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JAC Advance Access published online on November 1, 2002
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkf199
© 2002 by The British Society for Antimicrobial Chemotherapy
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© 2002 The British Society for Antimicrobial Chemotherapy

Original Paper

Evaluation of in vitro and in vivo activity of benzindazole-4,9-quinones against Cryptosporidium parvum

Oliver Kayser 1*, W. Ray Waters 2, Keith M. Woods 3, Steve J. Upton 3, Janet S. Keithly 4, Hartmut Laatsch 5, Albrecht F. Kiderlen 6

1 Freie Universität Berlin, Institut für Pharmazie, Pharmazeutische Technologie, Biopharmazie und Biotechnologie, Kelchstraße 31, 12169 Berlin, Germany
2 National Animal Disease Center, Agricultural Research Services, United States Department of Agriculture, Ames, IA 50010, USA
3 Kansas State University, Biology Department, Ackert Hall, Manhattan, KS 66506-4901, USA
4 Wadsworth Center, Division of Infectious Diseases, David Axelrod Institute for Public Health, Albany, NY 12201-2002, USA
5 Georg August-Universität Göttingen, Institut für Organische Chemie, Tammannstraße 2, 35077 Göttingen, Germany
6 Robert Koch-Institut, Abteilung für Infektionskrankheiten, Nordufer 20, 13353 Berlin, Germany

* Corresponding author. E-mail: kayser{at}zedat.fu-berlin.de.

Received 5 November 2001 ; revised 17 May 2002 ; accepted 8 August 2002

Abstract

A series of benzindazole-4,9-quinones was tested for growth-inhibitory effects on Cryptosporidium parvum in vitro and in vivo. Most compounds showed considerable activity at concentrations from 25 to 100 µM. For instance, at 25 µM the derivatives 5-hydroxy-8-chloro- N1-methylbenz[f]-indazole-4,9-quinone and 5-chloro-N2-methylbenz[f]indazole-4,9-quinone in-hibited growth of C. parvum 78-100%, and at 50 µM seven of the 23 derivatives inhibited growth >=90%. The activity of the former two compounds was confirmed in a T-cell receptor {alpha} (TCR-{alpha})-deficient mouse model of chronic cryptosporidiosis. In these mice, the mean infectivity scores (IS) in the caecum were 0.63-0.20, whereas in sham-treated mice the score was 1.44 (P < 0.05). There were similar differences in IS in the ileum, where the score for treated mice was 1.12-0.20 and that for mice receiving no drug was 1.32. There was no acute or chronic toxicity for any compound tested in vivo.

Keywords: naphthoquinones, benzindazole-4,9-quinones, Cryptosporidium, in vitro, in vivo, antiprotozoal, cytotoxicity, drug testing
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