Discovery and structure-activity relationships of a novel oxazolidinone class of bacterial type II topoisomerase inhibitors.

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.

Total synthesis of (-)-blepharocalyxin D and analogues.

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.

Bicyclic oxygen heterocycles from γ,δ-unsaturated alcohols: synthetic targets inspired by blepharocalyxin†D.

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.