyl on C3-isoxazole and ethoxyphenyl on C4-isoxazole) and 16b (methoxyphenyl on C3-isoxazole and n-propoxyphenyl on C4-isoxazole) were active with SI = 1087 and 38, respectively. Among the set of compounds with the acetic moiety, structurally more similar to mofezolac (SI = 6329), SI ranged between 1.4 and 943. It is noteworthy that 17b (n-propoxyphenyl on both C3- and C4-isoxazole) were found to be a COX-2 slightly selective inhibitor with SI = 0.072 (COX-1 IC50 > 50 μM and COX-2 IC50 = 3.6 μM). Platelet aggregation induced by arachidonic acid (AA) can be in vitro suppressed by the synthesized compounds, without affecting of the secondary hemostasia, confirming the biological effect provided by the selective inhibition of COX-1. A positive profile of hemocompatibility in relation to erythrocyte and platelet toxicity was observed. Additionally, these compounds exhibited a positive profile of hemocompatibility and reduced cytotoxicity. Quantitative structure activity relationship (QSAR) models and molecular modelling (Ligand and Structure based virtual screening procedures) provide key information on the physicochemical and pharmacokinetic properties of the COX-1 inhibitors as well as new insights into the mechanisms of inhibition that will be used to guide the development of more effective and selective compounds. X-ray analysis was used to confirm the chemical structure of 14 (MSA17).

Improvement of astrocytic gap junction involves the anti-depressive effect of celecoxib through inhibition of NF-κB

ContextCelecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, has been shown to exhibit anti-depressive effects in clinical trials. However, the direct mechanism underlying its effect on neuroinflammation remains unclear. Neuroinflammatory reaction from astrocytes leads to depression, and our previous study found that gap junction disorder between astrocytes aggravated neuroinflammatory reaction in depressed mice. ObjectiveTo investigate the potential mechanism of celecoxib's effects on astrocytic gap junctions during the central nervous inflammation-induced depression. Materials & methodsStereotaxic injection of lipopolysaccharide (LPS) into the prefrontal cortex (PFC) to establish a model of major depressive disorder (MDD). Celecoxib was administrated into PFC 15 min after LPS injection. The depressive performance was tested by tail suspension test and forced swimming test, and the levels of proinflammation cytokines were determined at mRNA and protein levels. Resting-state functional connection (rsFC) was employed to assess changes in the default mode network (DMN). Additionally, astrocytic gap junctions were also determined by lucifer yellow (LY) diffusion and transmission electron microscope (TEM), and the expression of connexin 43 (Cx43) was measured by western blotting, quantitative polymerase chain reaction, and immunofluorescence. ResultsLPS injection induced significant depressive performance, which was ameliorated by celecoxib treatment. Celecoxib also improved rsFC in the DMN. Furthermore, celecoxib improved astrocytic gap junctions as evidenced by increased LY diffusion, shortened gap junction width, and normalized levels of phosphorylated Cx43. Celecoxib also blocked the phosphorylation of p65, and inhibition of p65 abolished the improvement of Cx43. Discussion & conclusionAnti-depressive effects of celecoxib are mediated, at least in part, by the inhibition of nuclear factor- kappa B (NF-κB) and the subsequent improvement of astrocytic gap junction function

Analgesic Efficacy of Selective COX -2 Inhibitors in Post Endodontic Pain: A Systematic Review

