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J Med Chem ; 64(12): 8644-8665, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34080858


Due to the poor permeability across Gram-negative bacterial membranes and the troublesome bacterial efflux mechanism, only a few GyrB/ParE inhibitors with potent activity against Gram-negative pathogens have been reported. Among them, pyrimido[4,5-b]indole derivatives represented by GP-1 demonstrated excellent broad-spectrum antibacterial activity against both Gram-positive and Gram-negative bacteria but were limited by hERG inhibition and poor pharmacokinetics profile. To improve their drug-like properties, we designed a series of novel pyrimido[4,5-b]indole derivatives based on the tricyclic scaffold of GP-1 and the C-7 moiety of acorafloxacin. These efforts have culminated in the discovery of a promising compound 18r with reduced hERG liability and an improved PK profile. Compound 18r exhibited superior broad-spectrum in vitro antibacterial activity compared to GP-1, including a variety of clinical multidrug G- pathogens, especially Acinetobacter baumannii, and the in vivo efficacy was also demonstrated in a neutropenic mouse thigh model of infection with multidrug-resistant A. baumannii.

Infecções por Acinetobacter/tratamento farmacológico , Antibacterianos/uso terapêutico , Bactérias/efeitos dos fármacos , Indóis/uso terapêutico , Pirimidinas/uso terapêutico , Animais , Antibacterianos/síntese química , Antibacterianos/metabolismo , Antibacterianos/farmacocinética , DNA Girase/metabolismo , Desenho de Fármacos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Estabilidade de Medicamentos , Células HEK293 , Humanos , Indóis/síntese química , Indóis/metabolismo , Indóis/farmacocinética , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Ratos , Relação Estrutura-Atividade
Bioorg Med Chem Lett ; 35: 127799, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33476772


Antimicrobial resistance is a global challenge and the effectiveness of old antibiotics is decreasing. Discovery and development of antibacterial agents have been accelerated to replenish the arsenal of antibiotics which is limited and shrinking. In recent years, significant advances have achieved in the antibacterial area, including new compounds of known classes and new compounds with new mechanisms. This review summarizes these advances and provides perspective on future directions of antibacterial agents.

Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Antibacterianos/química , Testes de Sensibilidade Microbiana , Conformação Molecular
Protein Pept Lett ; 21(10): 1031-47, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24975667


Glycopeptides with potent antibiotic activity are vital for the treatment of severe infections that caused by Gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus. Recently, the glycopeptide-resistant Grampositive bacteria present a serious challenge to public health after more than decades of clinical use. Additionally, the antibacterial activity and side effect become an increasing crisis and should have to be taken into account. As a consequence, new glycopeptide antibiotics are needed to face with these problems. In the past years, with the development of natural product chemistry, more and more glycopeptide compounds with promising biological properties were discovered. In addition, the chemical modification of the known glycopeptide provides an opportunity for the discovery of new potential glycopeptide antibiotics. Considerable efforts have been made in this field in order to meet the clinical needs. In this article, we mainly focus on the advances of glycopeptide as antibiotics, including many representative glycopeptides or its analogues and derivatives. Taken together, we hope all this information is helpful for the discovery of new potential glycopeptide antibiotics.

Antibacterianos/síntese química , Bactérias Gram-Positivas/efeitos dos fármacos , Vancomicina/síntese química , Antibacterianos/farmacologia , Bactérias Gram-Positivas/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Vancomicina/análogos & derivados , Vancomicina/farmacologia