ABSTRACT
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.
Subject(s)
Oxazolidinones , Topoisomerase Inhibitors , Animals , Anti-Bacterial Agents/pharmacology , DNA Gyrase/metabolism , Fluoroquinolones/pharmacology , Mice , Microbial Sensitivity Tests , Oxazolidinones/pharmacology , Structure-Activity Relationship , Topoisomerase II Inhibitors/pharmacology , Topoisomerase Inhibitors/pharmacologyABSTRACT
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.
Subject(s)
Alcohols/chemistry , Lactones/chemical synthesis , Pyrans/chemical synthesis , Alpinia/chemistry , Lactones/chemistry , Molecular Structure , Pyrans/chemistry , StereoisomerismABSTRACT
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.