Background: Endodontic treatment is considered a harrowing experience for patients in dental practice. COX-2 is a prime agent in inflammation and cell growth due to its relation with pro- inflammatory cytokines. Non -steroidal anti-inflammatory drugs are the most suited for treatment of post endodontic pain owing to their anti-inflammatory properties with the avoidance of cumbersome side effects such as nausea, vomiting, and respiratory problems associated with opioids. Aim: To assess the clinical efficacy of selective COX -2 inhibitors in comparison with other analgesics for managing postendodontic pain. Methods: This is an updated systematic review of studies between 2000 and 2023. Google Scholar, Web of science, Cochrane and PubMed databases were used to explore studies regarding our subject. The keywords included “selective COX-2 inhibitors; selective non- steroidal anti-inflammatory drug; endodontic pain; meloxicam; etoricoxib; metabolic complications” and were used in various combinations. In addition, original research reporting the clinical efficacy of selective COX -2 inhibitors in managing endodontic pain was evaluated. Full-text publications served as the inclusion criterion. Results: Among 100 articles were obtained, only nine met the inclusion criteria. All the studies were double-blinded randomized clinical trials. The study population was comprised of 1645 patients with endodontic pain. Conclusion: Selective COX -2 Inhibitors was an effective choice in managing endodontic pain. Celebrex was more effective than Celecoxib in relieving post-endodontic pain. When comparing Ibuprofen and Celecoxib, both were equally effective in relieving post-endodontic pain. Celecoxib was more effective than Naproxen in treating post-endodontic pain with minor gastrointestinal effects. Furthermore, etoricoxib considerably reduces post-endodontic pain with a single dosage.

The effect of nonsteroidal anti-inflammatory drug use on soft tissue and bone healing in the knee: a systematic review.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to mitigate pain and inflammation associated with musculoskeletal conditions; however, there is conflicting data on the adverse effects of these drugs on tissue and bone healing. The objective of this study was to investigate the effect of NSAIDs on the healing of knee, soft tissue, and bone. A systematic literature search was conducted across PubMed/MEDLINE, Excerpta Medical Database (Embase)/Ovid, and the Cochrane Central Register of Controlled Trials databases. Clinical, animal, and in vitro studies on the effect of NSAIDs on knee healing were included. Risk of bias assessment was performed using the Cochrane bias assessment tool and Methodological Index for Non-Randomized Studies scoring system for included clinical studies, and the Systematic Review Center for Laboratory Animal Experimentation assessment tool for all included animal studies. General study population characteristics, interventions used, NSAIDs utilized, outcome measures, and study results were analyzed using descriptive statistics. Fifteen articles met the inclusion criteria. Of the 15 studies, there were three clinical, ten animal, and two in vitro studies. In clinical studies, nonselective cyclooxygenase (COX) inhibitors and selective COX-2 inhibitors did not cause a significant increase in failure of anterior cruciate ligament (ACL) reconstructions or meniscal repairs with NSAID administration pre-, peri-, or post-operatively in comparison to placebo or no NSAID administration. Among animal studies assessing COX-2 inhibitor effects on soft tissue, healing was impaired (2/4), delayed but unaffected (1/4), or unaffected (1/4). In animal studies assessing COX-1 inhibitors, ligament healing was either increased (1/4), unaffected (2/4), or impaired (1/4). Meanwhile, administration of non-selective COX inhibitors in animals did not affect soft tissue (3/3) and cartilage (1/1) healing. Two in vitro studies identified a negative outcome on patellar tendon and ACL cell proliferation or viability after non-selective COX inhibition and variable results after selective COX-2 inhibition. Animal studies on postoperative NSAID use after knee surgery suggest that administration of selective and nonselective COX-2 inhibitors may impair healing of soft tissue, bone and tendon-to-bone; however, further clinical studies are needed to better characterize dose and duration dependent risks of NSAIDs.

Characterizing NSAID Allergy and Strategies for Management in Patients with Rheumatological and Orthopaedic Conditions, in a Single Tertiary Hospital in Hong Kong

