title: In vitro trypanocidal activities of new S-adenosylmethionine decarboxylase inhibitors.
abstract: A series of novel aromatic derivatives based on the structure of methylglyoxal bis(guanylhydrazone) (MGBG) was examined for in vitro antitrypanosomal activities and cytotoxicities for human cells. One-third of the compounds tested showed trypanocidal activity at concentrations below 0.5 microM after an incubation period of 72 h. Structure-activity analysis revealed that bicyclic compounds with homocyclic rings and unmodified termini were the most active compounds. Results obtained in three laboratories employing different methods and trypanosome populations consistently ranked compound CGP 40215A highest. This compound had a 50% inhibitory concentration of 0.0045 microM for Trypanosoma brucei rhodesiense, was also active against other trypanosome species, including a multidrug-resistant Trypanosoma brucei brucei, and was significantly less toxic than other compounds tested for a human adenocarcinoma cell line, with a 50% inhibitory concentration of 1.14 mM. The effect of CGP 40215A was time and dose dependent, and low concentrations of the compound required exposure times of > 2 days to exert trypanocidal activity. Compounds were inactive against Leishmania donovani and Trypanosoma cruzi amastigotes in murine macrophages in vitro.
authors.affiliation: Swiss Tropical Institute, Ciba-Geigy Ltd, Basel, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Brun
authors.forename: Y
authors.initials: Y
authors.lastname: Bühler
authors.forename: U
authors.initials: U
authors.lastname: Sandmeier
authors.forename: R
authors.initials: R
authors.lastname: Kaminsky
authors.forename: C J
authors.initials: CJ
authors.lastname: Bacchi
authors.forename: D
authors.initials: D
authors.lastname: Rattendi
authors.forename: S
authors.initials: S
authors.lastname: Lane
authors.forename: S L
authors.initials: SL
authors.lastname: Croft
authors.forename: D
authors.initials: D
authors.lastname: Snowdon
authors.forename: V
authors.initials: V
authors.lastname: Yardley
authors.forename: G
authors.initials: G
authors.lastname: Caravatti
authors.forename: J
authors.initials: J
authors.lastname: Frei
authors.forename: J
authors.initials: J
authors.lastname: Stanek
authors.forename: H
authors.initials: H
authors.lastname: Mett
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy; D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors*; D000818:Animals; D006801:Humans; D008935:Mitoguazone / Q000031:analogs & derivatives*; D013329:Structure-Activity Relationship; D013997:Time Factors; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014345:Trypanosoma / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D014344:Trypanocidal Agents; D012437:Adenosylmethionine Decarboxylase; D008935:Mitoguazone