Design, Synthesis, Computational and Biological Evaluation of Two New Series of 1, 3- and 1,6-dihydroxy xanthone Derivatives as Selective COX-2 Inhibitors

2021 ◽  
Vol 18 ◽  
Author(s):  
Urvashee Gogoi ◽  
Aparoop Das ◽  
Manash Pratim Pathak ◽  
Pronobesh Chattopadhyay ◽  
Surabhi Johari
Keyword(s):  
Molecular Mechanisms ◽  
Biological Evaluation ◽  
Inflammatory Activity ◽  
Significant Drop ◽  
Xanthone Derivatives ◽  
Cox Inhibitor ◽  
Tnf Α ◽  
Cox 2 ◽  
Anti Inflammatory

Background: Over the years, the xanthone nucleus has been serving as an interesting scaffold for the design of derivatives aiming at anti-inflammatory drug development. Objective: The objective of the current work was to design and synthesize two series of novel 3-(5'-substituted pentyloxy)-1-hydroxy xanthone & 6-(5'-substitutedpentyloxy)-1-hydroxy xanthone derivatives. The designed compounds were examined in vivo for anti-inflammatory activity. The effect of the synthesized xanthone derivatives on the serum expression of IL-10 and TNF-α was evaluated to understand the underlying molecular mechanisms. Method: The title compounds were virtually designed and screened for ADME/T properties and docked onto the COX-2 protein. The synthesis of the xanthone derivatives was achieved by the condensation of salicylic acid derivatives and a suitable phenol in presence of a mixture of phosphorus pentoxide–methanesulfonic acid as an acylation catalyst. The compounds were evaluated for in vivo anti-inflammatory activity by carrageenan induced paw edema method and serum expression of cytokines was evaluated using ELISA assays. Results: The selected compounds exhibited docking scores ranging between -10.7 to -6.8 (Kcal/mol) respectively as compared with standard Celecoxib (-7.9 Kcal/mol) and the non-selective COX inhibitor Indomethacin (-6.4 Kcal/mol). Among the tested compounds 9u have shown the highest activity with 65.6 % reduction in edema (69.8% for Celecoxib). Immunoassay results showed a significant drop in serum TNF-α and an elevation in serum IL-10. Conclusion: The findings highlight the fact that some of the synthesized xanthone derivatives displayed marked anti-inflammatory activity which can be further investigated to render efficient and novel non-ulcerogenic anti-inflammatory agents.

scholarly journals Design and Synthesis of 2-Mercapto Benzoxazole coupled Benzyl Triazoles as Anti-inflammatory Agents Targeting COX-2 Enzyme

2020 ◽  
Vol 32 (12) ◽  
pp. 3209-3218
Author(s):  
K. Praveen Kumar ◽  
Y. Prashanthi ◽  
G. Rambabu ◽  
Md. Ataur Rahman ◽  
J.S. Yadav
Keyword(s):  
Chemical Space ◽  
Biological Evaluation ◽  
Inflammatory Activity ◽  
Design Synthesis ◽  
Standard Drug ◽  
Design And Synthesis ◽  
Cox 2 ◽  
Anti Inflammatory

In this study, we report the design, synthesis and the biological evaluation of 19 analogues of 2-mercapto benzoxazole coupled benzyl triazoles (BOTs) based on analysis of the binding site and literature of chemical space. These BOTs were evaluated both in vitro and in vivo for their anti-inflammatory activity. Eleven compounds showed less than 10 μM in vitro COX-2 enzyme activities. The most potent analogue among the BOT analogues were BOT15, BOT3 and BOT19 with IC50 3.40 μM, 4.50 μM and 4.57 μM respectively against COX-2. The in vivo anti-inflammatory activity of two BOTs has significantly higher than that of standard drug, ibuprofen. 2-Mercapto benzoxazole coupled benzyl triazoles (BOTs) were also tested for their antioxidant capacity and proved to be an as active scavenger, better than ascorbic acid.

