Homophenylalanine-derived benzo[1,4]diazepine-2,5-diones are strong bacterial quorum sensing inhibitors

Benzo[1,4]diazepines show a large diversity of biological activities and are still commonly used as medications against a broad range of diseases. Within our research in the field of chemo-enzymatic alkaloid synthesis, we developed a synthetic route towards close structural relatives, namely benzo[1,4]diazepine-2,5-diones. Possible antimicrobial activities of these substances are barely known up to date. We thus screened a selection of 21 of these compounds and discovered their ability to interfere with bacterial communication (quorum sensing, QS). Derivatisation of the respective substances by a refined synthetic route resulted in a generation of 9 congeners with drastically enhanced activity, setting the stage for the application of benzo[1,4]diazepine-2,5-diones, a formerly under-investigated compound class, as QS modulators. Molecular docking experiments were performed to evaluate potential protein interaction partners - LuxP, LasR, AbaI, and RhlR - which are involved in QS. The results of the docking calculations show a high energy binding site for three analogues, 5q, 15a and 15b, in the autoinducer binding-pocket of LasR, with the position of a fluorine substituent on the diazepine core structure determining the exact spatial orientation of the compounds.