Novel benzofurane-pyrazole derivatives with anti-inflammatory, cyclooxygenase inhibitory and cytotoxicity evaluation

2022 ◽  
Vol 0 (0) ◽  
Author(s):  
Zafer Sahin ◽  
Yağmur Özhan ◽  
Hande Sipahi ◽  
Sevde Nur Biltekin ◽  
Leyla Yurttaş ◽  
...  

Abstract Novel benzofurane-pyrazolone hybrids have been synthesized for evaluating their anti-inflammatory and cytotoxic properties. 4-(2-chloroacetyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one were reacted with α-hydroxy aldehyde or α-hydroxy ketone derivatives to obtain nine novel pyrazolone derivatives. Structures were successfully elucidated by 1H NMR, 13C NMR, IR and HRMS. Enzyme inhibitory activity was measured on cyclooxygenases (COXs) as considered to address anti-inflammatory activity. Compound 2 showed the highest activity on both COX-1 and COX-2 subtypes with 12.0 μM and 8.0 μM IC50, respectively. This activity was found close to indomethacin COX-2 inhibition measured as 7.4 μM IC50. Rest of the compounds (1, 3–9) showed 10.4–28.1 μM IC50 on COX-2 and 17.0–35.6 μM IC50 on COX-1 (Compound 1 has no activity on COX-1). Tested compounds (1–9) showed activity on NO production. Only compound was the 4, which showed a low inhibition on IL-6 levels. Cell viability was up to 60% at 100 μM for all compounds (1–9) on RAW 264.7 and NIH3T3 cell lines, thus compounds were reported to be noncytotoxic.

Author(s):  
Yosie Andriani ◽  
Leni Marlina ◽  
Habsah Mohamad ◽  
Hermansyah Amir ◽  
Siti Aisha M Radzi ◽  
...  

  Objective: This study aimed to investigate the anti-inflammatory activity of methanol extract and fractions of bacteria associated with sponge (Haliclona amboinensis) and to evaluate their effect in reducing NO production and inhibiting cyclooxygenase-1 (COX-1), cyclooxgenase-2 (COX-2) and secretory phospholipase A2 (sPLA2) activity.Methods: All bacterial isolates were cultured and supernatants were collected for the extraction of secondary metabolites using diaion HP-20 to obtain methanol extracts. Evaluation of cytotoxicity property was carried out on macrophage cell lines (RAW264.7) by 3-(4,5-dimethylthiazol- 2-yl) 2,5-diphenyl tetrazoliumbromide assay. Anti-inflammatory screening was done by inducible nitric oxide assay on RAW264.7 cell lines with lipopolysaccharide (LPS) stimulation. Dianion HP-20 was used to remove salt content. A selected methanol extract was subjected to further fractionations by C-18 reverse phase and their anti-inflammatory potential was evaluated by COX-1 and COX-2, and sPLA2 enzymatic assay.Results: Seven methanol extracts showed no cytotoxic property against RAW 264.7 cell line (inhibitory concentration 50% > 30 μg/ml) and selected for anti-inflammatory screening assay. Result showed methanol extract HM 1.2 reduced NO production >80% and it has been selected for phytochemical screening, further fractionations and assay. Phytochemical screening showed alkaloids and terpenoids present in the HM 1.2. The HM 1.2 and its fractions (F1, F2, F1C1, F1C2, F1C3, and F1C4) were proven to inhibit COX-1, COX-2, and sPLA2 activity in the range of 60.516-116.886%, 20.554- 116.457%, and 70.2667-114.8148%, respectively.Conclusions: This study revealed that bacteria associated with H. amboinensis have produced anti-inflammatory activity via reducing NO production and inhibiting COX-1, COX-2, and sPLA2 activity. 


2010 ◽  
Vol 299 (2) ◽  
pp. L184-L191 ◽  
Author(s):  
Gu Seob Roh ◽  
Chin-ok Yi ◽  
Yu Ji Cho ◽  
Byeong Tak Jeon ◽  
Irina Tsoy Nizamudtinova ◽  
...  

