RESUMO
An improved and efficient method for the preparation of torezolid based on Suzuki cross-coupling reaction as the key step was developed on a gram scale in five steps. The total yield was 44% and the optical purity of torezolid by the improved method was above 99%.
Assuntos
Antibacterianos/síntese química , Oxazolidinonas/química , Tetrazóis/química , Antibacterianos/química , Catálise , Complexos de Coordenação/química , Espectroscopia de Ressonância Magnética , Oxazolidinonas/síntese química , Paládio/química , Tetrazóis/síntese químicaRESUMO
In recent studies some urea derivatives have been identified as potent anti-tuberculosis agents by targeting mycobacterial membrane protein large 3 (MmpL3). However, this compound series as exemplified by AU1235 exhibited poor in vitro pharmacokinetic profile. With AU1235 as the lead, we have identified a novel benzimidazole series as potential anti-tuberculosis agents by using scaffold hopping approach. Among these synthesized compounds, 2-aminobenzimidazole derivative 8b showed the potent anti-tuberculosis activity with the MIC value of 0.03 microg x mL(-1). This compound also showed improved metabolic stability compared to AU1235. Our investigation indicated that benzimidazole derivatives are the promising lead for further optimization as anti-tuberculosis agents.
Assuntos
Antituberculosos/farmacologia , Benzimidazóis/farmacologia , Tuberculose/tratamento farmacológico , Benzimidazóis/química , Desenho de Fármacos , Humanos , Relação Estrutura-AtividadeRESUMO
Magnesium lithospermate B (MLB) is a primary hydrophilic component of Danshen, the dried root of Salvia miltiorrhiza used in traditional medicine, and its beneficial effects on obesity-associated metabolic abnormalities were reported in our previous study. The present study investigated the anti-muscle atrophy potential of MLB in mice with high-fat diet (HFD)-induced obesity. In addition to metabolic abnormalities, the HFD mice had a net loss of skeletal muscle weight and muscle fibers and high levels of muscle-specific ubiquitin E3 ligases, namely the muscle atrophy F-box (MAFbx) and muscle RING finger protein 1 (MuRF-1). MLB supplementation alleviated those health concerns. Parallel changes were revealed in high circulating tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), skeletal TNF receptor I (TNFRI), nuclear factor-kappa light chain enhancer of activated B cells (NF-κB), p65 phosphorylation, and Forkhead box protein O1 (FoxO1) as well as low skeletal phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt) phosphorylation. The study revealed that MLB prevented obesity-associated skeletal muscle atrophy, likely through the inhibition of MAFbx/MuRF-1-mediated muscular degradation. The activation of the PI3K-Akt-FoxO1 pathway and inhibition of the TNF-α/TNFRI/NF-κB pathway were assumed to be beneficial effects of MLB.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Medicamentos de Ervas Chinesas/farmacologia , Atrofia Muscular/induzido quimicamente , Animais , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Citocinas/genética , Citocinas/metabolismo , Suplementos Nutricionais , Dislipidemias/tratamento farmacológico , Sequestradores de Radicais Livres/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição AleatóriaRESUMO
To research the structure-activity relationship (SAR) of glycinamide-bearing compounds that used as inhibitors of dipeptidyl peptidase IV (DPP-IV), P32/98 and compound A were chosen as the leading compounds, heterocycles containing nitrogen atom were introduced to form amide, and different residues on a-position of carbonyl were designed. The nineteen designed compounds were synthesized by a simple route and were evaluated as inhibitors of DPP-IV. All of the structures were characterized by 1H NMR and HRMS. The preliminary SAR result was obtained.
Assuntos
Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/síntese química , Glicina/análogos & derivados , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Desenho de Fármacos , Glicina/química , Espectroscopia de Ressonância Magnética/métodos , Estrutura Molecular , Piperazinas/química , Piperazinas/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of aromatic aminoketones were synthesized by Mannich reaction. Structures of these compounds were confirmed by 1H NMR, MS and HRMS or element analysis. Pharmacological screening showed that most target compounds inhibited the release of beta-glucuronidase in polymorphonuclear leucocytes by PAF (platelet activating factor) and compounds MA12, MA13, MA18, MA21 and MA33 were more active. The study suggests that target compounds are potential PAF receptor antagonists and their anti-inflammatory activities are due to the inhibition of release of lysosomal enzyme.