RESUMO
Inhibition of the biosynthesis of bacterial heptoses opens novel perspectives for antimicrobial therapies. The enzyme GmhA responsible for the first committed biosynthetic step catalyzes the conversion of sedoheptulose 7-phosphate into d-glycero-d-manno-heptose 7-phosphate and harbors a Zn2+ ion in the active site. A series of phosphoryl- and phosphonyl-substituted derivatives featuring a hydroxamate moiety were designed and prepared from suitably protected ribose or hexose derivatives. High-resolution crystal structures of GmhA complexed to two N-formyl hydroxamate inhibitors confirmed the binding interactions to a central Zn2+ ion coordination site. Some of these compounds were found to be nanomolar inhibitors of GmhA. While devoid of HepG2 cytotoxicity and antibacterial activity of their own, they demonstrated in vitro lipopolysaccharide heptosylation inhibition in Enterobacteriaceae as well as the potentiation of erythromycin and rifampicin in a wild-type Escherichia coli strain. These inhibitors pave the way for a novel treatment of Gram-negative infections.
Assuntos
Antibacterianos , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Humanos , Bactérias Gram-Negativas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Escherichia coli/efeitos dos fármacos , Escherichia coli/enzimologia , Cristalografia por Raios X , Sinergismo Farmacológico , Células Hep G2 , Modelos Moleculares , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/síntese química , Zinco/químicaRESUMO
Linear hydroformylation of N-protected allyl- or homoallylamines (cyclohydrocarbonylation: CHC), followed by a reductive amination constitute the two key steps toward convenient routes to aza-heterocycles.
Assuntos
Alcaloides/química , Compostos Heterocíclicos/química , Piperidinas/química , Quinolizidinas/química , Aminação , Ciclização , Espectroscopia de Ressonância Magnética , Estrutura Molecular , EstereoisomerismoRESUMO
Short and efficient access to (+)-lupinine and (+)-epiquinamide by means of an unprecedented double hydroformylation of a bis-homoallylic azide followed by a tandem catalytic hydrogenation/reductive bis-amination is reported.
Assuntos
Alcaloides/síntese química , Quinolizinas/síntese química , Esparteína/análogos & derivados , Alcaloides/química , Aminação , Azidas/química , Catálise , Hidrogenação , Estrutura Molecular , Quinolizinas/química , Esparteína/síntese química , Esparteína/química , EstereoisomerismoRESUMO
A multicomponent reaction between H(2), CO, an unsaturated carboxylic acid derivative, and binucleophiles has been discovered. This process represents a combination of diversity-oriented synthesis and multicomponent reactions including amidation and hydroformylation, followed by nucleophilic addition to an N-acyliminium ion allowing the generation of six new bonds. Using pi-nucleophiles, the sequence turns into a multicomponent Pictet-Spengler reaction.
Assuntos
Monóxido de Carbono/química , Ácidos Carboxílicos/química , Compostos Heterocíclicos/síntese química , Hidrogênio/química , Iminas/química , Compostos Heterocíclicos/química , Estrutura Molecular , EstereoisomerismoRESUMO
The development of hydroformylative domino reactions of easily accessible vinyl acetamides is described. Extremely regioselective hydroformylation of terminal double bounds provides a transient N-acyliminium that can be trapped by various nucleophiles to give several aza-heterocylic scaffolds in a diastereoselective manner.