RESUMO
3-Methoxybenzamide is a weak inhibitor of the essential bacterial cell division protein FtsZ. Exploration of the structure-activity relationships of 3-methoxybenzamide analogues led to the identification of potent anti-staphylococcal compounds.
Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Benzamidas/farmacologia , Proteínas do Citoesqueleto/antagonistas & inibidores , Staphylococcus/efeitos dos fármacos , Antibacterianos/química , Benzamidas/química , Testes de Sensibilidade Microbiana , Relação Estrutura-AtividadeRESUMO
Carboxylic acids are converted into alcohols by chemoselective reduction of their corresponding fluorides with sodium borohydride and dropwise addition of methanol. The method is general and mild and displays a high level of functional group compatibility. N-Protected amino and peptide alcohols, bearing varieties of protecting groups, are prepared in the same way from their corresponding amino acids and peptides without racemization.
RESUMO
3-Methoxybenzamide (1) is a weak inhibitor of the essential bacterial cell division protein FtsZ. Alkyl derivatives of 1 are potent antistaphylococcal compounds with suboptimal drug-like properties. Exploration of the structure-activity relationships of analogues of these inhibitors led to the identification of potent antistaphylococcal compounds with improved pharmaceutical properties.
Assuntos
Antibacterianos/síntese química , Proteínas de Bactérias/antagonistas & inibidores , Proteínas do Citoesqueleto/antagonistas & inibidores , Piridinas/síntese química , Staphylococcus aureus/efeitos dos fármacos , Tiazóis/síntese química , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Células CACO-2 , Divisão Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular , Hepatócitos/metabolismo , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Ligação Proteica , Piridinas/química , Piridinas/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/citologia , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologiaRESUMO
The synthesis of enantiopure gamma-substituted gamma-amino acids with proteinogenic side chains, starting from the corresponding natural alpha-amino acids, was studied. N-Protected amino aldehydes containing various protective groups were prepared from the corresponding amino alcohols by oxidation with NaOCl in the presence of AcNH-TEMPO and directly reacted with methyl, benzyl and tert-butyl phosphoranylidene acetate to produce alpha,beta-unsaturated gamma-amino esters. Simultaneous hydrogenation of the double bond and removal of either the benzyl or benzyloxycarbonyl group led to N- or C-protected gamma-amino acids in high yield. The enantiomeric purity was studied by 1H NMR analysis of Mosher amides and chiral HPLC analysis.