Spiroarsoranes of second generation: evaluation of trypanocidal properties against Trypanosoma brucei brucei.
The spiroarsoranes are a series of pentavalent arsenicals having interesting trypanocidal properties. They are less toxic than trivalent arsenicals but their activity appear at higher doses and concentrations. The structure-activity relationships study from the first series led to a new generation of spiroarsoranes which has been synthesized and evaluated in vitro and in vivo against Trypanosoma brucei brucei bloodstream forms. Among 40 compounds, 5 were active in vitro at concentrations less than 10 mumol/l and 7 were active in vivo. The most interesting compound of this series (compound I e 2) showed an in vitro activity at 125 mumol/l after 24 hours incubation time and in vivo all the mice were cured after a subcutaneous treatment at 600 mumol/kg in one single dose. The spiranization and the substitution of para-arsanilic acid allowed to obtain a better mean survival time at 300 mumol/kg comparatively to para-arsanilic acid itself used as reference compound. Nevertheless, this second generation of compounds was less active than the selected compound of the first series which was efficient at 150 mumol/kg in subcutaneously one single dose.
Biologie et Contrôle des Organismes Parasites, Université Paris-Sud, Châtenay-Malabry, France.
P M
PM
Loiseau
J G
JG
Wolf
P
P
Gayral
D000818:Animals; D001152:Arsenicals / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D051379:Mice; D008970:Molecular Weight; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014346:Trypanosoma brucei brucei / Q000187:drug effects*; D014353:Trypanosomiasis, African / Q000188:drug therapy*
D001152:Arsenicals; D013141:Spiro Compounds; D014344:Trypanocidal Agents