Anti-inflammatory effect of an Ayurveda polyherbal topical application and exploration of its mechanism of action

2017 ◽  
Vol 2 (06) ◽  
Author(s):  
Sitaram Ahalya ◽  
B. A. Venkatesh ◽  
R. Vijayasarathi ◽  
Tirumalapura Vijayanna Shalini
Keyword(s):  
Topical Application ◽  
Inflammatory Activity ◽  
Polyherbal Formulation ◽  
Tnf Α ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Ear Oedema ◽  
Inflammatory Effect

Background: Topical application of herbs is one of the recommended treatment modalities for Osteoarthritis (OA) in Ayurveda (Indian system of medicine). The current study intended to evaluate the anti-inflammatory effect of a polyherbal powder used as Upanaha (poultice) for OA by in vitro and in vivo techniques. Materials and Methods: The polyherbal formulation Upanaha Choornam (UC) was sourced from Vaidyaratnam Oushadhasala (P) Ltd., Thrissur, India. Changes in the secretion of TNF-α and NO and expression of Cox-2 genes were evaluated by semi quantitative PCR activity to establish anti-inflammatory action in vitro. Macrophages and connective tissue of mice were used as media for the former two experiments and only macrophages for the latter. In vivo anti–inflammatory activity was evaluated by TPA induced ear oedema in Swiss Albino mice (n=24), divided into 4 groups as Group I - saline treatment, Group II - Indomethacin treatment, and Groups III and IV treated with 30% and 60% of UC respectively. Results: In the in vitro study, UC at 1000 µg/ml and 500 µg/ml upregulated the COX-2 level by 0.08 and 0.03 folds respectively as compared to control. Release of TNF-α, and NO in LPS-induced RAW cells were significantly inhibited in a dose dependent manner. The TPA induced ear oedema significantly reduced in Groups III and IV (F=1250, p less than 0.001) Conclusion: The current study demonstrates the safety and anti-inflammatory activity of a polyherbal formulation Upanaha Choornam as a topical application. This indicates the potential of select herbs in managing degenerative conditions like OA.

scholarly journals In vivo anti-inflammatory activity of Liquidambar formosana Hance infructescence extract

2017 ◽  
Vol 16 (10) ◽  
pp. 2403-2410
Author(s):  
Haoran Ma ◽  
Fuqian Wang ◽  
Jie Jiang ◽  
Lu Cheng ◽  
Hong Zhang ◽  
...  
Keyword(s):  
Inflammatory Activity ◽  
Enzyme Linked Immunosorbent Assay ◽  
Paw Edema ◽  
Tnf Α ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Underlying Mechanisms ◽  
Anti Inflammatory Cytokine ◽  
Inflammatory Effect

Purpose: To evaluate the anti-inflammatory activity of Liquidambar formosana  Hance infructescence (Liquidambaris fructus, ELF) in vivo, and clarify its underlying mechanisms. Methods: The in vivo anti-inflammatory activity of ELF was examined by xylene-induced ear swelling test in mice as well as carrageenan-induced paw edema method in rats. The levels of inflammatory cytokines (TNF-α, IL-1β, IL-6 and IL-10) in serum were measured by enzyme-linked immunosorbent assay (ELISA), while the expressions of COX-2, iNOS and NF-κB p65 in paw tissue of rats were evaluated by western blot.Results: After ELF treatment, the levels of TNF-α (p < 0.001), IL-1β (p < 0.001) and IL-6 (p < 0.001) in serum decreased and the levels of anti-inflammatory cytokine IL-10 increased (p < 0.01). In addition, ELF treatment resulted in decrease of COX-2 (p < 0.01), iNOS (p < 0.01) and NF-κB p65 (p < 0.01) expressions in Wistar rats.Conclusion: The results reveal that ELF possesses significant anti-inflammatory effect in vivo. The anti-inflammatory activity is associated with the levels of TNF-α, IL-1β, IL-6 and IL-10 in serum. Furthermore, the suppression of NF-κB p65, iNOS and COX-2 is linked to its anti-inflammatory effect. These results provide a rationale for the use of Liquidambaris fructus in inflammatory disease in traditional medicine.Keywords: Anti-inflammatory activity, Liquidambaris fructus, Cytokines, Ear swelling test, Paw edema

scholarly journals A mechanistic study on the inhibition of bacterial growth and inflammation by Nerium oleander extract with comprehensive in vivo safety profile

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yousra Shafiq ◽  
Syed Baqir Shyum Naqvi ◽  
Ghazala H. Rizwani ◽  
Muhammad Arif Asghar ◽  
Rabia Bushra ◽  
...  
Keyword(s):  
Inflammatory Activity ◽  
Nerium Oleander ◽  
Flower Extract ◽  
Toxicity Potential ◽  
Tnf Α ◽  
Cotton Pellet ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Rat Paw

