Design, Synthesis, In vitro and In vivo Evaluation of New Imidazo[1,2-a]pyridine Derivatives as Cyclooxygenase-2 Inhibitors.

BACKGROUND: Cyclooxygenase-2 (COX-2), the key enzyme in the arachidonic acid conversion to prostaglandins, is one of the enzymes associated with different pathophysiological conditions, such as inflammation, cancers, Alzheimer's, and Parkinson's disease. Therefore, COX-2 inhibitors have emerged as potential therapeutic agents in these diseases. OBJECTIVE: The objective of this study was to design and synthesize novel imidazo[1,2-a]pyridine derivatives utilizing rational design methods with the specific aim of developing new potent COX-2 inhibitors. Additionally, we sought to investigate the biological activities of these compounds, focusing on their COX-2 inhibitory effects, analgesic activity, and antiplatelet potential. We aimed to contribute to the development of selective COX-2 inhibitors with enhanced therapeutic benefits. METHODS: Docking investigations were carried out using AutoDock Vina software to analyze the interaction of designed compounds. A total of 15 synthesized derivatives were obtained through a series of five reaction steps. The COX-2 inhibitory activities were assessed using the fluorescent Cayman kit, while analgesic effects were determined through writing tests, and Born's method was employed to evaluate antiplatelet activities. RESULTS: The findings indicated that the majority of the tested compounds exhibited significant and specific inhibitory effects on COX-2, with a selectivity index ranging from 51.3 to 897.1 and IC50 values of 0.13 to 0.05 µM. Among the studied compounds, derivatives 5e, 5f, and 5j demonstrated the highest potency with IC50 value of 0.05 µM, while compound 5i exhibited the highest selectivity with a selectivity index of 897.19. In vivo analgesic activity of the most potent COX-2 inhibitors revealed that 3-(4-chlorophenoxy)-2-[4-(methylsulfonyl) phenyl] imidazo[1,2-a]pyridine (5j) possessed the most notable analgesic activity with ED50 value of 12.38 mg/kg. Moreover, evaluating the antiplatelet activity showed compound 5a as the most potent for inhibiting arachidonic acidinduced platelet aggregation. In molecular modeling studies, methylsulfonyl pharmacophore was found to be inserted in the secondary pocket of the COX-2 active site, where it formed hydrogen bonds with Arg-513 and His-90. CONCLUSION: The majority of the compounds examined demonstrated selectivity and potency as inhibitors of COX-2. Furthermore, the analgesic effects observed of potent compounds can be attributed to the inhibition of the cyclooxygenase enzyme.

Development of Zeise's Salt Derivatives Bearing Substituted Acetylsalicylic Acid Substructures as Cytotoxic COX Inhibitors.

Zeise's salt derivatives of the potassium trichlorido[η2-((prop-2-en/but-3-en)-1-yl)-2-acetoxybenzoate]platinate(II) type (ASA-Prop-PtCl3/ASA-But-PtCl3 derivatives) were synthesized and characterized regarding their structure, stability, and biological activity. It is proposed that the leads ASA-Prop-PtCl3 and ASA-But-PtCl3 interfere with the arachidonic acid cascade as part of their mode of action to reduce the growth of COX-1/2-expressing tumor cells. With the aim to increase the antiproliferative activity by strengthening the inhibitory potency against COX-2, F, Cl, or CH3 substituents were introduced into the acetylsalicylic acid (ASA) moiety. Each structural modification improved COX-2 inhibition. Especially compounds with F substituents at ASA-But-PtCl3 reached the maximum achievable inhibition of about 70% already at 1 µM. The PGE2 formation in COX-1/2-positive HT-29 cells was suppressed by all F/Cl/CH3 derivatives, indicating COX inhibitory potency in cellular systems. The CH3-bearing complexes showed the highest cytotoxicity in COX-1/2-positive HT-29 cells with IC50 values of 16-27 µM. In COX-negative MCF-7 cells, they were 2-3-fold less active. These data clearly demonstrate that it is possible to increase the cytotoxicity of ASA-Prop-PtCl3 and ASA-But-PtCl3 derivatives by enhancing COX-2 inhibition.

