The Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA; Department of Molecular Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Center for Computational and Integrative, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Department of Microbiology and Immunobiology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Bioorg Med Chem Lett. 2013 Nov 15;23(22):6052-9. doi: 10.1016/j.bmcl.2013.09.035. Epub 2013 Sep 19.
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.
为了开发针对结核病治疗的新型有效药物，我们对结核分枝杆菌 H37Rv 菌株进行了高通量筛选。发现了两种具有中等活性的 6-芳基-5,7-二甲基-4-苯基香豆素化合物 1a 和 1b。我们合成了一系列香豆素衍生物以提高其活性，并研究了该系列化合物的构效关系。其中，化合物 1o 和 2d 的活性分别提高到了 2 μM 和 0.5 μM。进一步优化得到的化合物 3b 具有更好的理化性质，IC90 为 0.4 μM，在感染小鼠模型中具有活性。还描述了 4-和 6-芳基取代基构象的作用。
