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Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry

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A special issue of Molecules (ISSN 1420-3049).

Deadline for manuscript submissions: closed (30 April 2013) | Viewed by 91566

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Prof. Dr. Arduino A. Mangoni

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Discipline of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Bedfor Park, SA 5042, Australia
Interests: drug and biomarker discovery; drug repurposing; aging; cancer; cardiovascular disease
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Dear Colleagues,

Although anti-inflammatory agents are extensively prescribed across all age groups worldwide there are several unanswered questions about their exact mechanism of action and their potential renal and cardiovascular toxicity. These issues are largely related to 1) the validity of available methods for assessing selectivity towards the cyclooxygenase enzyme isoforms COX-1 and COX-2; 2) the exact role played by COX-1 and COX-2 in renal and vascular homeostasis in animal models and humans; and 3) the interpretation of data from pharmacoepidemiological studies and meta-analyses.
This special issue of Molecules welcomes previously unpublished manuscripts covering all aspects of pharmacology and chemistry of anti-inflammatory drugs, in particular the development of novel anti-inflammatory drugs and methods for assessing COX selectivity, pharmacodynamic effects of novel and existing anti-inflammatory drugs in animal models and humans, and the expression and role of different COX isoforms in the kidney and vasculature.

Prof. Dr. Arduino A Mangoni
Guest Editor

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Keywords

organic chemistry
drug development
enzyme kinetics
enzyme expression
pharmacokinetics
pharmacodynamics
cyclooxygenase
safety
renal toxicity
cardiovascular toxicity
inflammation
pain
medicinal chemistry

Related Special Issues

Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry-II in Molecules (7 articles)
Anti-inflammatory and Anti-allergy Agents in Medicinal Chemistry-III in Molecules (9 articles)

Published Papers (10 papers)

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Research

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1565 KiB

Open AccessArticle

Molecular Docking and Fluorescence Characterization of Benzothieno[3,2-d]pyrimidin-4-one Sulphonamide Thio-Derivatives, a Novel Class of Selective Cyclooxygenase-2 Inhibitors

by Mariarita Barone, Giovanna Pannuzzo, Andrea Santagati, Alfio Catalfo, Guido De Guidi and Venera Cardile

Molecules 2014, 19(5), 6106-6122; https://doi.org/10.3390/molecules19056106 - 14 May 2014

Cited by 10 | Viewed by 6716

Abstract

The aims of this study were: (i) to explore the structure-activity relationship of some new anti-inflammatory benzothieno[3,2-d]pyrimidin-4-one sulphonamide thio-derivatives 1–11; and (ii) to evaluate the possibility of using the most active compounds as fluorescent probes to determine tumours or their progression. Therefore, to know the precise mechanism by which these compounds interact with cyclooxygenase (COX)-2 enzyme, a molecular docking study was carried out; to assess spectroscopic characteristics, their absorption and emission properties were determined. The results demonstrated that some derivatives of benzothieno[3,2-d] pyrimidine exhibit interesting anti-inflammatory properties related to interactions with active sites of COX-2 and are fluorescent. The antipyrine-bearing compound 4 displayed high COX-2 affinity (ΔG = −9.4) and good fluorescent properties (Φ_fl = 0.032). Thus, some members of this new class of anti-inflammatory may be promising for fluorescence imaging of cancer cells that express the COX-2 enzyme. Further in vitro and in vivo studies are needed to confirm this hypothesis. Full article

(This article belongs to the Special Issue Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry)

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897 KiB

Open AccessArticle

Cyclooxygenase-2 (COX-2) Inhibition Constrains Indoleamine 2,3-Dioxygenase 1 (IDO1) Activity in Acute Myeloid Leukaemia Cells

by Maria Grazia Iachininoto, Eugenia Rosa Nuzzolo, Giuseppina Bonanno, Andrea Mariotti, Annabella Procoli, Franco Locatelli, Raimondo De Cristofaro and Sergio Rutella

Molecules 2013, 18(9), 10132-10145; https://doi.org/10.3390/molecules180910132 - 22 Aug 2013