Background Non-steroidal anti-inflammatory drugs (NSAIDs) are amongst the most frequently prescribed medications, their associated hypersensitivity reactions can not only lead to potentially severe reactions, but also limit analgesic and anti-inflammation options. This is especially true for those who are ailed with rheumatological or orthopaedic diseases leading to chronic pain and inflammatory conditions. This highlights the importance of identifying different types of NSAID hypersensitivity, and to find safe alternatives, namely selective COX-2 inhibitors, to groups of patients that may benefit the most from its utility. Objective To assess and categorise patients with suspected NSAID hypersensitivity, and to successfully provide alternatives to those with chronic rheumatologic and orthopedic ailments. Methods 115 patients with suspected NSAID hypersensitivity were referred to Queen Mary Hospital for specialist evaluation between Jan 2023 and March 2024, those suitable were later challenged and delabelled. Remaining patients were assessed as clinically compatible with NSAID hypersensitivity, and later separated into whether they had background of orthopedic or rheumatological conditions, hence strong indications for NSAIDs, and without, to which selective COX-2 inhibitors tolerance tests were offered. Results Of 115 patients, 20% (23/115) were assessed as unlikely to have NSAID hypersensitivity, and later challenged. 18.2% (21/115) had negative challenges and were delabelled; only 2 patients had positive reactions, confirming NSAID hypersensitivity, of which symptoms were mild and did not require hospitalization. 82% of the remaining patients (94/115) were then later stratified into different NSAID hypersensitivity reactions according to European Academy of Allergy &amp; Clinical Immunology (EAACI) guidelines. 57.3% (66/115) of patients were able to resume use of NSAIDs either by finding an alternative NSAID, namely a selective COX2 inhibitor (45/115, 39.1%), or through a negative drug challenge (21/115, 18.2%). Overall there was no significant difference in the proportion of patients with successful COX2 inhibitor challenges between the group with rheumatological and orthopedic diagnoses against those without (62% vs 54% p=0.414). 29 patients are still pending workup, likely underestimating the amount of patients that are able to resume NSAIDs. Conclusion NSAID hypersensitivity is amongst the most commonly reported drug allergies, and may present with many different clinical phenotypes. Patients with suspected NSAID hypersensitivity require allergist evaluation, and if not clinically suggestive of allergy, would benefit from drug challenges, especially in cases with underlying rheumatological or orthopedic conditions, where NSAIDs are essential. In situations where NSAID hypersensitivity is considered likely, selective COX-2 inhibitors can often be considered as a suitable alternative.

NSAIDs between past and present; a long journey towards an ideal COX-2 inhibitor lead.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most abundantly used classes among therapeutic agents in medicine. NSAIDs inhibit the enzyme cyclooxygenase (COX), which is responsible for the conversion of arachidonic acid to prostaglandins. Meanwhile, non-selective NSAIDs are considered as a double-edged weapon since inhibition of COX-1 can lead to gastrointestinal side effects and kidney damage, whereas selective COX-2 inhibition provides anti-inflammatory effects without gastrointestinal toxicity. The detection of COX-2 role in inflammation process launched a new era in its management. Several trials have been established to proceed towards selectivity of well-defined anti-inflammatory members. COX-2 selective inhibitors are evidently safer on the gastrointestinal tract than non-selective NSAIDs. Nevertheless, their unexpected cardiovascular risks cannot be ignored. This review article highlights the latest trials aimed at developing new compounds with promising selective COX-2 activity.

Long-Acting Drug Delivery Technologies for Meloxicam as a Pain Medicine.

Meloxicam, a selective COX-2 inhibitor, has demonstrated clinical effectiveness in managing inflammation and acute pain. Although available in oral and parenteral formulations such as capsule, tablet, suspension, and solution, frequent administration is necessary to maintain therapeutic efficacy, which can increase adverse effects and patient non-compliance. To address these issues, several sustained drug delivery strategies such as oral, transdermal, transmucosal, injectable, and implantable drug delivery systems have been developed for meloxicam. These sustained drug delivery strategies have the potential to improve the therapeutic efficacy and safety profile of meloxicam, thereby reducing the frequency of dosing and associated gastrointestinal side effects. The choice of drug delivery system will depend on the desired release profile, the target site of inflammation, and the mode of administration. Overall, meloxicam sustained delivery systems offer better patient compliance, and reduce the side effects, thereby improving the clinical applications of this drug. Herein, we discuss in detail different strategies for sustained delivery of meloxicam.

New pyrazole-pyridazine hybrids as selective COX-2 inhibitors: design, synthesis, molecular docking, in silico studies and investigation of their anti-inflammatory potential by evaluation of TNF-α, IL-6, PGE-2 and NO in LPS-induced RAW264.7 macrophages.

