title: Elucidation of Mycobacterium tuberculosis type II dehydroquinase inhibitors using a fragment elaboration strategy.
abstract: A library of novel Mycobacterium tuberculosis type II dehydroquinase (DHQase) inhibitors were discovered through the use of a fragment elaboration approach. Putative active site binding fragments were initially assessed in silico which led to the selection of two small aromatic fragments for further investigation. Synthetic elaboration of the fragments provided a library of 34 inhibitors that exhibited low-micromolar inhibition of type II DHQase. A number of these inhibitors also showed antibacterial activity in the low-micromolar range in screens against M. tuberculosis in vitro; these now serve as lead compounds for further development of therapeutics for the treatment of tuberculosis.
authors.affiliation: School of Chemistry, Building F11, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Anh Thu
authors.initials: AT
authors.lastname: Tran
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: West
authors.forename: Warwick J
authors.initials: WJ
authors.lastname: Britton
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Payne
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D006836:Hydro-Lyases; C020000:3-dehydroquinate dehydratase