Computational Molecular Docking and Simulation-Based Assessment of Anti-Inflammatory Properties of Nyctanthes arbor-tristis Linn Phytochemicals.

The leaves, flowers, seeds, and bark of the Nyctanthes arbor-tristis Linn plant have been pharmacologically evaluated to signify the medicinal importance traditionally described for various ailments. We evaluated the anti-inflammatory potentials of 26 natural compounds using AutoDock 4.2 and Molecular Dynamics (MDS) performed with the GROMACS tool. SwissADME evaluated ADME (adsorption, distribution, metabolism, and excretion) parameters. Arb_E and Beta-sito, natural compounds of the plant, showed significant levels of binding affinity against COX-1, COX-2, PDE4, PDE7, IL-17A, IL-17D, TNF-α, IL-1ß, prostaglandin E2, and prostaglandin F synthase. The control drug celecoxib exhibited a binding energy of -9.29 kcal/mol, and among the tested compounds, Arb_E was the most significant (docking energy: -10.26 kcal/mol). Beta_sito was also observed with high and considerable docking energy of -8.86 kcal/mol with the COX-2 receptor. COX-2 simulation in the presence of Arb_E and control drug celecoxib, RMSD ranged from 0.15 to 0.25 nm, showing stability until the end of the simulation. Also, MM-PBSA analysis showed that Arb_E bound to COX-2 exhibited the lowest binding energy of -277.602 kJ/mol. Arb_E and Beta_sito showed interesting ADME physico-chemical and drug-like characteristics with significant drug-like effects. Therefore, the studied natural compounds could be potential anti-inflammatory molecules and need further in vitro/in vivo experimentation to develop novel anti-inflammatory drugs.

Hepatoprotective Effect of Silver Nanoparticles at Two Different Particle Sizes: Comparative Study with and without Silymarin.

Silver nanoparticles have been used for numerous therapeutic purposes because of their increased biodegradability and bioavailability, yet their toxicity remains questionable as they are known to interact easily with biological systems because of their small size. This study aimed to investigate and compare the effect of silver nanoparticles' particle size in terms of their potential hazard, as well as their potential protective effect in an LPS-induced hepatotoxicity model. Liver slices were obtained from Sprague Dawley adult male rats, and the thickness of the slices was optimized to 150 µm. Under regulated physiological circumstances, freshly cut liver slices were divided into six different groups; GP1: normal, GP2: LPS (control), GP3: LPS + AgNpL (positive control), GP4: LPS + silymarin (standard treatment), GP5: LPS + AgNpS + silymarin (treatment I), GP6: LPS + AgNpL + silymarin (treatment II). After 24 h of incubation, the plates were gently removed, and the supernatant and tissue homogenate were all collected and then subjected to the following biochemical parameters: Cox2, NO, IL-6, and TNF-α. The LPS elicited marked hepatic tissue injury manifested by elevated cytokines and proinflammatory markers. Both small silver nanoparticles and large silver nanoparticles efficiently attenuated LPS hepatotoxicity, mainly via preserving the cytokines' level and diminishing the inflammatory pathways. In conclusion, large silver nanoparticles exhibited effective hepatoprotective capabilities over small silver nanoparticles.

Gene expression of prostaglandin EP4 receptor in three canine carcinomas.