Chronic airway inflammation is a characteristic feature of destructive cigarette smoking (CS)-induced lung disease, particularly in patients with emphysema. Celecoxib, a specific cyclooxygenase-2 (COX-2) inhibitor, is widely used to treat inflammation. However, the exact mechanisms underlying this drug's anti-inflammatory effects have not yet been determined in pulmonary emphysema. Here, we explore whether celecoxib attenuates CS-induced inflammation in rat lungs. Rats were exposed to smoke and received celecoxib via intragastric feeding daily for 20 wk. We found that celecoxib inhibited interalveolar wall distance and pulmonary inflammation in the lungs of CS-treated rats. Celecoxib inhibited serum NO production, iNOS, COX-2 expression, and PGE2 production in CS-treated lung tissues. Our immunohistochemical data showed that CS-induced CD68 and COX-2 expression were inhibited by celecoxib. Furthermore, celecoxib attenuated the activation of phospho-IκBα and NF-κB in CS-treated rat lung. In addition, there was an inhibitory effect of celecoxib on the COX-2 expression and NF-κB activation in LPS-stimulated RAW 264.7 macrophages. Celecoxib also attenuated NF-κB activation in COX-2 siRNA-transfected RAW 264.7 macrophages. Thus, our findings suggest that the anti-inflammatory effects of celecoxib are mediated by its effects on NF-κB-regulated gene expression, which ultimately reduces the progression of CS-induced pulmonary emphysema.


2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Chih-Hsuan Hsia ◽  
Thanasekaran Jayakumar ◽  
Wan-Jung Lu ◽  
Joen-Rong Sheu ◽  
Chih-Wei Hsia ◽  
...  

Objective. Oxidative stress-mediated inflammatory events involve in the progress of several diseases such as asthma, cancers, and multiple sclerosis. Auraptene (AU), a natural prenyloxycoumarin, possesses numerous pharmacological activities. Here, the anti-inflammatory effects of AU were investigated in lipoteichoic acid- (LTA-) induced macrophage cells (RAW 264.7). Methods. The expression of cyclooxygenase (COX-2), tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and inducible nitric oxide synthase (iNOS) and the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, p38 MAPK, c-Jun N-terminal kinase (JNK), heme oxygenase (HO-1), p65, and IκBα were all identified by western blotting assay. The level of nitric oxide (NO) was measured by spectrometer analysis. The nuclear translocation of p65 nuclear factor kappa B (NF-κB) was assessed by the confocal microscopic staining method. Native polyacrylamide gel electrophoresis was performed to perceive the activity of antioxidant enzyme catalase (CAT). Results. AU expressively reduced NO production and COX-2, TNF-α, IL-1 β, and iNOS expression in LTA-stimulated cells. AU at higher concentration (10 µM) inhibited ERK and JNK, but not p38 phosphorylation induced by LTA. Moreover, AU blocked IκB and p65 phosphorylation, and p65 nuclear translocation. However, AU pretreatment was not effective on antioxidant HO-1 expression, CAT activity, and reduced glutathione (GSH, a nonenzymatic antioxidant), in LTA-induced RAW 264.7 cells. Conclusion. The findings of this study advocate that AU shows anti-inflammatory effects via reducing NF-κB/MAPKs signaling pathways.


Author(s):  
Ahmed Basim ◽  
Zuhair A. Muhi Eldeen ◽  
Elham N. Al-kaissi ◽  
Ghadeer Suaifan ◽  
Mohammad A. Ghattas ◽  
...  

