Trypanocidal bisbenzylisoquinoline alkaloids are inhibitors of trypanothione reductase.
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 100 microM. Daphnoline and curine, with LC50 values of 10 microM, 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 15 microM, 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.
Fournet
A
A
ORSTOM (Institut Français de Recherche Scientifique pour le Développement en Coopération), Asuncion, Paraguay.
Inchausti
A
A
Yaluff
G
G
Rojas De Arias
A
A
Guinaudeau
H
H
Bruneton
J
J
Breidenbach
M A
MA
Karplus
P A
PA
Faerman
C H
CH
D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D044182:Benzylisoquinolines; D016831:Crithidia fasciculata / Q000201:enzymology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007700:Kinetics; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology; D052117:Benzodioxoles
D000470:Alkaloids; D044182:Benzylisoquinolines; D004791:Enzyme Inhibitors; D009247:NADH, NADPH Oxidoreductases; D011994:Recombinant Proteins; D014344:Trypanocidal Agents; C117762:daphnoline; C006947:cepharanthine; D052117:Benzodioxoles; C049608:trypanothione reductase