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Bioorg Med Chem. 2014 Dec 15;22(24):6965-79. doi: 10.1016/j.bmc.2014.10.007. Epub 2014 Oct 22.

Synthesis and evaluation of the 2,4-diaminoquinazoline series as anti-tubercular agents.

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Infectious Disease Research Institute, 1616 Eastlake Ave E, Seattle, WA 98102, USA.
Jubilant Chemsys Limited, B-34, Sector 58, Noida 201301, India.
Lilly Research Laboratories, Indianapolis, IN 46285, USA.
Department of Computer Science and Engineering, Texas A&M University, College Station, TX, USA.
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA.
Summit PLC, 91 Milton Park, Abingdon OX14 4RY, UK.
Infectious Disease Research Institute, 1616 Eastlake Ave E, Seattle, WA 98102, USA. Electronic address:


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.


2,4-Diaminoquinazoline; Antibacterial activity; Dioxygenase; Mycobacterium tuberculosis; Tuberculosis

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