Hybrid-based design has gained significant interest in the development of novel active substances with anti-inflammatory properties. In this study, two series of new pyrazole-pyridazine-based hybrids, 5a-f and 6a-f, were designed and synthesized. Molecules containing pyrazole and pyridazine pharmacophores in a single molecule, each with a unique mechanism of action and different pharmacological characteristics, are believed to exert higher biological activity. The cell viability of all compounds was evaluated using MTT assay in LPS-induced RAW264.7 macrophages. In vitro COX-1 and COX-2 inhibition assays were performed for the investigation of the anti-inflammatory activity of target compounds. Trimethoxy derivatives 5f and 6f were the most active candidates, demonstrating higher COX-2 inhibitory action than celecoxib, with IC50 values of 1.50 and 1.15 μM, respectively. Bromo derivative 6e demonstrated a COX-2 inhibitory activity comparable to celecoxib. Further, the ability of compounds 5f, 6e, and 6f to inhibit the generation of specific pro-inflammatory cytokines and mediators, including nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and prostaglandin-E2 (PGE-2), in RAW264.7 macrophages stimulated by LPS was also estimated. Compounds 5f and 6f demonstrated the most potent activity. Morover, according to the investigation using molecular modeling studies, derivatives 5f and 6f showed respectable binding affinity towards the COX-2 active site compared to the reference ligand. Moreover, the ADME parameters, physicochemical characteristics, pharmacokinetic characteristics, and l of the most potent compounds were also computed.

Synthesis, in silico and bio-evaluation studies of new isothiocyanate derivatives with respect to COX inhibition and H2S release profiles.

The development of H2S-donating derivatives of non-steroidal anti-inflammatory drugs (NSAIDs) is considered important to reduce or overcome their gastrointestinal side effects. Sulforaphane, one of the most extensively studied isothiocyanates (ITCs), effectively releases H2S at a slow rate. Thus, we rationally designed, synthesized, and characterized new ITC derivatives (I1-3 and I1a-e) inspired by the natural compound sulforaphane. The anti-inflammatory properties of these compounds were evaluated by their inhibitory activities against cyclooxygenase targets COX-1 and COX-2. Additionally, the cytotoxicity of the compounds was tested using the MTT assay on LPS-induced RAW 264.7 cells, revealing no cytotoxic effects at low doses. Notably, compounds I1 and fluorine-containing ester derivative I1c emerged as the most potent and selective COX-2 inhibitors, with selectivity indexes of 2611.5 and 2582.4, respectively. The H2S-releasing capacities of ITC derivatives were investigated and compared with that of sulforaphane, showing that while compounds I1-3 exhibit slow and similar H2S release to sulforaphane, the release from compounds I1a-e was not as pronounced as that of the standard. Physics-based molecular modeling studies including molecular docking and molecular dynamics (MD) simulations, binding free energy calculations and absorption, distribution, metabolism, and excretion (ADME) analyses were also conducted. MD simulations analysis underscored the crucial amino acids such as Tyr385, Trp387, Phe518, Val523, and Ser530 in the interactions between I1c hit compound and COX-2. The combined in silico and in vitro findings suggest that compounds I1 and I1c are promising NSAID candidates against selective COX-2 inhibition.

Association of COX-inhibitors with cancer patients' survival under chemotherapy and radiotherapy regimens: a real-world data retrospective cohort analysis.

