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Antimicrobial Agents and Chemotherapy, July 1998, p. 1771-1777, Vol. 42, No. 7
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Antiproliferative Effects and Mechanism of Action of SCH 56592 against Trypanosoma (Schizotrypanum) cruzi: In Vitro and In Vivo Studies

Julio A. Urbina,1,* Gilberto Payares,2 Lellys M. Contreras,1 Andreína Liendo,1 Cristina Sanoja,2 Judith Molina,2 Marta Piras,3 Romano Piras,3 Norma Perez,1,4 Patrick Wincker,4 and David Loebenberg5

Laboratorio de Química Biológica, Centro de Biofísica y Bioquímica, Instituto Venezolano de Investigaciones Científicas, Caracas 1020A,1 Departmento de Parasitología, Instituto de Zoología Tropical, Universidad Central de Venezuela, Caracas 1041,2 and Unidad de Investigacion, Centro Medico Docente "La Trinidad," Caracas 1060,3 Venezuela; Laboratoire `Genome des Parasites,' Faculté de Medecine, Université de Montpellier, Montpellier, France4; and Schering-Plough Research Institute, Kenilworth, New Jersey 07033-05395

Received 23 February 1998/Returned for modification 1 April 1998/Accepted 4 May 1998

We have investigated the antiproliferative effects of SCH 56592, a new experimental triazole, against Trypanosoma (Schizotrypanum) cruzi, the etiological agent of Chagas' disease in Latin America. SCH 56592 blocked the proliferation of the epimastigote form of the parasite in vitro at 30 nM, a concentration 30- to 100-fold lower than that required with the reference compounds ketoconazole and itraconazole. At that concentration all the parasite's endogenous sterols (ergosterol, 24-ethyl-cholesta-5,7,22-trien-3beta -ol, and its 22-dihydro analogs), were replaced by methylated sterols (lanosterol and 24-methylene-dihydrolanosterol), as revealed by high-resolution gas chromatography coupled with mass spectrometry. This indicated that the primary mechanism of action of the drug was inhibition of the parasite's sterol C-14alpha demethylase. Against the clinically relevant intracellular amastigote form, grown in cultured Vero cells at 37°C, the MIC of SCH 56592 was 0.3 nM, again 33- to 100-fold lower than that of ketoconazole or itraconazole. In a murine model of acute Chagas' disease, SCH 56592 given at >=  10 mg/kg of body weight/day for a total of 43 doses allowed 85 to 100% survival and 90 to 100% cure of the surviving animals, as verified by parasitological, serological, and PCR-based tests, while ketoconazole given at 30 mg/kg day allowed 60% survival but only 20% cure. In a murine model of chronic Chagas' disease, SCH 56592 was again more effective than ketoconazole, providing 75 to 85% protection from death, with 60 to 75% parasitological cures of the surviving animals, while no parasitological cures were observed with ketoconazole. The results indicate that SCH 56592 is the most powerful sterol biosynthesis inhibitor ever tested against T. cruzi and may be useful in the treatment of human Chagas' disease.

* Corresponding author. Present address: School of Chemical Sciences, Chemistry and Life Sciences Laboratory, Rm. A106, University of Illinois at Urbana-Champaign, 600 S. Mathews Ave., Urbana, IL 61821. Phone: (217) 333-8328. Fax: (217) 244-0997. E-mail: jaurbina{at}churchill.scs.uiuc.edu.

Antimicrobial Agents and Chemotherapy, July 1998, p. 1771-1777, Vol. 42, No. 7
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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