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The bacterial quorum sensing (QS) system is a target for non-lethal antibacterial agents that do not encourage the development of resistance. QS inhibitors commonly contain a polar "head" moiety and a lipidic "tail" moiety. In this work, we synthesised novel QS inhibitor candidates in which the lipidic "tail" is decorated with stereospecifically positioned fluorine atoms. The presence of fluorine is shown to bias the molecules into distinctive conformations that are pre-organised for binding to the QS receptor. This translates into significant increases in QS inhibitory potency.

Piperine, a natural product derived from peppercorns, has a variety of biological activities that make it an attractive lead compound for medicinal chemistry. However, piperine has some problematic physicochemical properties including poor aqueous solubility and a susceptibility to UV-induced degradation. In this work, we designed an analog of piperine in which the central conjugated hydrocarbon chain is replaced with a vicinal difluoroalkane moiety. We show that this fluorinated analog of piperine has superior physicochemical properties, and it also has higher potency and selectivity towards one particular drug target, acetylcholinesterase. This work highlights the potential usefulness of the threo -difluoroalkane motif as a surrogate for E -alkenes in medicinal chemistry., (Copyright © 2020, Lizarme-Salas et al.; licensee Beilstein-Institut.)