scholarly journals Design, Synthesis and Biological Evaluation of Arylpyridin-2-yl Guanidine Derivatives and Cyclic Mimetics as Novel MSK1 Inhibitors. An Application in an Asthma Model

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 391
Author(s):  
Maud Bollenbach ◽  
Simona Nemska ◽  
Patrick Wagner ◽  
Guillaume Camelin ◽  
François Daubeuf ◽  
...  
Keyword(s):  
Inflammatory Cell ◽  
Inflammatory Diseases ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Cell Recruitment ◽  
Inflammatory Conditions ◽  
Asthma Model ◽  
Inflammatory Cell Recruitment ◽  
Synthesis And Biological Evaluation

Mitogen- and Stress-Activated Kinase 1 (MSK1) is a nuclear kinase, taking part in the activation pathway of the pro-inflammatory transcription factor NF-kB and is demonstrating a therapeutic target potential in inflammatory diseases such as asthma, psoriasis and atherosclerosis. To date, few MSK1 inhibitors were reported. In order to identify new MSK1 inhibitors, a screening of a library of low molecular weight compounds was performed, and the results highlighted the 6-phenylpyridin-2-yl guanidine (compound 1a, IC50~18 µM) as a starting hit for structure-activity relationship study. Derivatives, homologues and rigid mimetics of 1a were designed, and all synthesized compounds were evaluated for their inhibitory activity towards MSK1. Among them, the non-cytotoxic 2-aminobenzimidazole 49d was the most potent at inhibiting significantly: (i) MSK1 activity, (ii) the release of IL-6 in inflammatory conditions in vitro (IC50~2 µM) and (iii) the inflammatory cell recruitment to the airways in a mouse model of asthma.

scholarly journals Design, Synthesis and Biological Evaluation of Novel 1, 3, 4-Oxadiazole Bearing Pyridine Moiety

2019 ◽  
pp. 300-307
Author(s):  
Asma D. Ambekari ◽  
Shrinivas K. Mohite
Keyword(s):  
Antimicrobial Activity ◽  
Mass Spectra ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Pyridine Moiety ◽  
Anti Inflammatory ◽  
Physicochemical Data ◽  
Synthesis And Biological Evaluation

Series of novel substituted Synthesis of N-{[5-(substituted)-1,3,4-oxadiazole-2-yl] carbamothioyl} derivatives containing 1,3,4-oxadiazole moiety were synthesized by microwave as a green chemistry method and conventional method by using pyridine 3- carboxylic acid as a starting material. The structures of the synthesized compounds were characterized by physicochemical data, IR, Mass spectra and 1HNMR. All the newly synthesized compound screened for their antimicrobial and In-vivo and In-vitro Anti-inflammatory studies. Anti-inflammatory studies revealed that compound 4f showed significant in-vivo and in-vitro anti-inflammatory activity as well potent antimicrobial activity.

Design, synthesis, and biological evaluation of new series of 2-amido-1,3,4-thiadiazole derivatives as cytotoxic agents

2016 ◽  
Vol 71 (3) ◽  
pp. 205-210 ◽  
Author(s):  
Ali Almasirad ◽  
Loghman Firoozpour ◽  
Maliheh Nejati ◽  
Najmeh Edraki ◽  
Omidreza Firuzi ◽  
...  
Keyword(s):  
Human Tumor ◽  
Inhibitory Effect ◽  
Biological Evaluation ◽  
Cytotoxic Agents ◽  
Antitumor Activities ◽  
Design Synthesis ◽  
Ethidium Bromide Staining ◽  
Thiadiazole Derivatives ◽  
Synthesis And Biological Evaluation

AbstractA series of novel 1,3,4-thiadiazole derivatives bearing an amide moiety were designed, synthesized, and evaluated for their in vitro antitumor activities against HL-60, SKOV-3 and MOLT-4 human tumor cell lines by MTT assay. Ethyl 2-((5-(4-methoxybenzamido)-1,3,4-thiadiazol-2-yl)thio)acetate (5f) showed the best inhibitory effect against SKOV-3 cells, with an IC50 value of 19.5 μm. In addition, the acridine orange/ethidium bromide staining assay in SKOV-3 cells suggested that the cytotoxic activity of 5f occurs via apoptosis.

scholarly journals The extracellular matrix protein mindin serves as an integrin ligand and is critical for inflammatory cell recruitment

Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3854-3859 ◽  
Author(s):  
Wei Jia ◽  
Hong Li ◽  
You-Wen He
Keyword(s):  
Extracellular Matrix ◽  
Matrix Protein ◽  
Inflammatory Cell ◽  
Neutrophil Migration ◽  
Extracellular Matrix Protein ◽  
Hek 293 ◽  
Cell Recruitment ◽  
Inflammatory Cell Recruitment

Leukocyte recruitment to inflammation sites depends on interactions between integrins and extracellular matrix (ECM). In this report we show that mice lacking the ECM protein mindin exhibit severely impaired recruitment of neutrophils and macrophages in 4 different inflammation models. Furthermore, neutrophils directly bind to immobilized mindin, and mindin matrix mediates neutrophil migration in vitro. The adhesion of neutrophils to mindin is blocked by anti–integrin α4, anti–integrin αM, and anti–integrin β2 antibodies. We also show that HEK-293 cells transfected with cDNA encoding these integrins exhibit enhanced binding to immobilized mindin matrix and the increased binding can be blocked by anti-integrin antibodies. Our results suggest that mindin serves as a novel ligand for integrins and mindin-integrin interactions are critical for inflammatory cell recruitment in vivo.