BACKGROUND: Chronic inflammation mediated by the cyclooxygenase enzymes, specifically their product prostaglandin E2 (PGE2), can result in the development of cancer. PGE2 promotes cell proliferation, apoptosis, and angiogenesis through interaction with its specific receptors (EP1 receptor - EP4 receptor [EP1R-EP4R]). In multiple human cancers, the expression of EP4R is associated with the development of malignancy and a poor prognosis. The expression of EP4R has not yet been evaluated in canine tumors. The aim of this study was to characterize the mRNA gene expression of EP4R (ptger4) in canine squamous cell carcinoma (SCC), apocrine gland anal sac adenocarcinoma (AGASACA), and transitional cell carcinoma (TCC). Archived tumor samples of canine cutaneous SCC (n = 9), AGASACA (n = 9), and TCC (n = 9), and matched archived normal tissue controls were evaluated for mRNA expression of canine EP4R using RNA in situ hybridization (RNAscope®). Quantification of RNAscope® signals in tissue sections was completed with an advanced digital pathology image analysis system (HALO). Data was expressed as copy number, H-index, and percent tumor cell expression of EP4R. RESULTS: In all canine SCC, AGASACA, and TCC samples evaluated, strong universal positive expression of EP4R was identified. For SCC and AGASACA, mRNA EP4R expression was statistically higher than that of their respective normal tissues. The TCC tissues displayed significantly less mRNA EP4R expression when compared to normal bladder mucosa. CONCLUSIONS: These results confirm the mRNA expression of canine EP4R in all tumor types evaluated, with SCC and AGASACA displaying the highest expression, and TCC displaying the lowest expression. This study also represents the first reported veterinary evaluation of EP4R expression using the novel in situ hybridization technique, RNAscope®.

Nonsteroidal Anti-inflammatory Drugs Utilization Patterns and Risk of Adverse Events due to Drug-Drug Interactions among Elderly Patients: A Study from Jordan.

BACKGROUND: Worldwide, the prescribing pattern of the Nonsteroidal Anti-inflammatory Drugs (NSAIDs) has increased. They are considered highly effective medications in controlling various conditions including inflammatory diseases. They are associated with various adverse effects including gastrointestinal bleeding and ulcer and renal toxicity though. These adverse effects are generally potentiated when NSAIDs are co-prescribed with other drugs that share similar adverse effects and toxicities. Developing severe side effects from NSAIDs is more prone among elderly patients. Hence, it is crucial to evaluate prescribing pattern of these agents to prevent/decrease the number of unwanted side effects caused by NSAIDs. AIM: The aim of this study is to assess the prescribing pattern of NSAIDs among elderly and the co-prescribing of NSAIDs and different interacting drugs, which could lead to more incidences of NSAIDs-induced toxicities among Jordanian elderly patients. SETTINGS AND METHODOLOGY: A multicenter retrospective study was performed during a three months period in Jordan. The study involves a total number of (n = 5916) elderly patient's records obtained from Four governmental hospitals in Jordan. RESULTS: A total number of (n = 20450) drugs were prescribed and dispensed for patient. NSAIDs drugs prescribing percentage was 10.3% of total medications number. Aspirin was the most commonly prescribed NSAIDs among patients (70.4%), followed by Diclofenac sodium in all dosage forms (25.1%) and oral Ibuprofen (3.1%. In addition, Aspirin was the highest NSAIDs co-prescribed with ACEI (e.g., Enalapril), ARBs (e.g. Candesartan and Losartan), Diuretics (Furosemide, Indapamide, Hydrochlorothiazide, Amiloride, and Spironolactone), Warfarin and antiplatelets (Clopidogreal and Ticagrelor) followed by Diclofenac and other NSAIDs. CONCLUSION: NSAIDs prescribing rate among elderly patients was high. Additionally the co-prescribing of NSAIDs especially Aspirin with other agents, which contributes to NSAIDs nephrotoxicity and gastrointestinal toxicity, were high. Strict measurements and action plans should be taken by prescribers to optimize the medical treatment in elderly through maximizing the benefits and decreasing the unwanted side effects.

Synthesis and Biological Evaluation of Zeise's Salt Derivatives with Acetylsalicylic Acid Substructure.

The development of novel biologically active organometallic compounds bearing an acetylsalicylic acid (ASA) substructure led to the synthesis of analogical Zeise-type salts that accordingly inhibit cyclooxygenase (COX) enzymes. In order to determine the influence of the length of the alkyl chain between the platinum(II) center and the ASA moiety, compounds with varying methylene groups (n = 1⁻4) were synthesized and characterized. For the propene derivative structural elucidation by X-ray crystallography was possible. Prior to evaluation of biological activity, the complexes were investigated regarding their stability in different media, such as water, physiological sodium chloride, and phosphate buffered saline. Therefore, an analytical method based on capillary electrophoresis was established. All of the compounds were tested for their COX inhibitory potential. In general, complexes with longer alkyl chains caused higher inhibition of COX enzymes and the inhibitory potential towards COX enzymes was enhanced when compared to Zeise's salt. The growth inhibitory effects of the synthesized substances were investigated in vitro against colon carcinoma (HT-29) and breast cancer (MCF-7) cells. The IC50 values of the new derivatives ranged from 30 to 50 µM, whereas neither Zeise's salt itself nor ASA showed any antiproliferative activity at the used concentrations.