Abstract Background Nerium oleander (L.) is well known traditionally used medicinal plant with several pharmacological activities. However, the anti-bacterial, anti-inflammatory activity and in vivo toxicity potential of floral parts of this plant are not reported. Therefore the present study was designed to investigate these activities of Nerium oleander ethanolic flower extract (NOEE) in different animal models. Methods Antimicrobial activity of plant extract was compared with five different antibiotics using the disk diffusion method. The time-killing kinetic assay and bacterial killing mechanism of NOEE were also performed. Anti-inflammatory activity was assessed using granuloma induced by cotton-pellet, rat paw edema induced by carrageenan and levels of different inflammatory biomarkers on healthy Wistar rats. The protein and mRNA expressions of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were also measured. Acute (14 days) and sub-acute (28 days) oral toxicity studies were also performed on healthy Sprague Dawley rats. Results NOEE produced highly significant (P < 0.005) and significant (P < 0.05) zones of inhibition at 30 mg/mL and 20 mg/mL respectively against most of the tested bacterial strains. NOEE produced a more drop in viable counts of Gram-negative isolates within 20 min. After 12 h exposure with NOEE, the SEM images of MRSA showed the destruction of cell membrane. NOEE showed highly significant (P < 0.005) anti-inflammatory activity in cotton-pellet and carrageenan inflammatory models. In addition, treatment with NOEE also decreased the production of NO, PGE2, TNF-α and IL-1β in the rat paw after treated with carrageenan. Similarly, NOEE also suppressed the inducible nitric oxide synthase (iNOS), TNF-α, IL-1β, and cyclooxygenase-2 (COX-2) mRNA expressions. It is also showed highly significant reduction in total leukocyte count (73.09%) and C-reactive protein levels (54.60%). NOEE also inhibited COX-1, COX-2, 5-LO and 12-LO in a highly significant manner. Moreover, acute and sub-acute toxicity studies of NOEE in rats confirm the toxicity with hepatotoxicity at higher doses (2000 mg/kg) i.e. four times greater than the therapeutic dose. Conclusion It is concluded that crude flower extract of N. oleander is a potent antimicrobial and anti-inflammatory agent with no toxicity potential at therapeutic doses.

scholarly journals The Anti-Inflammatory Effect of Smilax china L. Extract on LPS-Stimulated THP-1 via Downregulation of MAPK and NF-κB Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Siyi Jiang ◽  
Qiong Wei ◽  
Xiaochuan Ye ◽  
Dan Luo ◽  
Xiaoyan Zhang ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Positive Control ◽  
Inflammatory Activity ◽  
Mrna Levels ◽  
Tnf Α ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 1 ◽  
Inflammatory Effect

Background. Traditional Chinese medicine Smilax is the rhizome of liliaceous plant Smilax china L., which is used to treat pelvic inflammatory disease and anxieties. Purpose. To investigate the mechanism of anti-inflammatory activity of the extract from Smilax china L. (ES). Methods. The components of ES were identified by UPLC-QTOF-MS/MS. The anti-inflammatory activities were evaluated in xylene-induced ear oedema and egg white-induced plantar swelling test. Cell viability was examined by CCK-8 assay. The inflammatory mediators, proinflammatory cytokines, and MAPK and NF-κB signals in LPS-stimulated THP-1 cells were determined using ELISA, real-time PCR, and Western blot, respectively. Results. 20 compounds of ES were confirmed by comparing with the reference substance. ES displayed more prominent anti-inflammatory activity than the positive control “Jin Gang Teng” capsule in the in vivo acute inflammatory model. ES suppressed the expression of PGE2 and 6-Keot-PGF1α, and the ratio of IC50 (COX-1)/IC50 (COX-2) of ES was 3.15, which indicated that ES could selectively inhibit COX-2. ES dose-dependently (12.5, 25, and 50 mg/L) decreased the production and mRNA levels of proinflammatory cytokines IL-1β, IL-6, and TNF-α. Furthermore, ES significantly decreased LPS-induced phosphorylation of p38, JNK, ERK1/2, and p65, inhibiting the expression of IKKα and the degradation of IκBα. Conclusion. The results suggested that ES could selectively inhibit the activity of COX-2, and the anti-inflammatory effect of ES was associated with the inhibition of IL-1β, IL-6, and TNF-α via negative regulation of MAPK and NF-κB signaling pathways in LPS-induced THP-1 cells.

