RESUMO
Novel quinolone antibacterial agents bearing (3S)-amino-(4R)-ethylpiperidines were designed by using low energy conformation analysis and synthesized by applying a conventional coupling reaction of the quinolone nuclei with new piperidine side chains. These compounds were tested in MIC assays and found to be highly potent against Gram-positive and Gram-negative organisms. In particular, the new compounds exhibited high activity against the resistant pathogens Staphylococcus aureus (MRCR) and Streptococcus pneumoniae (PR). Importantly, when the (3S)-amino-(4R)-ethylpiperidinyl quinolones were compared with marketed quinolones sharing the same quinolone nuclei but different side chains at the C-7 position, the new quinolones showed superior activity against Gram-positive organisms, including resistant pathogens.
Assuntos
Antibacterianos/síntese química , Bactérias/efeitos dos fármacos , Farmacorresistência Bacteriana , Piperidinas/síntese química , Quinolonas/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , DNA Girase/química , DNA Girase/efeitos dos fármacos , DNA Super-Helicoidal/química , DNA Super-Helicoidal/efeitos dos fármacos , Escherichia coli/enzimologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Piperidinas/química , Piperidinas/farmacologia , Quinolonas/química , Quinolonas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Quinolones without the usual 6-fluorine substituent have been recently described as potent antibacterial agents. A series of non-fluorinated analogues of the antibacterial quinolone Levofloxacin were synthesized and tested.
Assuntos
Anti-Infecciosos/síntese química , Bactérias/efeitos dos fármacos , Levofloxacino , Ofloxacino/análogos & derivados , Ofloxacino/síntese química , Animais , Anti-Infecciosos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Conformação Molecular , Ofloxacino/farmacologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase IIRESUMO
[reaction: see text] trans-(3S)-Amino piperidines bearing various alkyl and aryl substituents at the C-4 position were synthesized via a ring-closing metathesis reaction. The absolute stereochemistry was controlled using a protected D-serine as a starting material. Stereoselective hydrogenation of allylamines provided trans-(3S)-amino-(4R)-alkyl- and -(4S)-aryl-piperidines. This procedure presents the first method for the asymmetric synthesis of 4-substituted 3-amino piperidines.
