Through the TAACF screening program sponsored by NIAID, a naturally occurring pyranocoumarin compounds were identified to be active against Mycobacterium tuberculosis. Further evaluation of the leading compound, (+)-calanolide A. demonstrated that it was active against Mycobacterium tuberculosis strains resistant to isoniazid, rifampin, streptomycin, and ethambutol, respectively. (+)-Calanolide A was also able to kill tubercle bacilli intracellularly in a bone marrow-derived murine macrophage. Preliminary mechanistic studies suggest that its novel anti-TB properties may be involved with unique target(s). Clearly, (+)-calanolide A and its related pyranocomarins represent a novel and unique pharmacophore for anti-TB activity. It is the objective of this SBIR program to embark on design, synthesis and evaluation of certain focused libraries of pyanocoumarin analogues in order to further understand the structural features necessary for the anti-TB activity, with an ultimate goal of developing a novel anti-TB drug. A systematic approach will be taken to initially investigate 4 structural characteristics during the SBIR Phase I research. It is hopeful that at the end of the phase II program an ideal candidate can be selected for a full IND-directed precIinicaI studies, leading to an lND submission and initiation of clinical trials in the SBIR Phase Ill program. PROPOSED COMMERCIAL APPLICATION: TB is the world's #1 killer among the infectious diseases and the leading cause of death among women of reproductive age. One-third (@ 2 billion) of the world's population, including 15 million Americans, is infected with TB and about 1/3 of the HIV-infected people are also co-infected with TB. Resistance has emerged to the current available anti-TB drugs and no standard optimal therapy in AIDS patients with TB infection. New anti-TB agent are in great demand worldwide.