Design, Synthesis, Characterization and in silico molecular docking studies and in vivo anti-inflammatory Activity of Pyrazoline clubbed Thiazolinone Derivatives

2020 ◽  
Vol 17 ◽  
Author(s):  
Deepak Kumar Singh ◽  
Mayank Kulshreshtha ◽  
Yogesh Kumar ◽  
Pooja A Chawla ◽  
Akash Ved ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Biological Activities ◽  
Inflammatory Activity ◽  
Standard Drug ◽  
Docking Score ◽  
Chemical Structures ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 1

Background: The pyrazolines give the reactions of aliphatic derivatives, resembling unsaturated compounds in their behavior towards permanganate and nascent hydrogen. This nucleus has been associated with various biological activities including inflammatory. Thiazolinone is a heterocyclic compound that contains both sulfur and nitrogen atom with a carbonyl group in their structure.Thiazolinone and their derivatives have attracted continuing interest because of their various biological activities, such as anti-inflammatory, antimicrobial, anti-proliferative, antiviral, anticonvulsant etc. The aim of the research was to club pyrazoline nucleus with thiazolinone in order to have significantanti-inflammatory activity. The synthesized compounds were chemically characterized for the establishment of their chemical structures and to evaluate as anti-inflammatory agent. Method: In the present work, eight derivatives of substituted pyrazoline (PT1-PT8) were synthesized by a three step reaction.The compounds were subjected to spectral analysis by Infrared, Mass and Nuclear magnetic resonance spectroscopy and elemental analysis data. All the synthesized were evaluated for their in vivo anti-inflammatory activity. The synthesized derivatives were evaluated for their affinity towards target COX-1 and COX-2, using indomethacin as the reference compound molecular docking visualization through AutoDock Vina. Results: Compounds PT-1, PT-3, PT-4 and PT-8 exhibited significant anti-inflammatory activity at 3rd hour being 50.7%, 54.3%, 52.3% and 57% respectively closer to that of the standard drug indomethacin (61.9%).From selected anti-inflammatory targets, the synthesized derivatives exhibited better interaction with COX-1 and COX-2 receptor, where indomethacin showed docking score of -6.5 kJ/mol, compound PT-1 exhibited highest docking score of -9.1 kJ/mol for COX-1 and compound PT-8 having docking score of 9.4 kJ/mol for COX-2. Conclusion: It was concluded that synthesized derivatives have more interaction with COX-2 receptors in comparison to the COX-1 receptors because the docking score with COX-2 receptors were very good. It is concluded that the synthesized derivatives (PT-1 to PT-8) are potent COX-2 inhibitors.

Design and Synthesis of Novel Ibuprofen Derivatives as Selective COX-2 inhibitors and potential anti-inflammatory agents: Evaluation of PGE2, TNF-α, IL-6 and histopathological study

2021 ◽  
Vol 17 ◽  
Author(s):  
Peter Amir Halim ◽  
Hala Bakr El-Nassan ◽  
Yara Sayed El-Dash
Keyword(s):  
Carboxylic Acid ◽  
Gastric Mucosa ◽  
Docking Simulation ◽  
Histopathological Study ◽  
Acid Moiety ◽  
Rat Serum ◽  
Tnf Α ◽  
Cox 2 ◽  
Anti Inflammatory

Background: The reported binding mode of ibuprofen in the COX-2 binding site indicated that the carboxylic group binds with Arg-120 and Tyr-355 at the entrance of the cyclooxygenase channel and does not extend into the pocket. This accounted for the non-selectivity of ibuprofen. Based on this fact, we assumed that extending the length of the carboxylic acid moiety in ibuprofen and adding more bulky rigid groups as well as bulky groups carrying H-bonding functions might increase the selectivity and reduce the side effects of ibuprofen while maintaining its analgesic and anti-inflammatory activities. Objective: In this work, four series of ibuprofen derivatives were designed and prepared. The compounds were designed by increasing the length of the carboxylate group along with the incorporation of large hydrophobic groups. Method: Four series of ibuprofen derivatives were synthesized starting from ibuprofen. Their chemical structure was confirmed by spectral data. All the compounds were tested for their COX inhibitory activity. Results : The best COX-2 activity and selectivity were obtained with compounds 5c and 5d, which were subjected to further in vivo testing (carrageenan-induced paw edema, rat serum PGE2, TNF- α and IL-6, hot plate latency test) to investigate their anti-inflammatory and analgesic activities as well as their effects on the gastric mucosa. The anti-inflammatory activity of both compounds was comparable to that of ibuprofen, diclofenac, and indomethacin. Both compounds suppressed the production of PGE2 as well as the rat serum concentrations of both TNF-α and IL-6. This potent anti-inflammatory and analgesic behavior was not accompanied by any effect on the gastric mucosa. Docking simulation studies of the two compounds explained the higher selectivity for the COX-2 enzyme. Conclusion: Potent and selective ibuprofen derivatives can be successively obtained by extending the length of the carboxylic acid moiety in ibuprofen and adding more bulky rigid groups as well as bulky groups with H-bonding functions.

