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2.
Bioorg Med Chem Lett ; 29(16): 2119-2123, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31281021

RESUMO

Pendrin is a transmembrane chloride/anion antiporter that is strongly upregulated in the airways in rhinoviral infection, asthma, cystic fibrosis and chronic rhinosinusitis. Based on its role in the regulation of airway surface liquid depth, pendrin inhibitors have potential indications for treatment of inflammatory airways diseases. Here, a completely regioselective route to tetrahydro-pyrazolopyridine pendrin inhibitors based on 1,3-diketone and substituted hydrazine condensation was been developed. Structure-activity relationships at the tetrahydropyridyl nitrogen were investigated using a focused library, establishing the privileged nature of N-phenyl ureas and improving inhibitor potency by greater than 2-fold.


Assuntos
Pirazóis/farmacologia , Piridinas/farmacologia , Transportadores de Sulfato/antagonistas & inibidores , Animais , Camundongos , Estrutura Molecular , Pirazóis/síntese química , Piridinas/síntese química , Ratos Endogâmicos F344 , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade
3.
Org Lett ; 20(5): 1308-1311, 2018 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-29431446

RESUMO

Reaction options, alkoxide vs hydroxide vs amine addition to the key intermediate (o-nitrosoimine) generated in the Davis-Beirut reaction of an o-nitrobenzylamine substrate, are reported to explain the nucleophilic addition selectivity of this one-pot indazole-forming process. The hydroxide addition/deprotection pathway as well as the fate of the resulting o-nitrosobenzaldehyde were both uncovered with several o-nitrobenzylamine substrates, and design elements required for an efficient double Davis-Beirut reaction, inspired by new mechanistic insights, were defined.


Assuntos
Hidróxidos/química , Aminas , Iminas , Indazóis , Estrutura Molecular
4.
Anal Bioanal Chem ; 380(4): 683-9, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15452677

RESUMO

This paper describes a method for speciation of Hg associated with airborne particulate matter. This method uses a mini-sampler for sample collection and analysis, thermal desorption for separating Hg species, and inductively coupled plasma mass spectrometry (ICP-MS) for identification and quantification of Hg. Coal fly ash spiked with different Hg compounds (e.g. Hg0, HgCl2, HgO, and HgS) was used for qualitative calibration. A standard reference material with a certified value for Hg concentration was used to evaluate the method. When the temperature of the furnace was programmed at a linear rate of increase of 50 degrees min(-1), different Hg compounds could clearly be separated. Three airborne particulate matter samples were collected in parallel in Toronto, ON, Canada and analyzed using this method. Reproducible results were obtained and Hg0, HgCl2, HgO, and HgS species from these samples were detected.

5.
Anal Bioanal Chem ; 376(7): 1137-40, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12845397

RESUMO

In this study, a diffusion-type device for generating gaseous mercuric chloride (HgCl(2)) was systematically evaluated and applied to validate the annular denuder method for sampling gaseous HgCl(2) species in a synthetic gas stream. The results show that it takes at least 48 h for the system to reach a steady-state condition after the diffusion cell reaches the temperature set-point and the carrier gas is activated. The primary Hg species from the source was proven to be HgCl(2). In the temperature range from -5.00 to 11.80 degrees C, the Hg emission rates from the source vary from 1.8 to 14.2 pg min(-1). It is shown that, under the experimental conditions examined, KCl-coated annular quartz denuders designed for ambient reactive gaseous mercury (RGM) collection could quantitatively collect HgCl(2). It is also demonstrated that the impactors used to remove coarse airborne particulate matter could lead to a loss of up to one third of the HgCl(2) in the gas stream.

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