| 1. |
- Bassyouni, Fatma A., et al.
(författare)
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Synthesis, pharmacological activity evaluation and molecular modeling of new polynuclear heterocyclic compounds containing benzimidazole derivatives
- 2012
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Ingår i: Archives of pharmacal research. - : Springer Science and Business Media LLC. - 0253-6269 .- 1976-3786. ; 35:12, s. 2063-2075
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Tidskriftsartikel (refereegranskat)abstract
- Novel heterocyclic compounds containing benzimidazole derivatives were synthesized from 2-(1Hbenzimidazol-2-yl) acetonitrile (1) and arylhydrazononitrile derivative 2 was obtained via coupling of 1 with 4-methyl phenyldiazonium salt, which was then reacted with hydroxylamine hydrochloride to give amidooxime derivative 3. This product was cyclized into the corresponding oxadiazole derivative 4 upon reflux in acetic anhydride. Compound 4 was refluxed in DMF in the presence of triethylamine to give the corresponding 5-(1H-benzimidazol-2-yl)-2-p-tolyl-2H-1,2,3-triazol-4-amine 6. Treatment of compound 6 with ethyl chloroformate afforded 2,6-dihydro-2-(4-methylphenyl)-1,2,3-triazolo[4aEuro(3),5aEuro(3)-4',5']pyrimido[1,6-a]benzimidazole-5(4H)-one (8). 1,2-bis(2-cyanomethyl-1H-benzimidazol-1-yl)ethane-1,2-dione (10) was synthesized via the condensation reaction of 2-(1H-benzimidazol-2-yl) acetonitrile (1) and diethyloxalate. The reactivity of compound 10 towards some diamine reagents was studied. The in vitro antimicrobial activity of the synthesized compounds was investigated against several pathogenic bacterial strains such as Escherichia coli O157, Salmonella typhimurium, E. coli O119, S. paratyphi, Pseudomonas aeruginosa, Staphylococcus aureus, Listeria monocytogenes and Bacillus cereus. The results of MIC revealed that compounds 12a-c showed the most effective antimicrobial activity against tested strains. On the other hand, compounds 12a, b exhibited high activity against rotavirus Wa strain while compounds 12b, c exhibited high activity against adenovirus type 7. In silico target prediction, docking and validation of the compounds 12a-c were performed. The dialkylglycine decarboxylase bacterial enzyme was predicted as a potential bacterial target receptor using pharmacophorebased correspondence with previous leads; giving the highest normalized scores and a high correlation docking score with mean inhibition concentrations. A novel binding mechanism was predicted after docking using the MOE software and its validation.
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| 2. |
- Kwon, Ho Jeong, et al.
(författare)
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Drug Compound Characterization by Mass Spectrometry Imaging in Cancer Tissue
- 2015
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Ingår i: Archives of Pharmacal Research. - : Springer Science and Business Media LLC. - 1976-3786 .- 0253-6269. ; 38:9, s. 1718-1727
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Forskningsöversikt (refereegranskat)abstract
- MALDI Mass spectrometry imaging (MSI) provides a technology platform that allows the accurate visualization of unlabeled small molecules within the two-dimensional spaces of tissue samples. MSI has proven to be a powerful tool-box concept in the development of new drugs. MSI allows unlabeled drug compounds and drug metabolites to be detected and identified and quantified according to their mass-to-charge ratios (m/z) at high resolution in complex tissue environments. Such drug characterization in situ, by both spatial and temporal behaviors within tissue compartments, provide new understandings of the dynamic processes impacting drug uptake and metabolism at the local sites targeted by therapy. Further, MSI in combination with histology and immunohistochemistry, provides the added value of defining the context of cell biology present at the sites of drug localization thus providing invaluable information relating to treatment efficacy. In this report we provide mass spectrometry imaging data within various cancers such as malignant melanoma in patients administered with Vemurafenib, a protein kinase inhibitor that is targeting both the BRAF, and ERK mutated target proteins and that has shown significant efficacy in restraining disease progression. We also provide an overview of other examples of the new generation of targeted drugs, and demonstrate the data on personalized medicine drugs localization within tumor compartments within in vivo models. In these cancer models we provide detailed data on drug and target protein co-localization of YCG185 and Sunitinib. These drugs are targeting VEGFR2 within the angiogenesis mechanism. Our ability to resolve drug uptake at targeted sites of directed therapy provides important opportunities for increasing our understanding about the mode of action of drug activity within the environment of disease.
