RESUMEN
There is an increasingly urgent and unmet medical need for novel antibiotic drugs that tackle infections caused by multidrug-resistant (MDR) pathogens. Novel bacterial type II topoisomerase inhibitors (NBTIs) are of high interest due to limited cross-resistance with fluoroquinolones, however analogues with Gram-negative activity often suffer from hERG channel inhibition. A novel series of bicyclic-oxazolidinone inhibitors of bacterial type II topoisomerase were identified which display potent broad-spectrum anti-bacterial activity, including against MDR strains, along with an encouraging in vitro safety profile. In vivo proof of concept was achieved in a A. baumannii mouse thigh infection model.
Asunto(s)
Oxazolidinonas , Inhibidores de Topoisomerasa , Animales , Antibacterianos/farmacología , Girasa de ADN/metabolismo , Fluoroquinolonas/farmacología , Ratones , Pruebas de Sensibilidad Microbiana , Oxazolidinonas/farmacología , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/farmacología , Inhibidores de Topoisomerasa/farmacologíaRESUMEN
An efficient strategy for the total synthesis of (-)-blepharocalyxin D and an analogue is described. The key step involves an acid-mediated cascade process in which reaction of methyl 3,3-dimethoxypropanoate with γ,δ-unsaturated alcohols possessing diastereotopic styrenyl groups gives trans-fused bicyclic lactones with the creation of two rings and four stereocenters in one pot.
Asunto(s)
Alcoholes/química , Lactonas/síntesis química , Piranos/síntesis química , Alpinia/química , Lactonas/química , Estructura Molecular , Piranos/química , EstereoisomerismoRESUMEN
trans-2,8-Dioxabicyclodecanes were prepared in high yield with the creation of up to three stereocenters in a single pot by the acid-mediated reaction of γ,δ-unsaturated alcohols with aldehydes (see scheme, Bn=benzyl). This versatile reaction enables the stereoselective introduction of substituents at the C3, C4, C7, and C9 positions of the bicyclic framework.