scholarly journals Anti-Inflammatory Activity of the Active Compounds of Sanguisorbae Radix In Macrophages and in Vivo Toxicity Evaluation in Zebrafish

Cosmetics ◽  
2019 ◽  
Vol 6 (4) ◽  
pp. 68
Author(s):  
Young-Ah Jang ◽  
Yong Hur ◽  
Jin-Tae Lee
Keyword(s):  
Target Genes ◽  
Inflammatory Activity ◽  
Dependent Manner ◽  
Active Components ◽  
Necrosis Factor Alpha ◽  
In Vivo Toxicity ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Sanguisorbae Radix

Sanguisorbae Radix (SR) is the root of the Sanguisorba officinalis L., a plant native to Asian countries and used in traditional medicine. We isolated the active components of SR and investigated their anti-inflammatory potential. Quercetin (QC), (+)-catechin (CC), and gallic acid (GA) were isolated from acetone extracts of SR. To elucidate the molecular mechanism by which these compounds suppress inflammation, we analyzed the transcriptional up-regulation of inflammatory mediators, such as nuclear factor-kappa B (NF-κB) and its target genes, inducible NOS (iNOS), and cyclooxygenase (COX)-2, in lipopolysaccharide (LPS)-stimulated macrophage RAW264.7 cells. Notably, QC, CC, and GA were found to inhibit the production of nitric oxide, tumor necrosis factor-alpha, and prostaglandin in a dose-dependent manner. Western blot results indicate that the compounds decreased the expression of iNOS and COX-2 proteins. Furthermore, the compounds decreased phosphorylation of IKK, IκB, ERK, p-38, and JNK proteins in LPS-induced cells. The results support the notion that QC, CC, and GA can potently inhibit the inflammatory response, with QC showing the highest anti-inflammatory activity. In in vivo toxicity studies in zebrafish (Danio rerio), QC showed no toxicity up to 25 μg/mL. Therefore, QC has non-toxic potential as a skin anti-inflammatory biomaterial.

scholarly journals Nerolidol Mitigates Colonic Inflammation: An Experimental Study Using both In Vivo and In Vitro Models

Nutrients ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 2032
Author(s):  
Vishnu Raj ◽  
Balaji Venkataraman ◽  
Saeeda Almarzooqi ◽  
Sanjana Chandran ◽  
Shreesh K. Ojha ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
In Vitro Models ◽  
Mrna Levels ◽  
Colonic Inflammation ◽  
Tnf Α ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Ht 29

Nerolidol (NED) is a naturally occurring sesquiterpene alcohol present in various plants with potent anti-inflammatory effects. In the current study, we investigated NED as a putative anti-inflammatory compound in an experimental model of colonic inflammation. C57BL/6J male black mice (C57BL/6J) were administered 3% dextran sodium sulfate (DSS) in drinking water for 7 days to induce colitis. Six groups received either vehicle alone or DSS alone or DSS with oral NED (50, 100, and 150 mg/kg body weight/day by oral gavage) or DSS with sulfasalazine. Disease activity index (DAI), colonic histology, and biochemical parameters were measured. TNF-α-treated HT-29 cells were used as in vitro model of colonic inflammation to study NED (25 µM and 50 µM). NED significantly decreased the DAI and reduced the inflammation-associated changes in colon length as well as macroscopic and microscopic architecture of the colon. Changes in tissue Myeloperoxidase (MPO) concentrations, neutrophil and macrophage mRNA expression (CXCL2 and CCL2), and proinflammatory cytokine content (IL-1β, IL-6, and TNF-α) both at the protein and mRNA level were significantly reduced by NED. The increase in content of the proinflammatory enzymes, COX-2 and iNOS induced by DSS were also significantly inhibited by NED along with tissue nitrate levels. NED promoted Nrf2 nuclear translocation dose dependently. NED significantly increased antioxidant enzymes activity (Superoxide dismutase (SOD) and Catalase (CAT)), Hemeoxygenase-1 (HO-1), and SOD3 mRNA levels. NED treatment in TNF-α-challenged HT-29 cells significantly decreased proinflammatory chemokines (CXCL1, IL-8, CCL2) and COX-2 mRNA levels. NED supplementation attenuates colon inflammation through its potent antioxidant and anti-inflammatory activity both in in vivo and in vitro models of colonic inflammation.

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