Trypanocidal Bisbenzylisoquinoline Alkaloids are Inhibitors of Trypanothione Reductase

Abstract

Eleven bisbenzylisoquinoline (BBIQ) alkaloids were studied for in vitro trypanocidal activity against trypomastigote forms of the Y strain of Trypanosoma cruzi. The inhibitory activity of these compounds against trypanothione reductase (TR), a target enzyme for chemotherapy against Chagas disease, was also studied. Six BBIQ alkaloids (antioquine, cepharanthine, daphnoline, limacine, cycleanine and (-) curine) displayed a 50% lethal concentration (LC₅₀) against T. cruzi of less than 100μM. Daphnoline and curine, with LC₅₀ values of 10μM, are attractive for further investigation as potential anti-Chagasic drugs. Kinetic analyses suggested the BBIQ alkaloids are mixed inhibitors of TR. These compounds are reasonably potent inhibitors of TR; the best TR inhibitor, cepharanthine, had an IC₅₀ of 15μM, which is in the same order of magnitude as its LC₅₀ against T. cruzi. The similar magnitudes of the IC₅₀ and LC₅₀ values suggest that inhibition of TR could contribute to the trypanocidal activity exhibited by the BBIQ alkaloids.