In the present work, we have assayed both the in vitro and in vivo action of two acridine compounds against Leishmania donovani. As part of this effort, we have studied the possible action mechanism of these compounds at the ultrastructural and biochemical levels and in relation to the synthesis of macromolecules. The two acridinones inhibit the in vitro growth of the promastigote forms of L. donovani at the highest concentration assayed (100 micrograms/ml). The in vivo results indicate that both compounds reduce the number of amastigotes per gram of spleen, and decrease parasitism, by more than 40%. With respect to the action mechanism, both compounds inhibit the incorporation of [3H]thymidine, inducing alterations at the ultrastructural level in the DNA and mitochondria. Alterations are also caused in the enzymes of the Krebs cycle.

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.

The three organometallic complexes [(Cis-PtII (DDH) (2,5-Dihidroxibenzensulfonic)2, RhI (CO)2 Cl(2-Aminobenzothiazole) and RhI (CO)2 Cl(5-Cl-2-Methilbenzothiazole)] used in this study had been previously found to have a high in vitro activity against promastigote and amastigote like forms of Leishmania donovani. Here, the cytotoxic effect of these new organometallic complexes on the J-774 macrophages were studied. Only the RhI(CO)2 Cl (2-Aminobenzothiazole) complex induced substantial toxicity in the cells. Also, we assayed the effect of this complex on the parasite's biosynthesis of macromolecules. The RhI(CO)2Cl (5-Cl-2-Methylbenzothiazole) complex inhibited DNA, RNA, and protein synthesis. On the other hand, the two other compounds tested did not inhibit the incorporation of radioactive precursors. Finally important ultrastructural alterations in the parasites treated with the two non-cytotoxic complexes were observed

The activities of 17 new rhodium drug complexes were determined against Leishmania donovani promastigotes. The five most active salts were selected: [Rh^III(2-amino-6-ethoxybenzothiazole)₄Br₂]⁺Br^–; [Rh^III(2-bromothiazole)₄(Br)₂]⁺Br^–; [Rh^III(mefloquine)⁴(Cl)₂]⁺Cl^–; [Rh^III(2-mepacrine)₄(Cl)₂]⁺Cl^–, and [Rh^III(oxamniquine)₄(Cl)₂]⁺Cl^–, 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 salts [Rh^III (mefloquine)₄(Cl)₂]⁺Cl^–, [Rh^III(2-mepacrine)₄(Cl)₂]⁺Cl^– and [Rh^III(oxaminquine)₄(Cl)₂]⁺Cl^– with a percentage of specific ¹⁵Cr release of 49.3, 64.8 and 53.2% at 24 h of incubation and 100 µg/ml. Meanwhile, assays of the other compounds showed practically no cytotoxicity. The ultrastructural studies in the flagellates treated with the salt [Rh^III(2-amino-6-ethoxybenzothiazole)₄Br₂]⁺Br^– showed some alterations in the nucleus of the parasites with a very condensed chromatin and an electrodense endosome. This compound showed a high in vivo activity in parasitized Wistar rats.

The lack of definitive chemotherapeutic agents to fight against visceral leishmaniasis has lead to the testing of numerous compounds. In the present work, we carry out an in-depth study of the activity against Leishmania donovani of three acridine derivatives both in vitro and in vivo. These compounds have proven to be highly effective at medium and high concentrations of 10 µg/ml, against both flagellate and nonflagellate forms of the parasite, which, though obtained in vitro, closely resemble natural intracellular amastigotes. The in vivo assays showed a significant reduction in the percentage of parasitation versus control, for all the compounds tested. In addition, we have studied the possible mechanism by which these acridine derivatives act: they displayed a greater inhibitory effect against macromolecule synthesis in treated flagellates, yet alterations are also caused in the production of end metabolites and in the activity of different enzymes. The data obtained indicate that the acridine derivatives had several targets, one of them is the synthesis of nucleic acids and proteins, while the second one might be interaction with the carbohydrate and energy-production processes in the parasite. This conclusion is consistent with our observations concerning the ultrastructural changes induced in the parasite by these compounds principally at the mitochondrial level.