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 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.

Evaluación in vitro de la actividad anti Trypanosoma cruzi de aceites esenciales de diez plantas medicinales

“…Se ha reportado que el extracto de la hoja de B. dracunculifolia, a una concentración de 3 mg/mL, produjo 100% de lisis de formas tripomastigotes de T. cruzi (13) ; los extractos y fracciones de A. amazonicus mostraron lisis de las formas tripomasigotes de T. cruzi in vitro (14) ; otros investigadores también han demostrado el efecto tripanocida de diversos extractos vegetales (10,15,16) , así como de diversas estructuras terpénicas contra uno o todos los estadíos de T. cruzi (17)(18)(19)(20) . También han mostrado efecto tripanocida algunos alcaloides (21)(22)(23) , flavonoides (24)(25)(26) , lignanos (27) y artemisininas (28) .…”

Parasite-specific trypanothione reductase as a drug target molecule

“…Cepharanthine (compound 14) S81 was the most potent TR inhibitor within this group of compounds with K i and K i ¢ values of 7.6 and 51.6 lM, respectively (Fournet et al 1998). Subsequent studies on the efficacy upon oral treatment of Balb/c mice acutely and chronically infected with T. cruzi yielded promising results for daphnoline but not for the excellent TR inhibitor cepharanthine (Fournet et al 2000).…”

Antileishmanial, antitrypanosomal, and cytotoxic screening of ethnopharmacologically selected Peruvian plants

“…Previous studies have reported that BBIQ alkaloids act on the trypanothione reductase (a pathogen-specific enzyme which is one of the main targets in the search for new drugs against T. cruzi) similarly to other inhibitors of this enzyme (nitrofurans and naphthoquinones), which have a positive charge attached to a hydrophobic group. The enzyme is inhibited when binding occurs, interfering with catalysis of trypanothione disulfide reduction (the compound responsible for oxygen exchange), the level of oxygen in the parasite is reduced, and death occurs (Fournet et al 1998). …”