We conducted an extensive, sex-oriented real-world data analysis to explore the impact and safety of non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors (coxibs) on cancer treatment outcomes. This is particularly relevant given the role of the COX-2/PGE2 pathway in tumor cell resistance to chemotherapy and radiotherapy. The study applied a retrospective cohort design utilizing the TriNetX research database consisting of patients receiving cancer treatment in 2008-2022. The treated cohorts included patients who were prescribed with coxibs, aspirin or ibuprofen, while individuals in the control cohort did not receive these medicines during their cancer treatment. A 1:1 propensity score matching technique was used to balance the baseline characteristics in the treated and control cohorts. Then, Cox proportional hazards regression and logistic regression were applied to assess the mortality and morbidity risks among patient cohorts in a 5-year follow-up period. Use of coxibs (HR, 0.825; 95% CI 0.792-0.859 in females and HR, 0.884; 95% CI 0.848-0.921 in males) and ibuprofen (HR, 0.924; 95% CI 0.903-0.945 in females and HR, 0.940; 95% CI 0.917-0.963 in males) were associated with improved survival. Female cancer patients receiving aspirin presented increased mortality (HR, 1.078; 95% CI 1.060-1.097), while male cancer patients also had improved survival when receiving aspirin (HR, 0.966; 95% CI 0.951-0.980). Cancer subtype specific analysis suggests coxibs and ibuprofen correlated with survival, though ibuprofen and aspirin increased emergency department visits' risk. Secondary analyses, despite limited by small cohort sizes, suggest that COX inhibition post-cancer diagnosis may benefit patients with specific cancer subtypes. Selective COX-2 inhibition significantly reduced mortality and emergency department visit rates. Further clinical trials are needed to determine the optimal conditions for indication of coxibs as anti-inflammatory adjuvants in cancer treatment.

Synthesis and elucidation of strained galactopyronose esters as selective cyclooxygenase-2 inhibitor: a comprehensive computational approach.

Cyclooxygenase-2 (COX-2) is critically implicated in various pathologies, including inflammation, cancer, disorders involving the nervous system, and multidrug resistance. In both academic and pharmaceutical research, the development of COX-2 selective drugs as anti-inflammatory and anti-tumor therapeutics is a key focus. Traditional nonsteroidal anti-inflammatory drugs (NSAIDs) have ulcerogenic, gastrointestinal adverse effects, and myocardial infarction risk, which resulted in their limited applications. In response to this challenge, we synthesized a series of glycoconjugates featuring six-membered sugar rings and acyl chains of varying lengths attached at the C-6 position. Using molecular docking techniques, we identified galactose esters with optimal acyl chain lengths that selectively and effectively bind to the active site of COX-2 over COX-1. These compounds exhibited enhanced binding affinity and superior inhibition constants (pK i) for COX-2, thereby offering selective inhibition with potentially reduced ulcerogenic risks, as COX-1 inhibition is thought to contribute to these side effects. The molecular docking study identified two potential compounds, G6 and G8, which were validated via MD simulation for the assessment of their stability and were compared to the complex of the standard drugs, aspirin and rofecoxib. In addition, compound structures were optimized using the DFT method under the B3LYP/6-31+g(d,p) basis set to study their physio-spectral properties, frontier molecular orbitals (HOMO-LUMO), and their energy gap that correlates to their reactivity and stability. ADMET, drug-likeness, and PASS analyses were also carried out to assess their drug-ability and toxicity profiling.

Synthesis and anti-inflammatory activity of novel firocoxib analogues with balanced COX inhibition.

The adverse effects caused by nonselective and selective cyclooxygenase-2 (COX-2) inhibitors remain a challenge for current anti-inflammatory medications. A balanced inhibition of COX-1/-2 represents a promising strategy for the development of novel COX-2 inhibitors. In this study, we present the design and synthesis of a novel series of firocoxib analogues incorporating an amide bond to facilitate essential hydrogen bonding with amino residues in COX-2. The synthesized analogs were evaluated for their inhibitory activity against both COX-1 and COX-2 enzymes. Among them, compound 9d demonstrated potent and balanced inhibition. Inhibition of COX enzymes by 9d in lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophages resulted in the suppression of the NF-κB signaling pathway to reduced expression of pro-inflammatory factors such as inducible nitric oxide synthase (iNOS), COX-2, nitric oxide (NO), and reactive oxygen species (ROS). The remarkable invitro anti-inflammatory activity exhibited by 9d positions it as a promising candidate for further development as a novel lead compound for inflammation treatment.

Discovery of a new pyrido[2,3-d]pyridazine-2,8-dione derivative as a potential anti-inflammatory agent through COX-1/COX-2 dual inhibition.

