RESUMO
The diterpenoid compound 5 was identified as an antibacterial lead in our screening of small synthetic natural product-like (NPL) library. A series of novel diterpene derivatives were synthesized and investigated for their activity against Staphylococcus aureus Newman strain and multidrug-resistant strains (NRS-1, NRS-70, NRS-100, NRS-108 and NRS-271). Among the compounds tested, 42 and 43 showed highest activity with a MIC of 1 µg/mL against strain Newman, 45 and 52 showed the most potent activity with MIC values of 0.71-3.12 µg/mL against five multidrug-resistant S. aureus. All high-antimicrobial active compounds showed no obvious toxicity to human fibroblast (HAF) cells at the MIC concentration.
Assuntos
Antibacterianos/farmacologia , Diterpenos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Pirazóis/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Cristalografia por Raios X , Diterpenos/síntese química , Diterpenos/química , Relação Dose-Resposta a Droga , Fibroblastos/citologia , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Pirazóis/química , Relação Estrutura-AtividadeRESUMO
Lead compound 7 has neuroprotective effects, and it was discovered by screening a small synthetic natural product-like (NPL) library. Based on the lead, a series of tricyclic diterpene derivatives was designed and synthesized, and their neuroprotective effects were further evaluated against glutamate-, oxygen and glucose deprivation (OGD)- and nutrient deprivation-induced neuronal injury using cell-based assays. To our delight, most of these synthetic compounds exhibited increased neuroprotective effects and blood-brain barrier (BBB) permeability without cellular toxicity. The most potent compound, compound 30, showed significantly improved neuroprotection against neuronal injury in primary neurons. Furthermore, compound 30 exhibited remarkable neuroprotection in transient middle cerebral artery occlusion (tMCAO) rats by reducing their infarct sizes and neurological deficit scores. A mechanistic exploration using in vitro and in vivo experiments showed that the neuroprotection of these compounds was at least partly mediated by improving the levels of glutathione (GSH), superoxide dismutase (SOD) and heme oxygenase-1 (HO-1) protein. Therefore, these tricyclic diterpene derivatives could be used as promising leads for the development of a new type of neuroprotective agents against ischemic brain injury.