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
The synthesis and antibacterial activities of three chemotypes of DNA supercoiling inhibitors based on imidazolo[1,2-a]pyridine and [1,2,4]triazolo[1,5-a]pyridine scaffolds that target the ATPase subunits of DNA gyrase and topoisomerase IV (GyrB/ParE) is reported. The most potent scaffold was selected for optimization leading to a series with potent Gram-positive antibacterial activity and a low resistance frequency.
Assuntos
Anti-Infecciosos/farmacologia , Química Farmacêutica/métodos , DNA Topoisomerase IV/antagonistas & inibidores , Inibidores da Topoisomerase II , Adenosina Trifosfatases/antagonistas & inibidores , Adenosina Trifosfatases/química , Desenho de Fármacos , Enterococcus faecalis/metabolismo , Escherichia coli/metabolismo , Bactérias Gram-Positivas/metabolismo , Humanos , Imidazóis/química , Concentração Inibidora 50 , Piridinas/química , Staphylococcus aureus/metabolismo , Relação Estrutura-Atividade , Triazóis/químicaRESUMO
Heat shock protein 90 (Hsp90) plays a key role in stress response and protection of the cell against the effects of mutation. Herein we report the identification of an Hsp90 inhibitor identified by fragment screening using a high-concentration biochemical assay, as well as its optimisation by in silico searching coupled with a structure-based drug design (SBDD) approach.