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Bioorganic & medicinal chemistry letters DOI:10.1016/j.bmcl.2013.09.035

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

Publication TypeJournal Article
Year of Publication2013
AuthorsKawate, T, Iwase, N, Shimizu, M, Stanley, SA, Wellington, S, Kazyanskaya, E, Hung, DT
JournalBioorganic & medicinal chemistry letters
Volume23
Issue22
Pages6052-9
Date Published2013/11/15
ISSN0960-894X
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 2μM and 0.5μM, respectively. Further optimization provided compound 3b with better physiochemical properties with IC90 0.4μM which had activity in a mouse model of infection. The role of the conformation of the 4- and 6-aryl substituents is also described.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S0960-894X(13)01109-8
DOI10.1016/j.bmcl.2013.09.035
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24103299?dopt=Abstract