scholarly journals Design, synthesis and biological evaluation of N-oxide derivatives with potent in vivo antileishmanial activity

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0259008
Author(s):  
Leandro da Costa Clementino ◽  
Guilherme Felipe Santos Fernandes ◽  
Igor Muccilo Prokopczyk ◽  
Wilquer Castro Laurindo ◽  
Danyelle Toyama ◽  
...  
Keyword(s):  
Parasite Burden ◽  
Peritoneal Macrophages ◽  
Biological Evaluation ◽  
Antileishmanial Activity ◽  
Dual Effect ◽  
Design Synthesis ◽  
Murine Peritoneal Macrophages ◽  
Synthesis And Biological Evaluation

Leishmaniasis is a neglected disease that affects 12 million people living mainly in developing countries. Herein, 24 new N-oxide-containing compounds were synthesized followed by in vitro and in vivo evaluation of their antileishmanial activity. Compound 4f, a furoxan derivative, was particularly remarkable in this regard, with EC50 value of 3.6 μM against L. infantum amastigote forms and CC50 value superior to 500 μM against murine peritoneal macrophages. In vitro studies suggested that 4f may act by a dual effect, by releasing nitric oxide after biotransformation and by inhibiting cysteine protease CPB (IC50: 4.5 μM). In vivo studies using an acute model of infection showed that compound 4f at 7.7 mg/Kg reduced ~90% of parasite burden in the liver and spleen of L. infantum-infected BALB/c mice. Altogether, these outcomes highlight furoxan 4f as a promising compound for further evaluation as an antileishmanial agent.

Design, synthesis, and biological evaluation of glycine-based molecular tongs as inhibitors of Aβ1–40 aggregation in vitro

2008 ◽  
Vol 16 (9) ◽  
pp. 4810-4822 ◽  
Author(s):  
Saverio Cellamare ◽  
Angela Stefanachi ◽  
Diana A. Stolfa ◽  
Teodora Basile ◽  
Marco Catto ◽  
...  
Keyword(s):  
Biological Evaluation ◽  
Design Synthesis ◽  
Synthesis And Biological Evaluation

scholarly journals Heparanase induces inflammatory cell recruitment in vivo by promoting adhesion to vascular endothelium

2014 ◽  
Vol 306 (12) ◽  
pp. C1184-C1190 ◽  
Author(s):  
Rebecca Lever ◽  
Mark J. Rose ◽  
Edward A. McKenzie ◽  
Clive P. Page
Keyword(s):  
Inflammatory Cell ◽  
Mononuclear Cells ◽  
Human Neutrophils ◽  
Inflammatory Cell Infiltrate ◽  
Dependent Manner ◽  
Cell Recruitment ◽  
Tumor Cell Migration ◽  
Inflammatory Cell Recruitment

Heparanase (HPSE1) is known to be involved in mechanisms of metastatic tumor cell migration. This enzyme selectively cleaves heparan sulfate proteoglycans (HSPG), which are ubiquitously expressed in mammals and are known to be involved in regulating the activity of an array of inflammatory mediators. In the present study, we have investigated the effects of human recombinant heparanase, the inactive precursor of this enzyme (proheparanase) and enzymatically inactivated heparanase, on inflammatory cell recruitment in the rat and on human leukocyte-endothelial adhesion in vitro. Intraperitoneal injection of heparanase (500 μg) induced a significant inflammatory cell infiltrate in the rat, as assessed by peritoneal lavage 4 h later. Intravital microscopy of the mesenteric microcirculation of anesthetized rats showed an increase in rolling and adherent cells in postcapillary venules that was sensitive to heparin, a nonselective inhibitor of heparanase activity. In vitro, heparanase augmented the adhesion of human neutrophils and mononuclear cells to human umbilical vein endothelial cells in a concentration-dependent manner. Proheparanase had similar effects to the active enzyme both with respect to leukocyte accumulation in the peritoneal cavity and adhesion in vitro. However, heat-inactivated heparanase induced cell adhesion in vitro but was without effect in vivo. Together, these data indicate a role for heparanase in inflammatory cell trafficking in vivo that appears to require enzymatic activity.

Design, synthesis and biological evaluation of (1,3-diphenyl-1H-pyrazol-4-yl) methyl benzoate derivatives as potential BRAFV600E inhibitors

RSC Advances ◽  
2014 ◽  
Vol 4 (95) ◽  
pp. 52702-52711 ◽  
Author(s):  
Ya-Juan Qin ◽  
Man Xing ◽  
Ya-Liang Zhang ◽  
Jigar A. Makawana ◽  
Ai-Qin Jiang ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Biological Evaluation ◽  
Methyl Benzoate ◽  
Design Synthesis ◽  
Synthesis And Biological Evaluation ◽  
Potent Inhibitory Activity ◽  
Benzoate Derivatives

A series of (1,3-diphenyl-1H-pyrazol-4-yl) methyl benzoate derivatives (6a–10d) were designed and synthesized and evaluated as BRAFV600 inhibitors. Among them, compound 10a showed the most potent inhibitory activity against A375, WM266.4 and BRAFV600Ein vitro with IC50 values of 1.36 μM, 0.94 μM and 0.11 μM, respectively.

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