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| 3. |
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| 4. |
- Zhang, Jin-Yan, et al.
(författare)
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Dimethylsulfoxide-soluble Smoking Particles and Nicotine Affect Vascular Contractibility
- 2009
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Ingår i: Archives of Pharmacal Research. - : Springer Science and Business Media LLC. - 1976-3786 .- 0253-6269. ; 32:10, s. 1475-1481
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Tidskriftsartikel (refereegranskat)abstract
- The aim is to study the effect of dimethylsulfoxide-soluble smoking particles (DSP) and nicotine on the contractility of rat mesenteric artery. The superior mesenteric artery segments were cultured with DSP or nicotine for 24 h. The vascular contractibility was recorded with myograph system. DSP 0.4 mL/L and nicotine 0.48 and 0.96 mg/L shifted the concentration-contractile curves induced by sarafotoxin 6c, a selective agonist for ETB receptor toward the left with increased E-max. DSP 0.4 mL/L and nicotine 0.96 mg/L shifted ETA receptor-mediated the concentration-contractile curves toward the left with increased E-max. However, nicotine 0.06 mg/L which is the equivalent concentration of nicotine in DSP 0.4 mL/L did not affect the curves and the E-max mediated with ETA receptor and ETB receptor. DSP 0.2 and 0.4 mL/L shifted the concentration-contractile curves induced by noradrenaline toward the right with decreased E-max. Neither did nicotine 0.06 and 0.96 mg/L. Both DSP and nicotine shifted the concentration-contractile curves induced by 5-hydroxytryptamine (5-HT) toward the right parallely. DSP changed the phenotypes towards an increased efficacy of ETA receptor and ETB receptor, and a reduced efficacy of 5-HT receptor and alpha-adrenocceptor. The effects of DSP on ETB receptor, ETA receptor and alpha-adrenocceptor were independent of nicotine. The effect on 5-HT receptor was responsible to nicotine.
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| 5. |
- Cao, YX, et al.
(författare)
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Induces vasodilatation of rat mesenteric artery in vitro mainly by inhibiting receptor-mediated Ca2+-influx and Ca2+-release
- 2005
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Ingår i: Archives of Pharmacal Research. - 1976-3786. ; 28:6, s. 709-715
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to investigate the effect of atropine on peripheral vasodilation and the mechanisms involved. The isometric tension of rat mesenteric artery rings was recorded in vitro on a myograph. The results showed that atropine, at concentrations greater than 1 mu M, relaxed the noradrenalin (NA)-precontracted rat mesenteric artery in a concentration-dependent manner. Atropine-induced vasodilatation was mediated, in part, by an endothelium-dependent mechanism, to which endothelium-derived hyperpolarizing factor may contribute. Atropine was able to shift the NA-induced concentration-response curve to the right, in a non-parallel manner, suggesting the mechanism of atropine was not mediated via the alpha(1)-adrenoreceptor. The beta-adrenoreceptor and ATIP sensitive potassium channel, a voltage dependent calcium channel, were not involved in the vasodilatation. However, atropine inhibited the contraction derived from NA and CaCl2 in Ca2+-free medium, in a concentration dependent manner, indicating the vasodilatation was related to the inhibition of extracellular Ca2+ influx through the receptor-operated calcium channels and intracellular Ca2+ release from the Ca (2+) store. Atropine had no effect on the caffeine-induced contraction in the artery segments, indicating the inhibition of intracellular Ca2+ release as a result of atropine most likely occurs via the IP3 pathway rather than the ryanodine receptors. Our results suggest that atropine-induced vasodilatation is mainly from artery smooth muscle cells due to inhibition of the receptor-mediated Ca2+-influx and Ca2+-release, and partly from the endothelium mediated by EDHF.
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