RESUMO
An effort to identify novel inhibitors of peptidoglycan synthesis with antibacterial activity resulted in the discovery of a series of biaryl urea-based antibacterial agents through isolation of a by-product from a mixture-based combinatorial library of semi-carbazones and subsequent parallel synthesis efforts. The compounds were shown to possess broad spectrum antibacterial activity against gram-positive drug resistant pathogens, and showed apparent specificity for disruption of the bacterial cell wall biosynthesis pathway.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Hidrazinas/síntese química , Hidrazinas/farmacologia , Ureia/análogos & derivados , Ureia/química , Ureia/farmacologia , Bactérias/crescimento & desenvolvimento , Bactérias/ultraestrutura , Parede Celular/efeitos dos fármacos , Fenômenos Químicos , Físico-Química , Cromatografia Líquida de Alta Pressão , Técnicas de Química Combinatória , Espectrometria de Massas , Testes de Sensibilidade MicrobianaRESUMO
A series of 1,2,4-oxadiazoles and 1,2,4-thiadiazoles containing a 2,6-di-tert-butylphenol substituent were prepared and evaluated as dual inhibitors of 5-lipoxygenase and cyclooxygenase in rat basophilic leukemia (RBL-1) cells. Several of these compounds show oral efficacy in the rat carrageenan footpad edema (CFE) and mycobacterium footpad edema (MFE) antiinflammatory models, without concomitant gastric ulceration. Structure-activity relationships are discussed. The best compounds (ID40 values in MFE of 3-8 mg/kg po) contain guanidine-derived substituents on the heterocyclic ring.