In this paper, we present the design and synthesis of a novel series of pyrido[2,3-d]pyridazine-2,8-dione derivatives via the annulation of the 2-pyridone pattern. The synthesized derivatives were evaluated for in vivo anti-inflammatory activity using an ear edema model. Compound 7c, which showed a greater inhibition of ear edema (82%), was further tested for its in vitro COX-1/COX-2 inhibitory activity. Compound 7c showed similar inhibitory activities against COX-1 and COX-2 isoenzymes. The structural features that ensure the dual inhibition of COX-1 and COX-2 were elucidated using molecular docking studies. Overall, the ring closing of 2-pyridone pattern I transformed this highly selective COX-2 inhibitor into a dual COX inhibitor (7c), which could serve as a model for determining selectivity for COX-2.

Design, synthesis, pharmacological evaluation, and in silico studies of the activity of novel spiro pyrrolo[3,4-d]pyrimidine derivatives.

In the present study, spiro compounds are shown to have distinctive characteristics because of their interesting conformations and their structural impacts on biological systems. A new family of functionalized spiro pyrrolo[3,4-d]pyrimidines is prepared via the one-pot condensation reaction of amino cyclohexane derivatives with benzaldehyde to prepare fused azaspiroundecanedione and azaspirodecenone/thione derivatives. A series of synthesized spiro compounds were scanned against DPPH and evaluated for their ability to inhibit COX-1 and COX-2. All compounds exhibit significant antiinflammatory activity, and they inhibited both COX-1 and COX-2 enzymes with a selectivity index higher than celecoxib as a reference drug. The most powerful and selective COX-2 inhibitor compounds were 11 and 6, with selectivity indices of 175 and 129.21 in comparison to 31.52 of the standard celecoxib. However, candidate 14 showed a very promising antiinflammatory activity with an IC50 of 6.00, while celecoxib had an IC50 of 14.50. Our findings are promising in the area of medicinal chemistry for further optimization of the newly designed and synthesized compounds regarding the discussed structure-activity relationship study (SAR), in order to obtain a superior antioxidant lead compound in the near future. All chemical structures of the novel synthesized candidates were unequivocally elucidated and confirmed utilizing spectroscopic and elemental investigations.

Design, QSAR Methodology, Synthesis and Assessment of Some Structurally Different Xanthone Derivatives as Selective Cox-2 Inhibitors for their Anti-inflammatory Properties.

Inflammation can be defined as a complex biological response that is produced by body tissues to harmful agents like pathogens, irritants, and damaged cells and thereby acts as a protective response incorporating immune cells, blood vessels, and molecular mediators. Histamine, serotonin, bradykinin, leukotrienes (LTB4), prostaglandins (PGE2), prostacyclins, reactive oxygen species, proinflammatory cytokines like IL-1, IL-11, TNF- anti-inflammatory cytokines like IL-4, IL-10, IL-11, IL-6 and IL-13, etc. all have different effects on both pro and anti-inflammatory mediators. Incorporation of combinatorial chemistry and computational studies have helped the researchers to design xanthones moieties with high selectivity that can serve as a lead compound and help develop potential compounds that can act as effective COX-2 inhibitors. The study aims to design and develop different series of substituted hydroxyxanthone derivatives with anti-inflammatory potential. The partially purified synthetic xanthone derivatives were orally administered to the carrageenan induced paw oedemic rat models at the dose of 100 mg/kg, and their effect in controlling the degree of inflammation was measured at the time interval of 30 min, 1, 2, 3, 4 and 6 hrs. respectively. Further, these compounds were also subjected to modern analytical studies like UV, IR, NMR and mass spectrometry or their characterization. The results drawn out of the in silico, in vitro, in vivo and analytical studies concluded that the hydroxyxanthone derivatives can obstruct the enzyme COX-2 and produce anti-inflammatory action potentially. With the aim to evaluate the compounds for their anti-inflammatory activity, it was observed that the newly designed xanthonic compounds also possess a safe toxicity margin and hence can be utilized by the researchers to develop hybrid xanthonic moieties that can specifically target the enzyme COX-2.

