title: Uptake into leishmania donovani promastigotes and antileishmanial action of an organometallic complex derived from pentamidine.
abstract: Iridium (Ir)-(COD)-pentamidine tetraphenylborate (CAS 225-75-4) was selected from a primary screening to be evaluated in vitro on three Leishmania (L.) strains comparatively to pentamidine used as reference compound. The IC50 values obtained from in vitro evaluation on promastigotes of L. major CRE 26, L. donovani DD8 and L. donovani LV9 were 3.9, 23.5, and 3.3 mumol/l for Ir-(COD)-pentamidine tetraphenylborate and 1.6, 7.7, and 3.9 mumol/l for pentamidine isethionate, respectively. Cytotoxicity on mouse peritoneal macrophages led to determine a chemotherapeutic index of 1.7 for Ir-(COD)-pentamidine tetraphenylborate and 4 for pentamidine. Considering L. donovani DD8, the uptake of iridium complex by the promastigotes was shown to be saturable with a Km value of 17.4 mumol/l and Vmax of 1.3 nmol/mg protein/2 h. After 2 and 4 h incubation of treated promastigotes in drug free medium the absence of Ir-complex efflux is in favour of intracellular drug binding. As a matter of fact iridium complex was shown to bind ribosomal subunits in vitro, with no effect on macromolecular biosynthesis.
authors.affiliation: Centre National de la Recherche Scientifique, Institut de Chimie des Substances Naturelles, Gif sur Yvette, France.
authors.forename: N
authors.initials: N
authors.lastname: Mbongo
authors.forename: P M
authors.initials: PM
authors.lastname: Loiseau
authors.forename: F
authors.initials: F
authors.lastname: Lawrence
authors.forename: D G
authors.initials: DG
authors.lastname: Craciunescu
authors.forename: M
authors.initials: M
authors.lastname: Robert-Gero
mesh_terms: D000818:Animals; D006224:Cricetinae; D006207:Half-Life; D020128:Inhibitory Concentration 50; D007495:Iridium; D007893:Leishmania donovani / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism*; D018320:Leishmania major / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000469:parasitology; D008297:Male; D008647:Mesocricetus; D051379:Mice; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D010419:Pentamidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism; D013775:Tetraphenylborate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D009942:Organometallic Compounds; D014344:Trypanocidal Agents; C115222:iridium (cyclooctadiene) pentamidine tetraphenylborate; D013775:Tetraphenylborate; D007495:Iridium; D010419:Pentamidine