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Synthesis and structure-activity relationships of phenyl-substituted coumarins with anti-tubercular activity that target FadD32.
|Publication Type||Journal Article|
|Authors||Kawate, T., Iwase N., Shimizu M., Stanley SA, Wellington S., Kazyanskaya E., and Hung DT|
|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.|
|Year of Publication||2013|
|Journal||Bioorganic & medicinal chemistry letters|
|Date Published (YYYY/MM/DD)||2013/11/15|