<p><strong>Objective: </strong>To design and synthesise a new amino acetylenic tetrahydro phthalimide derivative and investigate their selective inhibitory activity to COXs.</p><p><strong>Methods: </strong>Aminoacetylenic tetrahydro phthalimide derivatives were synthesised by alkylation of tetrahydro phthalimide with propargyl bromide afforded 2-(prop-2-yn-1-yl)-2,3,3a,4,7,7a-hexahydro-1H-isoindole-1,3-dione. The alkylated tetrahydro phthalimide was subjected to Mannich reaction afforded the desired amino acetylenic tetra phthalimide derivatives (AZ 1-6). The elemental analysis was indicated by the EuroEA elemental analyzer and biological characterization was via IR, <sup>1</sup>H-NMR, [13]C-NMR, DSC was determined with the aid of Bruker FT-IR and Varian 300 MHz spectrometer and DMSO-d<sub>6</sub> as a solvent, molecular docking was done using the Autodock Tool software (version 4.2). ChemBioDraw was used in the drawing of our schemes.</p><p><strong>Results</strong>:<strong> </strong>The IR, <sup>1</sup>H-NMR, <sup>13</sup>C-NMR, DSC and elemental analysis were consistent with the assigned structures. The designers of the compounds as COXs inhibitor activity were based on the nationalisation of the important criteria that provide effective inhibitory binding with COXs–receptor. The results indicated that the synthesised compounds (AZ1-6) showed a close similarity in the binding affinity to both COXs and may be more specific to COX-1. AZ-5 showed the highest % of inhibition for COX-1 even better than aspirin. Which may suggest that the aryl group is required for COX-2 inhibition.</p><p><strong>Conclusion: </strong>For the first time, we indicate the requirement of aromaticity in COX-2 structural inhibitory activity. </p>


Medicines ◽  
2019 ◽  
Vol 6 (2) ◽  
pp. 55 ◽  
Author(s):  
Jun-Xian Zhou ◽  
Michael Wink

Background: We investigated the effect of root extracts from the traditional Chinese medicine (TCM) plants Glycyrrhiza glabra L., Paeonia lactiflora Pall., and the leaf extract of Eriobotrya japonica (Thunb.) Lindl., and their six major secondary metabolites, glycyrrhizic acid, 18β glycyrrhetinic acid, liquiritigenin, isoliquiritigenin, paeoniflorin, and ursolic acid, on lipopolysaccharide (LPS)-induced NF-κB expression and NF-κB-regulated pro-inflammatory factors in murine macrophage RAW 264.7 cells. Methods: The cytotoxicity of the substances was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. RAW 264.7 cells were treated with LPS (1 μg/mL) or LPS plus single substances; the gene expression levels of NF-κB subunits (RelA, RelB, c-Rel, NF-κB1, and NF-κB2), and of ICAM-1, TNF-α, iNOS, and COX-2 were measured employing real-time PCR; nitric oxide (NO) production by the cells was quantified with the Griess assay; nuclear translocation of NF-κB was visualized by immunofluorescence microscopy with NF-κB (p65) staining. Results: All the substances showed moderate cytotoxicity against RAW 264.7 cells except paeoniflorin with an IC50 above 1000 μM. Glycyrrhiza glabra extract and Eriobotrya japonica extract, as well as 18β glycyrrhetinic acid and isoliquiritigenin at low concentrations, inhibited NO production in a dose-dependent manner. LPS upregulated gene expressions of NF-κB subunits and of ICAM-1, TNF-α, iNOS, and COX-2 within 8 h, which could be decreased by 18β glycyrrhetinic acid, isoliquiritigenin and ursolic acid similarly to the anti-inflammatory drug dexamethasone. NF-κB translocation from cytoplasm to nucleus was observed after LPS stimulation for 2 h and was attenuated by extracts of Glycyrrhiza glabra and Eriobotrya japonica, as well as by 18β glycyrrhetinic acid, isoliquiritigenin, and ursolic acid. Conclusions: 18β glycyrrhetinic acid, isoliquiritigenin, and ursolic acid inhibited the gene expressions of ICAM-1, TNF-α, COX-2, and iNOS, partly through inhibiting NF-κB expression and attenuating NF-κB nuclear translocation. These substances showed anti-inflammatory activity. Further studies are needed to elucidate the exact mechanisms and to assess their usefulness in therapy.


