Synthesis and structure-activity relationships of phenyl-substituted coumarins with anti-tubercular activity that target FadD32.

Bioorg Med Chem Lett
Authors
Keywords
Abstract

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 μM and 0.5 μM, respectively. Further optimization provided compound 3b with better physiochemical properties with IC90 0.4 μM which had activity in a mouse model of infection. The role of the conformation of the 4- and 6-aryl substituents is also described.

Year of Publication
2013
Journal
Bioorg Med Chem Lett
Volume
23
Issue
22
Pages
6052-9
Date Published
2013 Nov 15
ISSN
1464-3405
URL
DOI
10.1016/j.bmcl.2013.09.035
PubMed ID
24103299
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