title: A prodrug approach for improving antituberculosis activity of potent Mycobacterium tuberculosis type II dehydroquinase inhibitors.
abstract: The synthesis of high-affinity reversible competitive inhibitors of Mycobacterium tuberculosis type II dehydroquinase, an essential enzyme in Mycobacterium tuberculosis bacteria, is reported. The inhibitors reported here are mimics of the enol intermediate and the effect of substitution on C2 was studied. The crystal structures of Mycobacterium tuberculosis type II dehydroquinase in complex with three of the reported inhibitors are also described. The results show that an aromatic substituent on C2 prevents the closure of the active site by impeding the hydrogen-bonding interaction of Arg108 with the essential Tyr24 of the flexible loop, the residue that initiates catalysis. Chemical modifications of the reported acids were also carried out to improve internalization into Mycobacterium tuberculosis through an ester prodrug approach. Propyl esters proved to be the most efficient in achieving optimal in vitro activities.
authors.affiliation: Centro Singular de Investigación en Química Biológica y Materiales Moleculares, Universidad de Santiago de Compostela, calle Jenaro de la Fuente s/n, 15782 Santiago de Compostela, Spain.
authors.forename: Lorena
authors.initials: L
authors.lastname: Tizón
authors.forename: José M
authors.initials: JM
authors.lastname: Otero
authors.forename: Verónica F V
authors.initials: VF
authors.lastname: Prazeres
authors.forename: Antonio L
authors.initials: AL
authors.lastname: Llamas-Saiz
authors.forename: Gavin C
authors.initials: GC
authors.lastname: Fox
authors.forename: Mark J
authors.initials: MJ
authors.lastname: van Raaij
authors.forename: Heather
authors.initials: H
authors.lastname: Lamb
authors.forename: Alastair R
authors.initials: AR
authors.lastname: Hawkins
authors.forename: José A
authors.initials: JA
authors.lastname: Ainsa
authors.forename: Luis
authors.initials: L
authors.lastname: Castedo
authors.forename: Concepción
authors.initials: C
authors.lastname: González-Bello
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002384:Catalysis; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D010078:Oxazines; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014966:Xanthenes
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D010078:Oxazines; D011355:Prodrugs; D014966:Xanthenes; C005843:resazurin; D006836:Hydro-Lyases; C020000:3-dehydroquinate dehydratase