Cited by 39 | Viewed by 9411

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) metabolizes L-tryptophan to kynurenines (KYN), inducing T-cell suppression either directly or by altering antigen-presenting-cell function. Cyclooxygenase (COX)-2, the rate-limiting enzyme in the synthesis of prostaglandins, is over-expressed by several tumours. We aimed at determining whether COX-2 inhibitors down-regulate the IFN-g-induced expression of IDO1 in acute myeloid leukaemia (AML) cells. IFN-γ at 100 ng/mL up-regulated COX-2 and IDO1 in HL-60 AML cells, both at mRNA and protein level. The increased COX-2 and IDO1 expression correlated with heightened production of prostaglandin (PG)E₂ and kynurenines, respectively. Nimesulide, a preferential COX-2 inhibitor, down-regulated IDO1 mRNA/protein and attenuated kynurenine synthesis, suggesting that overall IDO inhibition resulted both from reduced IDO1 gene transcription and from inhibited IDO1 catalytic activity. From a functional standpoint, IFN-g-challenged HL-60 cells promoted the in vitro conversion of allogeneic CD4⁺CD25⁻ T cells into bona fide CD4⁺CD25⁺FoxP3⁺ regulatory T cells, an effect that was significantly reduced by treatment of IFN-γ-activated HL-60 cells with nimesulide. Overall, these data point to COX-2 inhibition as a potential strategy to be pursued with the aim at circumventing leukaemia-induced, IDO-mediated immune dysfunction. Full article

(This article belongs to the Special Issue Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry)

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1372 KiB

Open AccessArticle

Luteolin Inhibits Inflammatory Responses via p38/MK2/TTP-mediated mRNA Stability

by Wanling Wu, Dongye Li, Yu Zong, Hong Zhu, Defeng Pan, Tongda Xu, Tao Wang and Tingting Wang

Molecules 2013, 18(7), 8083-8094; https://doi.org/10.3390/molecules18078083 - 09 Jul 2013

Cited by 38 | Viewed by 6413

Abstract

Luteolin (Lut) is a common dietary flavonoid present in Chinese herbal medicines that has been reported to have important anti-inflammatory properties. The purposes of this study were to observe the inhibition of lipopolysaccharide (LPS)-induced inflammatory responses in bone marrow macrophages (BMM) by Lut, and to examine whether this inhibition involves p38/MK2/TTP-mediated mRNA stability. Lut suppressed the production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in a dose-dependent manner according to enzyme-linked immunosorbent assay (ELISA) analysis. Lut also shortened the half-lives of the TNF-α and IL-6 mRNAs according to real-time PCR analysis. Western blots were performed to assess the activation of p38 and MK2 as well as the expression of TTP. The results indicated that Lut inhibited p38 and MK2 phosphorylation while promoting TTP expression. These results suggest that the anti-inflammatory effects of Lut are partially mediated through p38/MK2/TTP-regulated mRNA stability. Full article

(This article belongs to the Special Issue Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry)

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765 KiB

Open AccessArticle

A Soft Coral Natural Product, 11-Episinulariolide Acetate, Inhibits Gene Expression of Cyclooxygenase-2 and Interleukin-8 through Attenuation of Calcium Signaling

by Wen-Li Hsu, Siou-Jin Chiu, Yao-Ting Tsai, Che-Mai Chang, Jaw-Yan Wang, Eric Terry Wang, Ming-Feng Hou, Chiung-Yao Huang, Jyh-Horng Sheu and Wei-Chiao Chang

Molecules 2013, 18(6), 7023-7034; https://doi.org/10.3390/molecules18067023 - 17 Jun 2013

Cited by 12 | Viewed by 7470

Abstract

Epidermal growth factor receptor (EGFR) is overexpressed in many types of cancer cells. EGFR-mediated signaling involves inflammatory gene expression including cyclooxygenase (COX)-2 and interleukin (IL)-8, and is associated with cancer pathogenesis. In a search of phytochemicals with anti-inflammatory activity, the COX-2 and IL-8 inhibitory activities of some marine compounds were examined. After screening these compounds 11-episinulariolide acetate (1) from soft coral exhibited the most potent activity. Reverse-transcription PCR; western blotting; ELISA and luciferase assays were used to test the effect of compound 1 on EGF-stimulated expressions of COX-2 and IL-8 in A431 human epidermoid carcinoma cells. After exposure to 10 μM of compound 1, expression levels of COX-2 and IL-8 were reduced. In addition; intracellular Ca²⁺ increase and Ca²⁺-dependent transcription factor activation were blocked by compound 1. Thus, compound 1 can potentially serve as a lead compound for targeting Ca²⁺ signaling-dependent inflammatory diseases. Full article

(This article belongs to the Special Issue Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry)

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2293 KiB

Open AccessArticle

Indomethacin Inhibits Cancer Cell Migration via Attenuation of Cellular Calcium Mobilization

by Yuh-Cherng Guo, Che-Mai Chang, Wen-Li Hsu, Siou-Jin Chiu, Yao-Ting Tsai, Yii-Her Chou, Ming-Feng Hou, Jaw-Yan Wang, Mei-Hsien Lee, Ke-Li Tsai and Wei-Chiao Chang

