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Action of new organometallic complexes against Leishmania donovani
C M Mesa-Valle1, V Moraleda, J Lazuen
1Department of Applied Biology, University of Almeria, Spain.
Abstract:
The action of 16 newly synthesized metal complexes having the general structure cis-Pt-(II)-Xn-Ln have been tested in vitro against the promastigote forms of Leishmania donovani. The metal complexes at 24 h and maximum dosages inhibited growth from 0%, e.g. in cis-Pt-nifurtimox, to 100%, e.g. in cis-Pt-(2,3,4,5,6-pentafluoroaniline)2Br2 or cis-Pt-pentamidine-I2. A study of the cytotoxicty of these latter complexes on the phagocytic cell line J-774 showed neither high cytotoxicity nor cytolysis. At the maximum dosage after 24 h of permanent contact with the cells (extreme, non-physiological conditions), cytolysis did not exceed 30%. For most of the compounds, cytolysis ranged from 0%, for cis-Pt-oxamniquine-Cl2 to 27.7%, for cis-Pt-pentamidine-I2. The compound cis-Pt-(2,3,4,5,6-pentafluoroaniline)2-Br2 caused up to 1.4% cytolysis under the above conditions. Parasites exposed to cis-Pt-pentamidine-I2 showed notably reduced DNA, RNA and protein synthesis, unlike those exposed to other compounds. Parasites examined by electron microscopy showed effects mainly on the nucleus, though in some cases the mitochondria were affected, altering the internal membranes of the cytoplasmic organelles. The in-vivo activity of the complex cis-Pt-guanethidine-Cl2 was evaluated in parasitized Wistar rats, in which the number of amastigotes per gram of spleen was reduced by 75% compared with controls.
Insights
Sixteen novel platinum metal complexes were evaluated against Leishmania donovani parasites. One complex, cis-Pt-guanethidine-Cl2, demonstrated significant in-vivo activity, reducing parasite load by 75% in rats.
Area of Science:
- Medicinal Chemistry
- Parasitology
- Inorganic Chemistry
Background:
- Leishmaniasis remains a significant global health concern, necessitating the development of novel therapeutic agents.
- Platinum (Pt) complexes are recognized for their diverse biological activities, including anticancer and antimicrobial properties.
- Exploring new metal-based compounds offers a promising avenue for combating drug-resistant parasitic infections.
Purpose of the Study:
- To synthesize and characterize novel platinum (Pt) (II) metal complexes.
- To evaluate the in vitro efficacy of these complexes against the promastigote forms of Leishmania donovani.
- To assess the cytotoxicity of promising compounds on mammalian cell lines and investigate their in vivo activity.
Main Methods:
- Synthesis of 16 cis-Pt(II) metal complexes with varying ligands (XnLn).
- In vitro testing against Leishmania donovani promastigotes, measuring growth inhibition.
- Cytotoxicity assays on J-774 cell lines and in vivo studies in Wistar rats infected with Leishmania donovani.
Main Results:
- Several Pt(II) complexes exhibited significant in vitro growth inhibition of Leishmania donovani, with some achieving 100% inhibition.
- Cytotoxicity studies revealed low to moderate cytolysis for most complexes, with cis-Pt-(2,3,4,5,6-pentafluoroaniline)2Br2 showing minimal effect.
- The complex cis-Pt-pentamidine-I2 notably reduced parasite DNA, RNA, and protein synthesis, affecting parasite nuclei and mitochondria.
- In vivo evaluation of cis-Pt-guanethidine-Cl2 in rats resulted in a 75% reduction in splenic amastigote burden.
Conclusions:
- Novel platinum (Pt) (II) complexes show potent in vitro antileishmanial activity with acceptable cytotoxicity profiles.
- Specific complexes, such as cis-Pt-pentamidine-I2, interfere with essential parasite biomolecular processes.
- cis-Pt-guanethidine-Cl2 demonstrates promising in vivo efficacy, warranting further investigation as a potential anti-leishmanial drug candidate.