In vitro and in vivo Activity of Two Pt(IV) Salts against <i>Leishmania donovani</i>

Abstract

The activities of 8 platinum drug complex salts were determined against Leishmania donovani promastigotes. The three most active salts were selected: [Pt^IVBr₆]H₂ (pentamidine); [Pt^IVBr₆]H₂ (stilbamidine), and [Pt^IVCl₆]H₂ (2-piperazinyl(1) ethyl amine), which induced growth-inhibition rates of more than 50% at 24 h of treatment and at the maximum dosage tested. The cytotoxicity assays on the macrophage cell line J-774 showed high cytotoxicity for the salt [Pt^IVBr₆]H₂ (stilbamidine) with a percentage of specific ⁵¹Cr release of 58.2% at 24 h of incubation and 100 µg/ml. Meanwhile, assays of the other compounds showed practically no cytotoxicity. The salt [Pt^IVBr₆]H₂ (pentamidine) notably inhibited the incorporation of ³H-thymidine in the treated parasites. The ultrastructural alterations observed in the flagellates treated with the salts [Pt^IVCl₆]H₂ (2-piperazinyl(1)ethyl amine) and [Pt^IVBr₆]H₂ (pentamidine) suggest that both act preferentially at the nuclear level and at the kinetoplast-mitochondrion complex. Both compounds showed a high in vivo activity in parasitized Wistar rats.

In vitro and in vivo Activity of New Rhodium (III) Complexes against <i>Leishmania donovani</i>

“…In addition, Steck [30] observed that the combination of pentamidine with anionic compounds gave rise to complexes with stronger prophylactic activity against the African trypanosomes. Also other authors [31] demonstrated the antileishmania activity of some Pt(IV) complexes.…”

Metal compounds for the treatment of parasitic diseases

“…Metal compounds have been shown to have anti-parasitic properties in models of parasitic disease [23][24][25][26][27][28][29][30][31], and the antimonial drugs are still first line treatment for leishmaniasis [2]. However the molecular mechanism of these metal compounds is undefined.…”

“…Several metal complexes have been reported to have anti-parasitic activity such as gold(I) phosphine and chloroquine complexes [23][24][25], platinum(II) and (IV) complexes [26][27][28][29] and organometallic complexes of iridium, rhodium, palladium and osmium [29][30][31] against a variety of trypanosomatids. Though there is evidence to suggest that these complexes target organelles such as the nucleus and kinetoplast [27][28][29][30][31], the molecular target of these compounds has not been defined.…”

“…Though there is evidence to suggest that these complexes target organelles such as the nucleus and kinetoplast [27][28][29][30][31], the molecular target of these compounds has not been defined. Previously we have investigated the anti-tumor activity of gold(III) (compounds 1-3 in Fig.…”

Leishmanicidal activity of phenylene bridged C2 symmetric glycosyl ureides

“…These include mostly the nitrogen heterocycles; quinolines, 9 acridines, 10 phenothiazines, 11 pyrimidines 12 and purines; 13 and many other class of compounds including anilines, 14 flavonoids, 15 quinones, 16 amino acid esters and amides, 17 amino alcohols, 18 alkyl phospholipids, 19 and certain Pt complexes. 20 Development of most active and selective chemotherapeutic agents could be achieved by rational drug design taking into consideration the biochemical machinery of the parasite. Protozoan parasites of the genus Leishmania are prone to oxidative stress or oxidative siege from various ROS.…”