Comparison of the effectiveness of diclofenac sodium and tenoxicam in the prevention of epidural fibrosis by topical application with an absorbable gelatin sponge on the dura in an experimental laminectomy model.

There has been an increasing trend in spinal surgery interventions in recent years. Low back pain is a disorder that is seen at least once in the lifetime of approximately 80% of the general population. Today, neurosurgeons perform operations including laminectomy for various reasons. Epidural fibrosis is a scar tissue that develops after posterior spinal surgery. Various synthetic and organic materials have been used in experimental studies to prevent epidural fibrosis in laminectomy defects. In this study we aimed to investigate and observe histopathologically the effectiveness of cyclooxygenase inhibitor drugs; tenoxicam and diclofenac sodium in the experimental rat laminectomy model in preventing the postoperative spinal epidural fibrosis. In this study, 32 Wistar-Albino female rats were used. 8 mg/kg tenoxicam and 1.5 mg/kg diclofenac sodium were applied on the dura with an absorbable gelatin sponge. After decapitation, L1-L4 laminectomy area was totally removed and histopathological examination was performed. It has been shown that the topical application of diclofenac sodium and tenoxicam, which are selective Cox inhibitor drugs, prevents fibroblast migration by forming a local barrier and Cox inhibitors are caused by the inhibition of prostanoids, which are inflammatory mediators.

The effect of oral administration of robenacoxib on hematological and biochemical parameters in different goat breeds

Robenacoxib is a coxib-class, highly selective cyclooxygenase-2 inhibitor that is used for the control of pain and inflammation. This study aimed to determine the effect on hematological and biochemical parameters 24 hours after oral administration of robenacoxib to healthy Alpine and Saanen goats. The study was conducted on healthy females, 1-2 years old Alpine (n=5) and Saanen (n=5) goats. A single dose of robenacoxib was administered orally to goats at a dose of 4 mg/kg body weight. Blood samples were taken before (0 hour) and 24 hours after the administration of robenacoxib for the evaluation of hematological and biochemical changes. The results of this study showed that statistical differences in hematological and biochemical parameters were within the normal limits in Alpine and Saanen goats except lactate dehydrogenase in Saanen goats. Furthermore, no differences were observed in hematological parameters between goat breeds; it can be claimed that the Alpine breed is more susceptible to negative pharmacological side effects than the Saanen breed according to changes in biochemical parameters. As a result, it was concluded that robenacoxib did not have a negative effect on kidney and liver functions and blood components in Alpine and Saanen goats in administered dose and treatment period in this study. Further studies need to investigate the effects of robenacoxib in high doses, long-term use, and in disease conditions, especially on the kidney.

An in vivo drug screen in zebrafish reveals that cyclooxygenase 2-derived prostaglandin D2 promotes spinal cord neurogenesis.

The study of neurogenesis is essential to understanding fundamental developmental processes and for the development of cell replacement therapies for central nervous system disorders. Here, we designed an in vivo drug screening protocol in developing zebrafish to find new molecules and signalling pathways regulating neurogenesis in the ventral spinal cord. This unbiased drug screen revealed that 4 cyclooxygenase (COX) inhibitors reduced the generation of serotonergic interneurons in the developing spinal cord. These results fitted very nicely with available single-cell RNAseq data revealing that floor plate cells show differential expression of 1 of the 2 COX2 zebrafish genes (ptgs2a). Indeed, several selective COX2 inhibitors and two different morpholinos against ptgs2a reduced the number of serotonergic neurons in the ventral spinal cord and led to locomotor deficits. Single-cell RNAseq data and different pharmacological manipulations further revealed that COX2-floor plate-derived prostaglandin D2 promotes neurogenesis in the developing spinal cord by promoting mitotic activity in progenitor cells. Rescue experiments using a phosphodiesterase-4 inhibitor suggest that intracellular changes in cAMP levels underlie the effects of COX inhibitors on neurogenesis and locomotion. Our study provides compelling in vivo evidence showing that prostaglandin signalling promotes neurogenesis in the ventral spinal cord.