Molecules 2013, 18(6), 6584-6596; https://doi.org/10.3390/molecules18066584 - 04 Jun 2013

Cited by 47 | Viewed by 8497

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) were shown to reduce the risk of colorectal cancer recurrence and are widely used to modulate inflammatory responses. Indomethacin is an NSAID. Herein, we reported that indomethacin can suppress cancer cell migration through its influence on the focal complexes formation. Furthermore, endothelial growth factor (EGF)-mediated Ca²⁺ influx was attenuated by indomethacin in a dose dependent manner. Our results identified a new mechanism of action for indomethacin: inhibition of calcium influx that is a key determinant of cancer cell migration. Full article

(This article belongs to the Special Issue Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry)

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1073 KiB

Open AccessArticle

The Ameliorative Effect of Sophoricoside on Mast Cell-Mediated Allergic Inflammation in Vivo and in Vitro

by Su-Jin Kim, Gil-Yong Lee, Ji-Wook Jung, Sa-Rang Oh, Eun-Mi Ahn, Sung-Hoon Kim, Seung-Heon Hong and Jae-Young Um

Molecules 2013, 18(5), 6113-6127; https://doi.org/10.3390/molecules18056113 - 22 May 2013

Cited by 16 | Viewed by 8460

Abstract

Sophoricoside exhibits numerous pharmacological effects, including anti- inflammatory and anti-cancer actions, yet the exact mechanism that accounts for the anti-allergic effects of sophoricoside is not completely understood. The aim of the present study was to elucidate whether and how sophoricoside modulates the mast cell-mediated allergic inflammation in vitro and in vivo. We investigated the pharmacological effects of sophoricoside on both compound 48/80 or histamine-induced scratching behaviors and 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis in mice. Additionally, to find a possible explanation for the anti-inflammatory effects of sophoricoside, we evaluated the effects of sophoricoside on the production of histamine and inflammatory cytokines and activation of nuclear factor-κB (NF-κB) and caspase-1 in phorbol 12-myristate 13-acetate plus calcium ionophore A23187 (PMACI)-stimulated human mast cells (HMC-1). The finding of this study demonstrated that sophoricoside reduced compound 48/80 or histamine-induced scratching behaviors and DNCB-induced atopic dermatitis in mice. Additionally, sophoricoside inhibited the production of inflammatory cytokines as well as the activation of NF-κB and caspase-1 in stimulated HMC-1. Collectively, the findings of this study provide us with novel insights into the pharmacological actions of sophoricoside as a potential molecule for use in the treatment of allergic inflammation diseases. Full article

(This article belongs to the Special Issue Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry)

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336 KiB

Open AccessArticle

Synthesis and Characterization of Celecoxib Derivatives as Possible Anti-Inflammatory, Analgesic, Antioxidant, Anticancer and Anti-HCV Agents

by Ş. Güniz Küçükgüzel, İnci Coşkun, Sevil Aydın, Göknur Aktay, Şule Gürsoy, Özge Çevik, Özlem Bingöl Özakpınar, Derya Özsavcı, Azize Şener, Neerja Kaushik-Basu, Amartya Basu and Tanaji T. Talele

Molecules 2013, 18(3), 3595-3614; https://doi.org/10.3390/molecules18033595 - 21 Mar 2013

Cited by 43 | Viewed by 10227

Abstract

A series of novel N-(3-substituted aryl/alkyl-4-oxo-1,3-thiazolidin-2-ylidene)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamides 2a–e were synthesized by the addition of ethyl a-bromoacetate and anhydrous sodium acetate in dry ethanol to N-(substituted aryl/alkylcarbamothioyl)-4-[5-(4-methylphenyl)-3-(trifluoro-methyl)-1H-pyrazol-1-yl]benzene sulfonamides 1a–e, which were synthesized by the reaction of alkyl/aryl isothiocyanates with celecoxib. The structures of the isolated products were determined by spectral methods and their anti-inflammatory, analgesic, antioxidant, anticancer and anti-HCV NS5B RNA-dependent RNA polymerase (RdRp) activities evaluated. The compounds were also tested for gastric toxicity and selected compound 1a was screened for its anticancer activity against 60 human tumor cell lines. These investigations revealed that compound 1a exhibited anti-inflammatory and analgesic activities and further did not cause tissue damage in liver, kidney, colon and brain compared to untreated controls or celecoxib. Compounds 1c and 1d displayed modest inhibition of HCV NS5B RdRp activity. In conclusion, N-(ethylcarbamothioyl)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (1a) may have the potential to be developed into a therapeutic agent. Full article

(This article belongs to the Special Issue Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry)

