A search for novel chemotherapy against tuberculosis amongst natural products

Novel screens have been developed for the detection of antitubercular activity among natural product extracts and these were compared with existing methodologies. Using bioassay-directed methods these screens have been employed to isolate novel antitubercular natural products from higher plant extracts and their structures have been determined. In particularly promising cases, exemplified by tryptanthrin, an alkaloid from the Chinese herb Strobilanthes cusia, i.a., conventional and combinatorial/matrix synthesis methodologies allowed the construction of hundreds of analogs in an attempt to optimize the activity. Tryptanthrin and its analogs are potent against multiresistant tuberculosis strains, are non toxic and give promising blood and tissue levels after oral administration to mice. The more potent of these, PA-505 and PA-510, are two orders of magnitude more potent than tryptanthrin itself and have been extensively evaluated in vivo but failed to cure infected mice. Nonetheless, the methodologies developed are promising for discovering novel natural products for evaluation against multiresistant tubercular and other bacterial infections.