RESUMO
The oxazolidine-2,4-dione motif is found frequently in biologically important compounds. A tandem phosphorus-mediated carboxylative condensation of primary amines and α-ketoesters/base-catalyzed cyclization reaction have been developed. These processes provide a novel and convenient access to various oxazolidine-2,4-diones in a one-pot fashion using atmospheric carbon dioxide and readily available substrates under very mild and transition-metal-free conditions.
Assuntos
Atmosfera/química , Dióxido de Carbono/química , Oxazolidinonas/síntese química , Fósforo/química , Aminas/química , Catálise , Ciclização , Ésteres/química , Metanol/química , Estrutura Molecular , Oxazolidinonas/químicaRESUMO
A variety of new mono-oxazolidinone molecules by modifying the C-ring of Linezolid, a marketed antibiotic for MRSA, were synthesized and tested for their in vitro antibacterial activities against several Staphylococcus aureus, Mycobacterium smegmatis and two Gram-negative bacteria strains (Escherichia coli and Pseudomonas aeruginosa). Among them, compounds 4-7 displayed moderate antimicrobial activities. After development of a second oxazolidinone ring in the western part of the mono-oxazolidinone compounds 4-7 by a ring closure reaction with N,N'-carbonyldiimidazole (CDI), we found thus obtained bis-oxazolidinone compounds 22-25 possess excellently inhibitory activities against H37Rv but poor or no effects on other test bacteria. Among them, bis-oxazolidinone compound 22 and 24 are the most potent two compounds with a same MIC value of 0.125µg/mL against H37Rv virulent strain. Compound 22 also exhibited extremely low cytotoxicity on monkey kidney Vero cells with a selective index (IC50/MIC) over 40,000, which suggested bis-oxazolidinone compound 22 is a promising lead compound for subsequent investigation in search of new antitubercular agents.
Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Oxazolidinonas/química , Animais , Antituberculosos/síntese química , Antituberculosos/química , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Avaliação Pré-Clínica de Medicamentos , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Mycobacterium smegmatis/efeitos dos fármacos , Oxazolidinonas/síntese química , Oxazolidinonas/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Células VeroRESUMO
Several novel oxazolidinone antibiotics with a spiropiperazinyl substituent at the 4'-position of the phenyl ring were synthesized through nitroso Diels-Alder chemistry and the in vitro antibacterial activities were evaluated against various Gram-positive bacteria (Bacillus subtilis, Staphylococcus aureus, Enterococcus faecalis), Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa) and mycobacteria (Mycobacterium vaccae, Mycobacterium tuberculosis). Analogs (8a and 12) were active against selected drug resistant microbes, like methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) and had no mammalian toxicity in a Hep-2 cellular assay (CC(50) >100 µM).
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Oxazolidinonas/síntese química , Oxazolidinonas/farmacologia , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos/métodos , Farmacorresistência Bacteriana , Enterococcus/efeitos dos fármacos , Enterococcus faecalis/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium/efeitos dos fármacos , Oxazolidinonas/química , Staphylococcus aureus/efeitos dos fármacos , Vancomicina/farmacologiaRESUMO
High-throughput screening of the corporate compound collection led to the discovery of a novel series of N-substituted-5-aryl-oxazolidinones as potent human CCR8 antagonists. The synthesis, structure-activity relationships, and optimization of the series that led to the identification of SB-649701 (1a), are described.
Assuntos
Oxazolidinonas/síntese química , Oxazolidinonas/farmacologia , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Células CHO , Quimiotaxia de Leucócito/efeitos dos fármacos , Simulação por Computador , Cricetinae , Cricetulus , Avaliação Pré-Clínica de Medicamentos , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Indicadores e Reagentes , Miotonina Proteína Quinase , Proteínas Serina-Treonina Quinases/efeitos dos fármacos , Receptores CCR8 , Relação Estrutura-Atividade , Células Th2/efeitos dos fármacosRESUMO
Compounds structurally related to the known antimicrobial drug linezolid were selected in order to evaluate the influence of electron-withdrawing properties and altered geometric features as a result of the N-substituent modification. After a preliminary study of molecular modeling, cinnamoyl-, pyridin- and pyrimidinoxazolidin-2-ones were synthesized. None of the new compounds showed antibacterial activity.
