title: Synthesis and evaluation of the 2,4-diaminoquinazoline series as anti-tubercular agents.
abstract: The 2,4-diaminoquinazoline class of compounds has previously been identified as an effective inhibitor of Mycobacterium tuberculosis growth. We conducted an extensive evaluation of the series for its potential as a lead candidate for tuberculosis drug discovery. Three segments of the representative molecule N-(4-fluorobenzyl)-2-(piperidin-1-yl)quinazolin-4-amine were examined systematically to explore structure-activity relationships influencing potency. We determined that the benzylic amine at the 4-position, the piperidine at 2-position and the N-1 (but not N-3) are key activity determinants. The 3-deaza analog retained similar activity to the parent molecule. Biological activity was not dependent on iron or carbon source availability. We demonstrated through pharmacokinetic studies in rats that good in vivo compound exposure is achievable. A representative compound demonstrated bactericidal activity against both replicating and non-replicating M. tuberculosis. We isolated and sequenced M. tuberculosis mutants resistant to this compound and observed mutations in Rv3161c, a gene predicted to encode a dioxygenase, suggesting that the compound may act as a pro-drug.
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Ave E, Seattle, WA 98102, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Odingo
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Ave E, Seattle, WA 98102, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: O'Malley
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Ave E, Seattle, WA 98102, USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Kesicki
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Ave E, Seattle, WA 98102, USA.
authors.forename: Torey
authors.initials: T
authors.lastname: Alling
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Ave E, Seattle, WA 98102, USA.
authors.forename: Mai Ann
authors.initials: MA
authors.lastname: Bailey
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Ave E, Seattle, WA 98102, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Early
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Ave E, Seattle, WA 98102, USA.
authors.forename: Juliane
authors.initials: J
authors.lastname: Ollinger
authors.affiliation: Jubilant Chemsys Limited, B-34, Sector 58, Noida 201301, India.
authors.forename: Suryakanta
authors.initials: S
authors.lastname: Dalai
authors.affiliation: Jubilant Chemsys Limited, B-34, Sector 58, Noida 201301, India.
authors.forename: Naresh
authors.initials: N
authors.lastname: Kumar
authors.affiliation: Jubilant Chemsys Limited, B-34, Sector 58, Noida 201301, India.
authors.forename: Ravindra Vikram
authors.initials: RV
authors.lastname: Singh
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN 46285, USA.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Hipskind
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN 46285, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Cramer
authors.affiliation: Department of Computer Science and Engineering, Texas A&M University, College Station, TX, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ioerger
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA.
authors.forename: James
authors.initials: J
authors.lastname: Sacchettini
authors.affiliation: Summit PLC, 91 Milton Park, Abingdon OX14 4RY, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Vickers
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Ave E, Seattle, WA 98102, USA. Electronic address: tanya.parish@idri.org.
authors.forename: Tanya
authors.initials: T
authors.lastname: Parish
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D006207:Half-Life; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D011799:Quinazolines; C013474:2,4-diaminoquinazoline
keywords: 2,4-Diaminoquinazoline; Antibacterial activity; Dioxygenase; Mycobacterium tuberculosis; Tuberculosis