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The ultrastructural alterations induced in vitro by ICI 195,739, a recently developed bis-triazole derivative with potent antiproliferative effects on Trypanosoma (Schizotrypanum) cruzi, are reported. On epimastigotes, the triazole at its minimum growth-inhibitory concentration (0.1 microM) produced immediately (within 24 h) gross alterations in the organization of chromatin and the appearance of large electron-dense granules; at this time, many cells were binucleated, indicating a blockade in cytokinesis. At later times (120 h), mitochondrial swelling, a characteristic effect reported previously for the dioxolane-imidazole ketoconazole when the performed ergosterol pool is depleted, was the predominant effect and led to cell lysis. In amastigotes proliferating in Vero cells, the drug at 10 nM produced mitochondrial swelling, autophagic vacuoles, and massive alterations of the plasma membrane, leading to complete parasite destruction after 96 h of incubation of the infected monolayers with the drug. The results support previous conclusions that ICI 195,739 has a dual mechanism of action against T. cruzi, involving blockade of ergosterol biosynthesis and a direct effect on cell division which cannot be reversed by addition of exogenous ergosterol.

antimicrobial agents and chemotherapy

Ultrastructural alterations induced by ICI 195,739, a bis-triazole derivative with strong antiproliferative action against Trypanosoma (Schizotrypanum) cruzi