In vivoantileishmanial action of Ir-(COD)-pentamidine tetraphenylborate onLeishmania donovaniandLeishmania majormouse models

Abstract

Summary:lr-(COD)-pentamidine tetraphenylborate which has previously been studied on promastigote forms of Leishmania, was investigated for its antileishmanial properties compared with pentamidine used as reference compound. In vitro, the iridium complex had the same IC 50 value on intracellular forms of Leishmania as pentamidine (15 µM). In vivo, the compound could not be injected intravenously due to the DMSO excipient so that the treatments were performed intraperitoneally or subcutaneously. On the L. donovani LV9 /Balb/C mouse model, the iridium complex was not toxic after intraperitoneal treatment at 232 mg/kg/day x 5 or 147 µmoles/ kg/day x 5, whereas all the mice died within five days when treated at the same dose with pentamidine isethionate. However, only 23 % of parasite suppression was observed with the iridium complex. On a L. major MON 74/Balb/C mouse model, susceptible to intravenously administered pentamidine at 6.7 umoles/ kg/day x 5 (54 % of parasite suppression), the iridium complex exhibited 32 % of parasite suppression after a treatment at 76 umoles/ kg/day x 5 administered subcutaneously. This slight activity is of interest since pentamidine isethionate is not active under these conditions. Transmission electron microscopy of amastigotes from infected and treated mice show aggregation of ribosomal material, distension of the nuclear membrane and kDNA depolymerization. The mechanism of action therefore involves several targets: membranes, ribosomes and kDNA. According to our results, the Iridium complex is a suitable candidate to be encapsulated in drug carriers such as liposomes or nanoparticles.KEYWORDS : Iridium pentamidine complex, pentamidine, Leishmania, electron microscopy, mechani sm of action. MOTS CLÉS

Cellular Effects of Reversed Amidines on Trypanosoma cruzi

“…In our present TEM analysis, all reversed amidines and, to a lesser extent, the diguanidine induced marked and frequent alterations in the nuclei and mitochondria of both amastigotes and trypomastigotes. These ultrastructural alterations corroborate the findings from previous reports of studies with pentamidine and its analogues and their effectiveness for the in vitro treatment of L. amazonensis (5), Leishmania tropica (13), Leishmania major (11), and T. cruzi (7), as well as the in vivo treatment of L. donovani and L. major in mouse models (16), suggesting that these dicationic compounds have a common mechanism of action, at least in part. However, since aromatic diamidines have also been localized within non-DNA-containing cytoplasmic organelles such as acidocalcisomes in African trypanosomes (17), the possible involvement of the latter compartments in the mechanism of action of diamidines upon T. cruzi must be considered and represents an interesting matter, which is currently under investigation.…”

Gold complexes as potential anti-parasitic agents

“…justifies the screening of new compounds. Some organometallic and coordination complexes of iridium, rhodium and platinum and zinc sulfate have been tested against the leishmania parasite [62][63][64][65][66][67][68][69][70][71][72]. Also, some metallointercalators of DNA based on platinum, copper and silver have been evaluated and have shown remarkable antileishmanial activity [73].…”

Contributions of Ultrastructural Studies to the Cell Biology of Trypanosmatids: Targets for Anti-Parasitic Drugs

“…In T. cruzi, some of the new compounds (classified as reversed amidines) presented a high level of activity against amastigotes and trypomastigotes both in vivo and in vitro [18][19][20][21][22][23][24][25][26]. Ultrastructural analysis showed that the different aromatic diamines displayed similar effects in T. brucei, T cruzi and Leishmania, characterized by the presence of swollen mitochondria presenting low electron-density structures, fragmentation of the membrane and crista and mitochondrial disruption [12,13,18,20,23,24,[27][28][29][30][31][32].…”