Diversified Thiazole Substituted Coumarins and Chromones as Non- Cytotoxic ROS and NO Inhibitors

2020 ◽  
Vol 17 (5) ◽  
pp. 547-555
Author(s):  
Uzma Salar ◽  
Khalid Mohammed Khan ◽  
Almas Jabeen ◽  
Shafquat Hussain ◽  
Aisha Faheem ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Flufenamic Acid ◽  
Future Research ◽  
Active Compounds ◽  
Inflammatory Disorders ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Acidic Nature ◽  
Nih 3T3 ◽  
Substituted Coumarins

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, aspirin, indomethacin, flufenamic acid and phenylbutazone are used to treat most of the inflammatory disorders. These NSAIDs are also associated with serious side effects including gastric ulceration, nephrotoxicity, and bleeding, mainly due to acidic nature. Hence, there is a need to identify highly potent and safer treatment for inflammatory disorders. Methods: Herein, synthetic hydrazinyl thiazole substituted coumarins and chromones 1-48 were evaluated for ROS inhibitory activity. ROS were generated from zymosan activated whole blood phagocytes. Results: Among all tested compounds, compounds 1 (IC50 = 38.3 ± 7.1 μM), 2 (IC50 = 5.7 ± 0.2 μM), 5 (IC50 = 28.3 ± 3.5 μM), 23 (IC50 = 12.5 ± 3.1 μM), 27 (IC50 = 32.8 ± 1.1 μM), 39 (IC50 = 20.2 ± 1.6 μM), and 42 (IC50 = 43.2 ± 3.8 μM) showed potent ROS inhibition as compared to standard ibuprofen (IC50 = 54.3 ± 1.9 μM). Whereas, compounds 3 (IC50 = 134.7 ± 1.0 μM), 16 (IC50 = 75.4 ± 7.2 μM), 24 (IC50 = 102.4 ± 1.0 μM), and 31 (IC50 = 86.6 ± 1.5 μM) were found to be moderately active. Compounds 1, 2, 5, 23, 27, 39, and 42, having potent ROS inhibitory activity were also screened for their nitric oxide (NO) inhibition. Cytotoxicity was also checked for all active compounds on NIH-3T3 cell line. Cyclohexamide (IC50 = 0.13 ± 0.02 μM) was used as standard. Conclusion: Identified active compounds from these libraries may serve as lead candidates for future research in order to obtain a more potent, and safer anti-inflammatory agent.

ROS Inhibitory Activity and Cytotoxicity Evaluation of Benzoyl, Acetyl, Alkyl Ester, and Sulfonate Ester Substituted Coumarin Derivatives

2020 ◽  
Vol 16 (8) ◽  
pp. 1099-1111
Author(s):  
Uzma Salar ◽  
Khalid M. Khan ◽  
Almas Jabeen ◽  
Aisha Faheem ◽  
Farwa Naqvi ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Antiinflammatory Drug ◽  
Vital Role ◽  
Alkyl Ester ◽  
Flufenamic Acid ◽  
Coumarin Derivatives ◽  
Inflammatory Disorders ◽  
Enhanced Chemiluminescence ◽  
Anti Inflammatory ◽  
Sulfonate Ester

Background: A number of non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin, indomethacin, ibuprofen, flufenamic acid, and phenylbutazone are being clinically used to treat inflammatory disorders. These NSAIDs are associated with serious side effects such as gastric ulceration, nephrotoxicity, and bleeding. Therefore, the identification of potent and safe therapy for inflammatory disorders is still of great interest to the medicinal chemist. Methods: A series of varyingly substituted benzoyl, acetyl, alkyl ester, and sulfonate ester substituted coumarins 1-64 were screened for the inhibition of ROS, generated from zymosan activated whole blood phagocytes, using luminol-enhanced chemiluminescence technique. Results: Among all tested compounds, 8 (IC50 = 65.0 ± 3.1 μM), 24 (IC50 = 41.8 ± 1.5 μM), 26 (IC50 = 10.6 ± 2.8 μM), 28 (IC50 = 20.9 ± 1.5 μM), and 41 (IC50 = 4.6 ± 0.3 μM) showed good anti- inflammatory potential as compared to standard antiinflammatory drug ibuprofen (IC50 = 54.3 ± 1.9 μM). Specifically, compounds 24, 26, 28, and 41 showed superior activity than standard antiinflammatory drug. Furthermore, compounds 12 (IC50 = 219.0 ± 1.4 μM), 14 (IC50 = 216.5 ± 6.2 μM), 16 (IC50 = 187.4 ± 2.2 μM), and 20 (IC50 = 196.2 ± 2.0 μM) showed moderate ROS inhibitory activity. Limited SAR study revealed that the hydroxy-substituted compound showed better ROS inhibition potential in case of 3-benzoyl and 3-ethylester coumarin derivatives. Whereas, chloro substitution was found to be important in case of 3-acetyl coumarin derivatives. Similarly, in case of sulfonate ester, chloro, and nitro groups especially at positions -4 and -3 of ring “R” played vital role in ROS inhibition. Furthermore, cytotoxicity of all active compounds was also checked on NIH-3T3 cell line. Compounds 12, 14, and 20 were found to be non-cytotoxic. Whereas, 8, 16, 24, 26, 28, and 41 were found to be very weak cytotoxic as compared to standard cycloheximide (IC50 = 0.13 ± 0.02 μM). Conclusion: Identified ROS inhibitors offer the possibility of additional modifications that could give rise to lead structures for further research in order to obtain more potent, and safer antiinflammatory agent.

