Stereoselective Synthesis, Docking, and Biological Evaluation of Difluoroindanediol-Based MenE Inhibitors as Antibiotics

A stereoselective
synthesis has been developed to provide all four
side-chain stereoisomers of difluoroindanediol 2, the
mixture of which was previously identified as an inhibitor of the o-succinylbenzoate-CoA synthetase MenE in bacterial menaquinone
biosynthesis, having promising in vitro activity against methicillin-resistant Staphylococcus aureus and Mycobacterium tuberculosis. Only the (1R,3S)-diastereomer
inhibited the biochemical activity of MenE, consistent with computational
docking studies, and this diastereomer also exhibited in vitro antibacterial
activity comparable to that of the mixture. However, mechanism-of-action
studies suggest that this inhibitor and its diastereomers may act
via other mechanisms beyond inhibition of menaquinone biosynthesis.