title: Stereoselective Synthesis, Docking, and Biological Evaluation of Difluoroindanediol-Based MenE Inhibitors as Antibiotics.
abstract: 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.
authors.affiliation: Pharmacology Program, Weill Cornell Graduate School of Medical Sciences,  Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
authors.forename: Christopher E
authors.identifier: 0000-0001-9777-4114
authors.initials: CE
authors.lastname: Evans
authors.affiliation: Institute of Chemical Biology and Drug Discovery, Department of Chemistry,  Stony Brook University , Stony Brook, New York 11794, United States.|Department of Biochemistry and Cell Biology, Stony Brook University , Stony Brook, New York 11794, United States.
authors.forename: Joe S
authors.initials: JS
authors.lastname: Matarlo
authors.affiliation: Institute of Chemical Biology and Drug Discovery, Department of Chemistry,  Stony Brook University , Stony Brook, New York 11794, United States.|Department of Chemistry,  Stony Brook University , Stony Brook, New York 11794, United States.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tonge
authors.affiliation: Pharmacology Program, Weill Cornell Graduate School of Medical Sciences,  Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.|Chemical Biology Program and Tri-Institutional Research Program, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
authors.forename: Derek S
authors.initials: DS
authors.lastname: Tan
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003066:Coenzyme A Ligases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007189:Indans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D007189:Indans; D003066:Coenzyme A Ligases