Synthesis and structure–activity relationships of phenyl-substituted coumarins with anti-tubercular activity that target FadD32 |
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| Authors: | Tomohiko Kawate Noriaki Iwase Motohisa Shimizu Sarah A Stanley Samantha Wellington Edward Kazyanskaya Deborah T Hung |
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| Institution: | 1. The Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA;2. Department of Molecular Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA;3. Center for Computational and Integrative, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA;4. Department of Microbiology and Immunobiology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA |
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| 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. |
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| Keywords: | Coumarin Structure–activity relationship (SAR) Inhibitor |
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