Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 23, Issue 22, Pages 6052-6059Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2013.09.035
Keywords
Mycobacterium tuberculosis; Coumarin; Structure-activity relationship (SAR); Inhibitor
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In an effort to develop new and potent agents for therapy against tuberculosis, a high-throughput screen was performed against Mycobacterium tuberculosis strain H37Rv. Two 6-aryl-5,7-dimethyl-4-phenylcoumarin compounds 1a and 1b were found with modest activity. A series of coumarin derivatives were synthesized to improve potency and to investigate the structure-activity relationship of the series. Among them, compounds 1o and 2d showed improved activity with IC90 of 2 mu M and 0.5 mu M, respectively. Further optimization provided compound 3b with better physiochemical properties with IC90 0.4 mu M which had activity in a mouse model of infection. The role of the conformation of the 4- and 6-aryl substituents is also described. (c) 2013 Elsevier Ltd. All rights reserved.
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