title: Evaluation of in vitro and in vivo activity of benzindazole-4,9-quinones against Cryptosporidium parvum.
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 micro M. For instance, at 25 micro M the derivatives 5-hydroxy-8-chloro-N1-methylbenz[f]-indazole-4,9-quinone and 5-chloro-N2-methylbenz[f]indazole-4,9-quinone inhibited growth of C. parvum 78-100%, and at 50 micro M seven of the 23 derivatives inhibited growth > or = 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.
authors.affiliation: Freie Universität Berlin, Institut für Pharmazie, Pharmazeutische Technologie, Biopharmazie und Biotechnologie, Kelchstrasse 31, 12169 Berlin. kayser@zedat.fu-berlin.de
authors.forename: Oliver
authors.initials: O
authors.lastname: Kayser
authors.forename: W Ray
authors.initials: WR
authors.lastname: Waters
authors.forename: Keith M
authors.initials: KM
authors.lastname: Woods
authors.forename: Steve J
authors.initials: SJ
authors.lastname: Upton
authors.forename: Janet S
authors.initials: JS
authors.lastname: Keithly
authors.forename: Hartmut
authors.initials: H
authors.lastname: Laatsch
authors.forename: Albrecht F
authors.initials: AF
authors.lastname: Kiderlen
mesh_terms: D000818:Animals; D002417:Cattle; D002429:Cecal Diseases / Q000188:drug therapy / Q000382:microbiology; D002460:Cell Line; D003457:Cryptosporidiosis / Q000188:drug therapy* / Q000382:microbiology; D016785:Cryptosporidium parvum / Q000187:drug effects* / Q000254:growth & development* / Q000302:isolation & purification; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004847:Epithelial Cells / Q000187:drug effects; D019673:Genes, T-Cell Receptor alpha / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007077:Ileal Diseases / Q000188:drug therapy / Q000382:microbiology; D051379:Mice; D011809:Quinones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D011809:Quinones