TRYPANOCIDAL BISBENZYLISOQUINOLINE ALKALOIDS ARE INHIBITORS OF TRYPANOTHIONE REDUCTASE

Eleven bisbenzylisoquinoline (BBIQ) alkaloids were studied for in vitr o trypanocidal activity against trypomastigote forms of the Y strain o f Trypanosoma cruzi. The inhibitory activity of these compounds agains t trypanothione reductase (TR), a target enzyme for chemotherapy again st Chagas disease, was also studied. Six BBIQ alkaloids (antioquine, c epharanthine, daphnoline, limacine, cycleanine and (-) curine) display ed a 50% lethal concentration (LC50) against T. cruzi of less than 100 mu M. Daphnoline and curine, with LC50 values of 10 mu M, are attract ive for further investigation as potential anti-Chagasic drugs. Kineti c analyses suggested the BBIQ alkaloids are mixed inhibitors of TR. Th ese compounds are reasonably potent inhibitors of TR; the best TR inhi bitor, cepharanthine, had an IC50 of 15 mu M, which is in the same ord er of magnitude as its LC50 against T. cruzi. The similar magnitudes o f the IC50 and LC50 values suggest that inhibition of TR could contrib ute to the trypanocidal activity exhibited by the BBIQ alkaloids.