Open AccessStereoselective Synthesis, Docking, and Biological Evaluation of Difluoroindanediol-Based MenE Inhibitors as Antibiotics
Author(s) -
Christopher E. B. Evans,
Joe S. Matarlo,
Peter J. Tonge,
Derek S. Tan
Publication year - 2016
Publication title -
organic letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.94
H-Index - 239
eISSN - 1523-7060
pISSN - 1523-7052
DOI - 10.1021/acs.orglett.6b03272
Subject(s) - diastereomer , docking (animal) , chemistry , stereoselectivity , in vitro , stereochemistry , mycobacterium tuberculosis , antibiotics , biosynthesis , antibacterial activity , biochemistry , staphylococcus aureus , bacteria , combinatorial chemistry , enzyme , tuberculosis , biology , catalysis , medicine , nursing , pathology , genetics
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.