IN-VITRO TRYPANOCIDAL ACTIVITIES OF NEW S-ADENOSYLMETHIONINE DECARBOXYLASE INHIBITORS

A series of novel aromatic derivatives based on the structure of methy lglyoxal bis(guanylhydrazone) (MGBG) was examined for in vitro antitry panosomal activities and cytotoxicities for human cells, One-third of the compounds tested showed trypanocidal activity at concentrations be low 0.5 mu M after an Incubation period of 72 h, Structure-activity an alysis revealed that bicyclic compounds with homocyclic rings and unmo dified termini were the most active compounds, Results obtained in thr ee laboratories employing different methods and trypanosome population s consistently ranked compound CGP 40215A highest, This compound had a 50% inhibitory concentration of 0.0045 mu M for Trypanosoma brucei rh odesiense, was also active against other trypanosome species, includin g a multidrug-resistant Trypanosoma brucei brucei, and was significant ly less toxic than other compounds tested for a human adenocarcinoma c ell line, with a 50% inhibitory concentration of 1.14 mM. The effect o f CGP 40215A was time and dose dependent, and low concentrations of th e compound required exposure times of > 2 days to exert trypanocidal a ctivity, Compounds were inactive against Leishmania donovani and Trypa nosoma cruzi amastigotes in murine macrophages in vitro.