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Bioorg Med Chem Lett 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
JournalBioorg Med Chem Lett
Date Published2013 Nov 15
KeywordsAnimals, Antitubercular Agents, Coumarins, Crystallography, X-Ray, Disease Models, Animal, Humans, Male, Mice, Mice, Inbred BALB C, Microbial Sensitivity Tests, Molecular Conformation, Mycobacterium tuberculosis, Structure-Activity Relationship, Tuberculosis

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.


Alternate JournalBioorg. Med. Chem. Lett.
PubMed ID24103299