2017 ◽  
Vol 7 (6) ◽  
pp. 375 ◽  
Author(s):  
Xiu-Min Chen ◽  
David D Kitts ◽  
Zhili Ma

Background: Indigenous or traditional aqueous plant extracts are commonly used by as much as 80% of the world’s population for primary health needs. Teas including Camellia sinensis teas and herbal teas were characterized for phytochemical content and the potential to offer specific bioactivities that could benefit human health by mitigating oxidative stress and inflammation. Context and purpose of this study: In present study, we compared the phytochemical profiles, antioxidant and anti-inflammatory activities of four Camellia sinensis (white, green, oolong, and black) teas and two herbal (Rooibos and Yerba mate) teas that are produce and consumed by different population worldwide. We also studied the impact of Rooibos tea on the production of inflammatory mediators, including nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2) and different cytokines in Raw 264.7 cells, both with or without interferon γ (IFN-γ) and lipopolysaccharide (LPS) stimulation.Results: White tea had the highest total phenolic content (TPC) and antioxidant activity among these six teas examined, whereas, Rooibos tea has the lowest TPC, antioxidant and anti-inflammatory activities. Yerba mate tea had the greatest potential to inhibit NO production in IFN-γ and LPS-induced Raw 264.7 cells. The anti-inflammatory activity of teas was found to be correlated with antioxidant activity and phytochemical composition. Among the six teas examined, only Rooibos tea was found to induce NO in unstimulated Raw 264.7 cells. Under basal conditions, Rooibos tea induced interleukin (IL)-1α (IL-1α), IL-1β, IL-6, IL-10, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor- alpha (TNF-α), iNOS and COX-2 production. However, Rooibos tea also showed a dose-dependent inhibition of IL-6, IL-10, iNOS and COX-2 expression in stimulated Raw 264.7 cells. Although high concentration Rooibos tea was affective to inhibit induced IL-1α, G-CSF and GM-CSF, low concentration Rooibos tea also can up-regulate the expression of these cytokines. No inhibitory effects of all teas examined were found on mitigation of IL-1β and TNF-α.Conclusions: Rooibos tea can show dual functions on inflammation, by either promoting an inflammatory response to cytokines induction or, alternatively inhibit inflammation on exposure to cytokine treatment, such as tissue injury or a pathogen infection. Rooibos tea also has marked value in mitigating disease states such as hypertension and cardiovascular diseases where induction of NO production is important.Keywords: Camellia sinensis, Rooibos tea, herbal tea, inflammation, cytokine, antioxidant


2008 ◽  
Vol 3 (6) ◽  
pp. 1934578X0800300
Author(s):  
Mohamed-Elamir F. Hegazy ◽  
Ashraf A. Aly ◽  
Ahmed A. Ahmed ◽  
Djemgou C. Pierre ◽  
Pierre Tane ◽  
...  

A new 14,15-dinor-labdane glucoside, named crassoside A (1), was isolated from the aerial parts of Crassocephalum mannii. The structure of 1 was elucidated on the basis of spectroscopic analysis (1H NMR, 13C NMR, HMQC, HMBC and NOEs). Compound 1 demonstrated a low inhibitory effect against COX-1, but was inactive against COX-2.


Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4807
Author(s):  
Jianxin Han ◽  
Wei Liu ◽  
Miaomiao Li ◽  
Yanpei Gu ◽  
Ying Zhang ◽  
...  

In the current study, further chemical investigation of the fruiting bodies of Fomes officinalis led to isolate seven new 24-methyl-lanostane triterpenoids, named officimalonic acids I−O (1–7). Their structures were elucidated based on the analysis of spectroscopic data (HR-MS, 1D and 2D NMR, UV, IR). Compounds 1−3 possessed an unusual C-23 spirostructure moiety, while compounds 4−7 had 23,26-lactone unit. Anti-inflammatory assay revealed that compounds 3 and 5 exhibited significant inhibitory activities against NO production in LPS-induced RAW 264.7 cells and cyclooxygenase (COX-2).