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500 KiB

Open AccessArticle

Anti-Inflammatory and Anti-Allergic Activities of Pentaherb Formula, Moutan Cortex (Danpi) and Gallic Acid

by Kelly Y. P. Liu, Shuiqing Hu, Ben C. L. Chan, Elaine C. L. Wat, Clara B. S. Lau, Kam L. Hon, Kwok P. Fung, Ping C. Leung, Patrick C. L. Hui, Christopher W. K. Lam and Chun K. Wong

Molecules 2013, 18(3), 2483-2500; https://doi.org/10.3390/molecules18032483 - 25 Feb 2013

Cited by 56 | Viewed by 9488

Abstract

Pentaherb formula (PHF) has been proven to improve the quality of life of children with atopic dermatitis without side effects. The aim of this study was to elucidate the potential anti-inflammatory and anti-allergic activities of PHF, Moutan Cortex (Danpi/DP) and gallic acid (GA) using human basophils (KU812 cells), which are crucial effector cells in allergic inflammation. PHF, DP and GA could significantly suppress the expression of allergic inflammatory cytokine IL-33-upregulated intercellular adhesion molecule (ICAM)-1, and the release of chemokines CCL2, CCL5, CXCL8 and inflammatory cytokine IL-6 from KU812 cells (all p < 0.05). With the combined use of dexamethasone (0.01 μg/mL) and GA (10 μg/mL), the suppression of ICAM-1 expression and CCL5 and IL-6 release of IL-33-activated KU812 cells were significantly greater than the use of GA alone (all p < 0.05). The suppression of the IL-33-induced activation of intracellular signalling molecules p38 mitogen activated protein kinase, nuclear factor-kB and c-Jun amino-terminal kinase in GA-treated KU812 cells could be the underlying mechanism for the suppression on ICAM-1, chemokines and cytokines. The combined use of dexamethasone with the natural products PHF or DP or GA might therefore enhance the development of a novel therapeutic modality for allergic inflammatory diseases with high potency and fewer side effects. Full article

(This article belongs to the Special Issue Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry)

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Review

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218 KiB

Open AccessReview

Physiological Roles and Potential Therapeutic Applications of the P2X7 Receptor in Inflammation and Pain

by Luiz Anastacio Alves, Rômulo José Soares Bezerra, Robson Xavier Faria, Leonardo Gomes Braga Ferreira and Valber Da Silva Frutuoso

Molecules 2013, 18(9), 10953-10972; https://doi.org/10.3390/molecules180910953 - 05 Sep 2013

Cited by 77 | Viewed by 8725

Abstract

The P2X7 receptor (P2X7R) is a nonselective cation channel that is activated by extracellular ATP and triggers the secretion of several proinflammatory substances, such as IL-1β, IL-18, TNF-α, and nitric oxide. Recently, several preclinical studies have demonstrated that this receptor participates in inflammation and pain mechanisms. Taken together, these results indicate that P2X7R is a promising pharmacological target, and compounds that modulate the function of this receptor show potential as new anti-inflammatory medicines. In this review, we discuss aspects of P2X7R pharmacology and the participation of this protein in inflammation and pain and provide an overview of some promising compounds that have been tested as antagonists of P2X7R, with clinical applicability. Full article

(This article belongs to the Special Issue Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry)

348 KiB

Open AccessReview

Natural Products as a Source of Anti-Inflammatory Agents Associated with Inflammatory Bowel Disease

by Trishna Debnath, Da Hye Kim and Beong Ou Lim

Molecules 2013, 18(6), 7253-7270; https://doi.org/10.3390/molecules18067253 - 19 Jun 2013

Cited by 126 | Viewed by 14713

Abstract

Accumulating epidemiological and clinical study indicates that inflammation is a significant risk factor to develop various human diseases such as inflammatory bowel disease (IBD), chronic asthma, rheumatoid arthritis, multiple sclerosis, and psoriasis. Suppressing inflammation is therefore important to control or prevent various diseases. Among them, IBD is one of the major problems affecting people worldwide. IBD affects at least one in a thousand persons in many Western countries. Various natural products have been shown to safely suppress pro-inflammatory pathway and control IBD. In vivo and/or in vitro studies indicate that anti-IBD effects of natural products occur by inhibition of the expression of pro-inflammatory cytokines (for example, tumor necrosis factor-α (TNF-α), intercellular adhesion molecule expression and pro-inflammatory mediators (such as inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2), master transcription factors (such as nuclear factor-κB (NF-κB)), reactive oxygen species (ROS) and by improving the antioxidant activity. In this review, we summarize recent research focused on IBD and the effects that natural products have on IBD factors. Full article

(This article belongs to the Special Issue Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry)

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