title: Design and structural analysis of aromatic inhibitors of type II dehydroquinase from Mycobacterium tuberculosis.
abstract: 3-Dehydroquinase, the third enzyme in the shikimate pathway, is a potential target for drugs against tuberculosis. Whilst a number of potent inhibitors of the Mycobacterium tuberculosis enzyme based on a 3-dehydroquinate core have been identified, they generally show little or no in vivo activity, and were synthetically complex to prepare. This report describes studies to develop tractable and drug-like aromatic analogues of the most potent inhibitors. A range of carbon-carbon linked biaryl analogues were prepared to investigate the effect of hydrogen bond acceptor and donor patterns on inhibition. These exhibited inhibitory activity in the high-micromolar range. The addition of flexible linkers in the compounds led to the identification of more potent 3-nitrobenzylgallate- and 5-aminoisophthalate-based analogues.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW (UK).
authors.forename: Nigel I
authors.initials: NI
authors.lastname: Howard
authors.forename: Marcio V B
authors.initials: MV
authors.lastname: Dias
authors.forename: Fabienne
authors.initials: F
authors.lastname: Peyrot
authors.forename: Liuhong
authors.initials: L
authors.lastname: Chen
authors.forename: Marco F
authors.initials: MF
authors.lastname: Schmidt
authors.forename: Tom L
authors.initials: TL
authors.lastname: Blundell
authors.forename: Chris
authors.initials: C
authors.lastname: Abell
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007539:Isonicotinic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D056004:Molecular Dynamics Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D012765:Shikimic Acid / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D007539:Isonicotinic Acids; D012765:Shikimic Acid; D006836:Hydro-Lyases; C020000:3-dehydroquinate dehydratase; C560098:citrazinic acid
keywords: Mycobacterium tuberculosis; dehydroquinase; drug design; inhibitors; protein structures