Molecules ◽  
2019 ◽  
Vol 24 (21) ◽  
pp. 3848 ◽  
Author(s):  
Seulah Lee ◽  
Dahae Lee ◽  
Su Cheol Baek ◽  
Mun Seok Jo ◽  
Ki Sung Kang ◽  
...  

To discover new pharmacologically active natural products, here, we performed the phytochemical analysis of a Korean medicinal plant. Euonymus alatus (Thunb.) Sieb. is a traditional medicinal plant that has been used as a remedy for various diseases in Asian countries. In particular, the cork cambium on the twigs of E. alatus has been used to treat dysmenorrhea, tumors, diabetes, and wound. Phytochemical analysis of the methanolic extract of E. alatus twigs led to the isolation of a sterol, which was identified as (3β,16α)-3,16-dihydroxypregn-5-en-20-one (1) by 1D and 2D nuclear magnetic resonance (NMR) spectroscopy and high-resolution electrospray ionization mass spectrometry. The stereochemistry of 1 was established with nuclear Overhauser effect spectroscopy (NOESY) analysis and comparison of electronic circular dichroism (ECD) data. To the best of our knowledge, the isolation of compound 1 from nature is first reported here, as well as the complete and revised NMR data assignment of 1. In lipopolysaccharide (LPS)-stimulated RAW-264.7 macrophages, compound 1 significantly inhibited nitric oxide (NO) production at an IC50 value of 12.54 ± 0.05 μM as well as the protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Moreover, the pre-treatment with compound 1 attenuated the LPS-induced phosphorylation of nuclear factor kappa B (NF-κB) p65 through the inhibition of the phosphorylation of IκB kinase alpha (IKKα), IKKβ, and inhibitor of kappa B alpha (IκBα). Compound 1 also inhibited the LPS-induced phosphorylation of p38, c-Jun NH2-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK). Taken together, compound 1 may serve as an anti-inflammatory constituent of E. alatus twigs and its anti-inflammatory property is thought to be associated with the inhibition of NO production via suppression of iNOS and COX-2 expression through inhibition of IKKα/β, I-κBα and NF-κB p65 activation and downregulation of p38, JNK, and ERK mitogen-activated protein kinase signal pathways in RAW 264.7 macrophages. These findings also provide experimental evidence that compound 1 identified from E. alatus twigs could be a candidate for an anti-inflammatory agent.


2021 ◽  
Author(s):  
Samuel Kamatham ◽  
Naresh Babu V. Sepuri ◽  
Naresh Kumar

Abstract The transcription factor NF-κB regulates a large array of genes of immune and inflammatory responses. Deregulated NF-κB signalling is implicated in the pathogenesis and broad spectrum of human inflammatory disorders and malignancies. The mechanism for NF-κB activation is the inducible degradation of IκB, triggered through its site-specific phosphorylation by a multi-subunit IκB kinase (IKK) complex. Aspirin (acetylsalicylic acid) a well-known anti-inflammatory agent that binds to ATP binding pocket of IKKβ and inhibits its kinase activity. However, several side effects of aspirin due to the inactivation of COX-1 limits the therapeutic usage of ASA. Here we have demonstrate the effect of a plant phenolic compound benzoylsalicylic acid (BzSA) isolated first time in plants a potent anti-viral compound inhibits Tobacco mosaic virus (TMV) and enhance the plant defense response (Samuel et all 2016&2017) inhibit the IKKβ mediated NF-κB pathway higher than aspirin. Our In-vitro COX enzymatic assays with BzSA have shown less COX-1 and high COX-2 inhibition as compared to ASA. Western blotting analysis of Raw 264.7 cells that were pre-treated with BzSA down-regulated LPS stimulated pIKK-β, pIκB, NF-κBp65, TNF-α, COX-1, COX-2, 5-LOX, IL-1β, and IL-6 higher than ASA. Therefore, our observations suggested that the potencial therapeutic value of BzSA an upcoming new inhibitor of NF-KB pathway and the dual inhibitor of COX2/5-LOX without effecting the usefull COX-1. Hence useful as an anti-inflammatory agent like ASA.


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