title: 4-Substituted D-glutamic acid analogues: the first potent inhibitors of glutamate racemase (MurI) enzyme with antibacterial activity.
abstract: The first potent inhibitors of glutamate racemase (MurI) enzyme that show whole cell antibacterial activity are described. Optically pure 4-substituted D-glutamic acid analogues with (2R,4S) stereochemistry and bearing aryl-, heteroaryl-, cinnamyl-, or biaryl-methyl substituents represent a novel class of glutamate racemase inhibitors. Exploration of the D-Glu core led to the identification of lead compounds (-)-8 and 10. 2-Naphthylmethyl derivative 10 was found to be a potent competitive inhibitor of glutamate racemase activity (K(i) = 16 nM, circular dichroism assay; IC(50) = 0.1 microg/mL high-performance liquid chromatography (HPLC) assay). Thorough structure-activity relationship (SAR) studies led to benzothienyl derivatives such as 69 and 74 with increased potency (IC(50) = 0.036 and 0.01 microg/mL, respectively, HPLC assay). These compounds showed potent whole cell antibacterial activity against S. pneumoniae PN-R6, and good correlation with the enzyme assay. Compounds 69, 74 and biaryl derivative 52 showed efficacy in an in vivo murine thigh infection model against Streptococcus pneumoniae. Data described herein suggest that glutamate racemase may be a viable target for developing new antibacterial agents.
authors.affiliation: Eli Lilly and Co., Lilly S.A., Avenida de la Industria, 30, 28108 Alcobendas, Madrid, Spain. de_dios_alfonso@lily.com
authors.forename: Alfonso
authors.initials: A
authors.lastname: de Dios
authors.forename: Lourdes
authors.initials: L
authors.lastname: Prieto
authors.forename: Jose Alfredo
authors.initials: JA
authors.lastname: Martín
authors.forename: Almudena
authors.initials: A
authors.lastname: Rubio
authors.forename: Jesus
authors.initials: J
authors.lastname: Ezquerra
authors.forename: Mark
authors.initials: M
authors.lastname: Tebbe
authors.forename: Beatriz
authors.initials: B
authors.lastname: López de Uralde
authors.forename: Justina
authors.initials: J
authors.lastname: Martín
authors.forename: Ana
authors.initials: A
authors.lastname: Sánchez
authors.forename: Deborah L
authors.initials: DL
authors.lastname: LeTourneau
authors.forename: James E
authors.initials: JE
authors.lastname: McGee
authors.forename: Carole
authors.initials: C
authors.lastname: Boylan
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Parr
authors.forename: Michele C
authors.initials: MC
authors.lastname: Smith
mesh_terms: D000591:Amino Acid Isomerases / Q000037:antagonists & inhibitors*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005971:Glutamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D011008:Pneumococcal Infections / Q000188:drug therapy; D013237:Stereoisomerism; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D005971:Glutamates; D000591:Amino Acid Isomerases; C062292:glutamate racemase