scholarly journals NSAID Gastroenteropathy: Past, Present and Future

1996 ◽  
Vol 10 (7) ◽  
pp. 451-459 ◽  
Author(s):  
John L Wallace
Keyword(s):  
Gastrointestinal Tract ◽  
Inflammatory Disorders ◽  
The Past ◽  
Prostaglandin Synthase ◽  
Nsaid Enteropathy ◽  
The Future ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Identification And Characterization

The toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs) in the gastrointestinal tract continues to be a major limitation to their use in the treatment of inflammatory disorders. Better understanding of the pathogenesis of NSAID enteropathy has facilitated the development of novel NSAIDs that spare the gastrointestinal tract. In particular, identification and characterization of the inducible form of prostaglandin synthase has led to the design of novel NSAIDs that specifically target that enzyme. The pathogenesis of NSAID gastroenteropathy is reviewed, as are the strategies that have been used in the past and are used now to develop NSAIDs that spare the gastrointestinal tract. Also reviewed are the strategies being employed to achieve this goal in the future.

scholarly journals Crystal Structures of Prostaglandin D2 11-Ketoreductase (AKR1C3) in Complex with the Nonsteroidal Anti-Inflammatory Drugs Flufenamic Acid and Indomethacin

2004 ◽  
Vol 64 (5) ◽  
pp. 1802-1810 ◽  
Author(s):  
Andrew L. Lovering ◽  
Jon P. Ride ◽  
Christopher M. Bunce ◽  
Julian C. Desmond ◽  
Stephen M. Cummings ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Flufenamic Acid ◽  
Prostaglandin D2 ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

A new screening system for nonsteroidal anti-inflammatory drugs based upon inhibition of chemiluminescence produced from human cells (granulocytes).

1979 ◽  
Vol 25 (9) ◽  
pp. 1655-1661 ◽  
Author(s):  
K Van Dyke ◽  
C Van Dyke ◽  
J Udeinya ◽  
C Brister ◽  
M Wilson
Keyword(s):  
Active Compound ◽  
Inhibitory Activity ◽  
Sodium Salicylate ◽  
Human Cells ◽  
Screening System ◽  
Phagocytic Cells ◽  
Inhibitory Potency ◽  
Prostaglandin Synthase ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

Abstract A new screening system for nonsteroidal anti-inflammatory drugs that involves use of human phagocytic cells has been developed in which chemiluminescence measurement is used. Luminol-dependent chemiluminescence is measured after the addition of opsonized (coated with antibodies and complement) zymosan particles to human granulocytic leukocytes in the presence or absence of drugs. Of all the compounds tested, indomethacin was the most potent in blocking chemiluminescence, with measurable inhibitory activity at 5 mumol/L. The order of inhibitory potency at 0.1 mmol/L and in the presence of Ca2+ and Mg2+ was indomethacin greater than sodium salicylate greater than fenoprofen Ca greater than tolmetin greater than naproxen greater than ibuprofen. It is likely that the active compound itself must be added to the system because aspirin did not inhibit chemiluminescence, whereas its metabolite, sodium salicylate, was markedly inhibitory. Dexamethasone and methylprednisolone also did not inhibit chemiluminescence. The drugs that inhibit chemiluminescence are also known inhibitors of prostaglandin synthase (cyclooxygenase portion).

scholarly journals Localized and targeted delivery of NSAIDs for treatment of inflammation: A review

2018 ◽  
Vol 244 (6) ◽  
pp. 433-444 ◽  
Author(s):  
Rebecca M Haley ◽  
Horst A von Recum
Keyword(s):  
Drug Delivery ◽  
Side Effects ◽  
Targeted Delivery ◽  
Local Drug Delivery ◽  
Future Research ◽  
Systemic Delivery ◽  
Number Of Patients ◽  
Long Term Treatment ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

