4.7 Article

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

Journal

BIOORGANIC & MEDICINAL CHEMISTRY
Volume 22, Issue 24, Pages 6965-6979

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2014.10.007

Keywords

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

Funding

  1. Eli Lilly and Company of the mission of the Lilly TB Drug Discovery Initiative

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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. (C) 2014 The Authors. Published by Elsevier Ltd.

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