title: CoA Adducts of 4-Oxo-4-Phenylbut-2-enoates: Inhibitors of MenB from the M. tuberculosis Menaquinone Biosynthesis Pathway.
abstract: A high-throughput screen led to the discovery of 2-amino-4-oxo-4-phenylbutanoate inhibitors of the 1,4-dihydroxy-2-naphthoyl-CoA synthase (MenB) from the menaquinone biosynthesis pathway in Mycobacterium tuberculosis. However, these compounds are unstable in solution and eliminate to form the corresponding 4-oxo-4-phenylbut-2-enoates that then react with CoA in situ to form nanomolar inhibitors of MenB. The potency of these compounds results from interaction of the CoA adduct carboxylate with the MenB oxyanion hole, a conserved structural motif in the crotonase superfamily. 4-Oxo-4-chlorophenylbutenoyl methyl ester has MICs of 0.6 and 1.5 μg/ml against replicating and nonreplicating M. tuberculosis, respectively, and it is proposed that the methyl ester penetrates the cell where it is hydrolyzed and reacts with CoA to generate the active antibacterial. The CoA adducts thus represent an important foundation for the development of novel MenB inhibitors, and suggest a general approach to the development of potent inhibitors of acyl-CoA binding enzymes.
authors.affiliation: Institute for Chemical biology & Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400 USA.
authors.forename: Xiaokai
authors.initials: X
authors.lastname: Li
authors.forename: Nina
authors.initials: N
authors.lastname: Liu
authors.forename: Huaning
authors.initials: H
authors.lastname: Zhang
authors.forename: Susan E
authors.initials: SE
authors.lastname: Knudson
authors.forename: Huei-Jiun
authors.initials: HJ
authors.lastname: Li
authors.forename: Cheng-Tsung
authors.initials: CT
authors.lastname: Lai
authors.forename: Carlos
authors.initials: C
authors.lastname: Simmerling
authors.forename: Richard A
authors.initials: RA
authors.lastname: Slayden
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tonge