Microtubules as therapeutic target in Trypanosoma brucei brucei and Molinema dessetae: action of 2-(amino-methyl)acrylophenone derivatives.
2-(amino-methyl) acrylophenone derivatives as antimicrotubular agents were evaluated in vitro and in vivo against Trypanosoma brucei brucei and in vitro against infective larvae from the filaria Molinema dessetae. The compounds were active in vitro against T. b. brucei since the minimum effective concentrations were in a range from 22 to 35 microM after one hour incubation time and in a range from 10 to 35 microM after 24 hours incubation time. Nevertheless, no activity was recovered in vivo for all the compounds at 50 mumoles/kg subcutaneously administered in a single dose. Moreover, interesting activity was obtained on M. dessetae infective larvae in vitro model since EC50 range were from 0.2 to 30 microM after one day incubation time and from 0.2 to 1.5 microM after seven days incubation time. No clear-cut correlation between antimicrotubular effect and biological activity emerged; the antimicrotubular effect does not seem therefore the only mechanism of action for these compounds. Further pharmacomodulations could be studied to obtain better bioavailability and lower toxicity.
Loiseau
P M
PM
Université de Paris-Sud, Châtenay-Malabry, France.
Depreux
P
P
D000179:Acrylates / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D005368:Filariasis / Q000188:drug therapy; D005369:Filaricides / Q000494:pharmacology*; D005370:Filarioidea / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007659:Ketones / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects*; D014353:Trypanosomiasis, African / Q000188:drug therapy
D000179:Acrylates; D005369:Filaricides; D007659:Ketones; D014344:Trypanocidal Agents