Inflammatory processes are increasingly being identified at the core of many different disease states (e.g. heart disease, cancer, diabetes). As such, anti-inflammatory strategies available through drug delivery have undergone renewed interest. Due to the systemic side effects of steroidal drugs, non-steroidal anti-inflammatory drugs are often preferred for long-term treatment of inflammation in a variety of applications. While non-steroidal anti-inflammatory drugs are generally safe, there are some serious side effects that can be associated with their usage, particularly when given systemically or orally. Due to the high number of patients taking non-steroidal anti-inflammatory drugs, the reduction or elimination of these side effects, such as is possible through local drug delivery, could have a very powerful effect on patient quality of life. This review comments on a sampling of existing methods for localized or targeted delivery of non-steroidal anti-inflammatory drugs, with the goal of helping future research groups to focus on bettering methods shown to be effective and filling the gaps of knowledge in this field. Additionally, commentary is made on the field as a whole, and the standardization issues that arise from its expansiveness and diversity. Impact statement This work provides an overview of research currently being done exploring potential drug delivery device strategies for NSAIDs as an alternative to systemic delivery. Commentary on this field is made in an attempt to aid future experimental design, enabling researchers to determine the drugs and delivery vehicles which are most advantageous for them to pursue, as well as suggestions to standardize the reporting of such future research.

scholarly journals Non-steroidal anti-inflammatory drugs in chronic kidney disease: a systematic review of prescription practices and use in primary care

2019 ◽  
Vol 13 (1) ◽  
pp. 63-71 ◽  
Author(s):  
Claire Lefebvre ◽  
Jade Hindié ◽  
Michael Zappitelli ◽  
Robert W Platt ◽  
Kristian B Filion
Keyword(s):  
Systematic Review ◽  
Primary Care ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Observational Research ◽  
Quality Improvement Intervention ◽  
Future Research ◽  
Cross Sectional ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

Abstract Background Chronic kidney disease (CKD) management focuses on limiting further renal injury, including avoiding nephrotoxic medications such as non-steroidal anti-inflammatory drugs (NSAIDs). We performed a systematic review to evaluate the prevalence of primary care NSAID prescribing in this population. Methods We systematically searched MEDLINE and Embase from inception to October 2017 for observational studies examining NSAID prescribing practices or use in CKD patients in a primary care setting. The methodological quality of included studies was assessed independently by two authors using a modified version of the Agency for Healthcare Research and Quality’s Methodological Evaluation of Observational Research checklist. Results Our search generated 8055 potentially relevant publications, 304 of which were retrieved for full-text review. A total of 14 studies from 13 publications met our inclusion criteria. There were eight cohort and three cross-sectional studies, two quality improvement intervention studies and one prospective survey, representing a total of 49 209 CKD patients. Cross-sectional point prevalence of NSAID use in CKD patients ranged from 8 to 21%. Annual period prevalence rates ranged from 3 to 33%. Meta-analysis was not performed due to important clinical heterogeneity across study populations. Conclusions Evidence suggests that NSAID prescriptions/use in primary care among patients with CKD is variable and relatively high. Future research should explore reasons for this to better focus knowledge translation interventions aimed at reducing NSAID use in this patient population.

Flufenamic Acid and Placebo Compared in Rheumatoid Arthritis and Osteoarthritis

1981 ◽  
Vol 9 (4) ◽  
pp. 253-256 ◽  
Author(s):  
G Kagan ◽  
L Huddlestone ◽  
P Wolstencroft
Keyword(s):  
Rheumatoid Arthritis ◽  
General Practice ◽  
Side Effects ◽  
Crossover Study ◽  
Morning Stiffness ◽  
Flufenamic Acid ◽  
Moderate Pain ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

Forty patients in general practice with rheumatoid arthritis or osteoarthritis were identified as suffering from moderate pain and tenderness and moderate stiffness in excess of 30 minutes. After discontinuation of non-steroidal anti-inflammatory drugs for 2 weeks, a crossover study was conducted comparing the benefits of flufenamic acid, 100 mg, four times daily with placebo. At the same time, paracetamol at a dose up to 8 × 500 mg daily, could be used for pain which the patient judged to be unrelieved. Thirty-four patients completed the two 3-week test periods and twenty-one patients were improved in relation to morning stiffness and pain by flufenamic acid and twelve patients by placebo – a difference greater than would have occurred by chance (p = 0.05). At the same time, paracetamol consumption was reduced significantly from a mean of 91.29 tablets to 60.68 tablets for each 3-week period. Side-effects occurred in ten patients on placebo and fifteen patients on flufenamic acid. One patient on each medication had to discontinue for multiple side-effects. Diarrhoea occurred in two patients on flufenamic acid and in one patient on placebo. Flufenamic acid is clearly effective and side-effects do not occur more often than would be expected by chance when compared with placebo.