[Aspirin-exacerbated respiratory disease. Case-based review]. / Enfermedad respiratoria exacerbada por aspirina. Revisión a partir de casos clínicos.

Aspirin-exacerbated respiratory disease comprises a series of signs and symptoms mainly involving the upper and lower posterior airway after the consumption of cyclooxygenase enzyme inhibitors. Adverse reactions that occur are not considered to be an allergy and are common to all non-steroidal anti-inflammatory drugs, and cross-reactivity between these agents is therefore common. The description of 3 clinical cases serves to review key aspects of this condition, such as epidemiology, pathophysiology, clinical manifestations, diagnosis and management. Adequate diagnosis and education on the use or elimination of all different NSAIDs is essential, as well as availability of different analgesic options, verified with challenge tests. Aspirin-exacerbated respiratory disease management includes surgical procedures for nasal polyp control, pharmacological treatment for asthma control and desensitization with aspirin in selected individuals.

La enfermedad respiratoria exacerbada por aspirina comprende un conjunto de signos y síntomas que involucran principalmente la vía aérea superior e inferior posterior al consumo de inhibidores de la enzima ciclooxigenasa. Las reacciones adversas que se presentan no se consideran una alergia y son comunes a todos los antiinflamatorios no esteroideos, por lo que la reactividad cruzada entre estos es común. La descripción de tres casos clínicos con diferentes situaciones sirve para revisar aspectos clave de la enfermedad como la epidemiologia, fisiopatología, manifestaciones clínicas, diagnóstico y manejo. El adecuado diagnóstico y educación en el uso o eliminación de los diferentes AINE es fundamental, al igual que la disposición de opciones analgésicas alternativas, comprobadas mediante pruebas de provocación. El manejo de la enfermedad respiratoria exacerbada por aspirina incluye procedimientos quirúrgicos para el control de los pólipos nasales, tratamiento farmacológico para el control del asma y desensibilización con aspirina en individuos seleccionados.

Evaluation of the reproductive toxicity of naproxen sodium and meloxicam in male rats.

Nonsteroidal anti-inflammatory drugs that are cyclooxygenase (COX) enzyme inhibitors have generally been used in short-term pain management and also to treat inflammation chronically. It is known that COX enzyme and prostaglandins play important roles in the regulation of reproductive functions in females. However, there are relatively few studies for the male reproductive system, and the results of these studies are contradictory. In this study, sperm count and motility, COX-1, COX-2, prostaglandin E1 (PGE1), prostaglandin E2 (PGE2), and prostaglandin F2α (PGF2α) levels in testis tissue, plasma follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone levels, and histopathological examination of testis tissue were evaluated after naproxen sodium and meloxicam administration in male rats. Also, testis superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and glutathione (GSH) levels were measured to investigate the oxidation status. According to our results, sperm count and motility were significantly decreased in treatment groups. Plasma hormone levels did not show any statistical differences between the groups. COX-1, PGE2, and PGF2α levels were significantly decreased, while the decreases in COX-2 and PGE1 levels did not show any significance statistically. Testis SOD, catalase, GPx, and GSH levels were decreased significantly. According to the results of histopathological examination, damage in seminiferous tubules, where spermatogenesis developed, was observed. In conclusion, naproxen sodium and meloxicam decreased the sperm count and motility and also induced the damage of seminiferous tubules as a direct effect without affecting plasma hormone levels in our study. The mechanism of the reproductive toxicity induced by these agents may be based on the inhibition of prostaglandin synthesis and the induction of oxidative stress can be emphasized as a secondary factor.