|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Kawate, T, Iwase, N, Shimizu, M, Stanley, SA, Wellington, S, Kazyanskaya, E, Hung, DT|
|Journal||Bioorg Med Chem Lett|
|Date Published||2013 Nov 15|
|Keywords||Animals, 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 Journal||Bioorg. Med. Chem. Lett.|