scholarly journals Targeting residual inflammatory risk in coronary disease: to catch a monkey by its tail

2021 ◽  
Author(s):  
A. T. L. Fiolet ◽  
T. S. J. Opstal ◽  
M. J. M. Silvis ◽  
J. H. Cornel ◽  
A. Mosterd
Keyword(s):  
Coronary Disease ◽  
Morphological Changes ◽  
Lipid Lowering ◽  
Future Research ◽  
Risk Factor Modification ◽  
Atherosclerotic Burden ◽  
Coronary Syndromes ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Near Future

AbstractPatients with coronary disease remain at high risk for future cardiovascular events, even with optimal risk factor modification, lipid-lowering drugs and antithrombotic regimens. A myriad of inflammatory pathways contribute to progression of the atherosclerotic burden in these patients. Only in the last few years has the inflammatory biology of atherosclerosis translated into clinical therapeutic options. Low-dose colchicine can provide a clinically relevant reduction in the risk for composite and individual major cardiovascular outcomes in patients with acute and chronic coronary syndromes. Among others, its anti-inflammatory effects in atherosclerosis seem to be related to neutrophil recruitment and adhesion, inflammasome inhibition, and morphological changes in platelets and platelet aggregation. Future research is aimed at further elucidating its particular mechanism of action, as well as identifying patients with the highest expected benefit and evaluating efficacy in other vascular beds. These data will help to formulate the role of colchicine and other anti-inflammatory drugs in patients with coronary disease and atherosclerosis in general in the near future.

Antimicrobial and antifungal activities of bifunctional cooper(ii) complexes with non-steroidal anti-inflammatory drugs, flufenamic, mefenamic and tolfenamic acids and 1,10-phenanthroline

2020 ◽  
Vol 18 (1) ◽  
pp. 1444-1451
Author(s):  
Lenka Hudecova ◽  
Klaudia Jomova ◽  
Peter Lauro ◽  
Miriama Simunkova ◽  
Saleh H. Alwasel ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Antibacterial Activities ◽  
Redox Cycling ◽  
Yeast Cells ◽  
Model Organisms ◽  
Flufenamic Acid ◽  
Antifungal Activities ◽  
E Coli ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

AbstractCooper(ii) complexes represent a promising group of compounds with antimicrobial and antifungal properties. In the present work, a series of Cu(ii) complexes containing the non-steroidal anti-inflammatory drugs, tolfenamic acid, mefenamic acid and flufenamic acid as their redox-cycling functionalities, and 1,10-phenanthroline as an intercalating component, has been studied. The antibacterial activities of all three complexes, [Cu(tolf-O,O′)2(phen)] (1), [Cu(mef-O,O′)2(phen)] (2) and [Cu(fluf-O,O′)2(phen)] (3), were tested against the prokaryotic model organisms Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) and their antifungal activities were evaluated towards the yeast, Saccharomyces cerevisiae (S. cerevisiae). The antibacterial activity of both strains has been compared with the antibiotic Neomycin. The calculated IC50 values revealed slight differences in the antibacterial activities of the complexes in the order 1 ∼ 3 > 2. The most profound growth inhibition of E. coli was observed, at its highest concentration, for the complex 1, which contains chlorine atoms in the ligand environment. The trend obtained from IC50 values is generally in agreement with the determined MIC values. Similarly, the complex 1 showed the greatest growth inhibition of the yeast S. cerevisiae and the overall antifungal activities of the Cu(ii) complexes were found to follow the order 1 > 3 ≫ 2. However, for complex 2, even at the highest concentration tested (150 μM), a 50% decrease in yeast growth was not achieved. It appears that the most potent antimicrobial and antifungal Cu(ii) complexes are those containing halogenated NSAIDs. The mechanisms by which Cu(ii) complexes cause antibacterial and antifungal activities can be understood on the basis of redox-cycling reactions between cupric and cuprous species which lead to the formation of free radicals. The higher efficacy of the Cu(ii) complexes against bacterial cells may be due to an absence of membrane-protected nuclear DNA, meaning that on entering a cell, they can interact directly with its DNA. Contrastingly, for the complexes to interact with the DNA in yeast cells, they must first penetrate through the nuclear membrane.

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