Assuntos
Acetamidas/síntese química , Antibacterianos/síntese química , Oxazolidinonas/síntese química , Acetamidas/farmacologia , Antibacterianos/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Linezolida , Testes de Sensibilidade Microbiana/estatística & dados numéricos , Oxazolidinonas/farmacologia , Staphylococcus/efeitos dos fármacos , Staphylococcus/crescimento & desenvolvimento , Relação Estrutura-AtividadeRESUMO
A series of oxazolidinone antibacterial agents containing a 5-substituted isoxazol-3-yl moiety were synthesized via a nitrile oxide [3+2] dipolar cycloaddition reaction. These compounds were screened against a panel of susceptible and resistant Gram-positive organisms. Several analogs from this series were comparable to or more potent than linezolid in vitro.
Assuntos
Antibacterianos/síntese química , Isoxazóis/síntese química , Oxazolidinonas/síntese química , Animais , Antibacterianos/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Isoxazóis/farmacologia , Camundongos , Testes de Sensibilidade Microbiana/métodos , Oxazolidinonas/farmacologiaRESUMO
Oxazolidinone-quinolone hybrids that combine the pharmacophores of a quinolone and an oxazolidinone were synthesised and shown to be active against a variety of resistant and susceptible Gram-positive and fastidious Gram-negative organisms. The best compounds in this series overcome all types of resistance in relevant clinical Gram-positive pathogens. The nature of the spacer greatly influences the antibacterial activity. The dual mode of action could be demonstrated for compounds having a piperazinyl spacer. Antibacterial activity was higher at acidic pH.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Oxazolidinonas/química , Oxazolidinonas/farmacologia , Quinolonas/química , Quinolonas/farmacologia , Antibacterianos/síntese química , DNA Girase/metabolismo , DNA Topoisomerase IV/metabolismo , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Resistência a Múltiplos Medicamentos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxazolidinonas/síntese química , Biossíntese de Proteínas , Quinolonas/síntese química , Relação Estrutura-Atividade , Transcrição GênicaRESUMO
Due to the key role played by monoamine oxidases (MAOs) in the metabolism of neurotransmitters, MAO inhibitors (MAOIs) represent an useful tool for the treatment of several neurological diseases. Among selective MAOIs, MAO-A inhibitors (e.g. clorgyline) are used as antidepressant and antianxiety drugs and are claimed to protect neuronal cells against apoptosis, and selective MAO-B inhibitors (e.g. L-deprenyl) can be used in the treatment of Parkinson's disease either alone or in combination with L-DOPA. However, they engender covalent bonds with the active site of the enzyme and induce irreversible inhibition; moreover, they tend to lose their initial selectivity at high dosages or with repeated administrations. Phenyloxazolidinones belong to third-generation-MAOIs, characterized by a selective and reversible inhibition of the enzyme. Among these molecules, the most representative are toloxatone and befloxatone, two selective and reversible MAO-A inhibitors used in therapy as antidepressant drugs. Going on our searches on CNS potentially active compounds containing a pyrrole moiety we prepared 3-(1H-pyrrol-1-yl)-2-oxazolidinones (1) and isomeric 3-(1H-pyrrol-2-and -3-yl)-2-oxazolidinones (2 and 3) as anti-MAO agents. Such derivatives resulted selective and reversible MAO-A inhibitors. The most potent compound is (R)-5-methoxymethyl-3-(1H-pyrrol-1-yl)-2-oxazolidinone (1b), endowed with very high potency (K(iMAO-A) = 4.9 nM) and A-selectivity (A-selectivity = 10,200, about 116-fold greater than that of befloxatone).