Therapeutic Potential of New Pt(II) and Ru(III) Triazole-Pyrimidine Complexes against <i>Leishmania donovani</i>

Abstract

We have already established an in vitro culture system using murine macrophages infected with Leishmania donovani in which the time course of parasite growth is determined quantitatively. We adopted this system for the screening of three triazole-pyrimidine derivatives that would ideally prove to be effective against L. donovani with no toxicity to the host cell. Amphotericin B deoxycholate was used as the standard drug and gave a IC₅₀ value of 3.89 µg/ml. The three triazole-pyrimidine compounds assayed have been reported to be potent growth inhibitors of L. donovani promastigote and amastigote stages. Compounds SPIV and SPVI exhibited the highest toxicity for extracellular forms of parasites, with IC₅₀ values of 19.95 and 21.61 µg/ml, respectively. The triazole-pyrimidine SPV, although to a lower degree, also showed pronounced effects against promastigote forms with IC₅₀ of 33.14 µg/ml. Drug activity was higher against amastigote than against promastigote stages. The compounds SPIV and SPVI interfered with the synthesis of macromolecules, affecting primarily DNA at the lower concentration tested (5 µg/ml), while SPV also showed interference, though to a lesser extent, and at a higher concentration (15 µg/ml) the percentage of inhibition rose considerably. The synthesis or RNA and proteins was also depressed significantly by these compounds at administration rates of 15 µg/ml. Ultrastructural alterations were evident in the main organelles of L. donovani (nucleus, kinetoplast, mitochondria), after the addition of the three compounds at a concentration of 5 µg/ml, to the in vitro culture. The in vitro promastigote forms of L. donovani can degrade glucose to carbon dioxide, and part of the carbon skeleton of the glucose is excreted as end metabolites. The excretion of these metabolites, mainly acetate, was also inhibited by the three compounds assayed, suggesting that this could be due to a direct effect on some of the enzymes related to this fermentation pathway or to the inhibition exerted by the compounds on enzyme synthesis.

Synthesis, characterization and in vitro cytotoxicity of three types of platinum(II) complexes containing 5,7-diethyl-1,2,4-triazolo[1,5-a]pyrimidine

“…Compared with purines, the fused-ring system of these ligands differs only in the presence of a pyrimidine nitrogen atom in a bridgehead position and the disappearance of the acidic H-proton of the five-membered ring [6,7]. Furthermore, these bicyclic heterocycles have been subjected to chemical and biological tests due to their pharmacological properties, including anticancer [8,9], antibacterial [10], antiviral [11], anti-inflammatory [12,13], fungicidal [14], antiparasitic [15][16][17][18][19] and leishmanicidal properties [20][21][22][23][24].…”

A Novel One-Pot Method for Highly Regioselective Synthesis of Triazoloapyrimidinedicarboxylates Using Silica Sodium Carbonate

“…Then, the model reaction was screened in various solvents at room temperature. The best results were obtained in chloroform (Table 1, entries [8][9][10][11][12][13][14][15][16][17][18]. Different basic catalysts were examined subsequently.…”

“…5 Furthermore, these heterocycles have a structure similar to that of purine and adenine, 6 and, in addition, they are structural components of herbicides such as flumetsulam, azafenidin, cloransulam, and penoxsulam. 7,8 Finally, they have been used as starting materials for the synthesis of other fused heterocyclic systems. [9][10][11] One-pot multicomponent reactions (MCR) that bring together three or more components with high atom economy play an important role in combinatorial chemistry and have become an important focus for research in recent years.…”

Synthesis and anti-tumor activities of new [1,2,4]triazolo[1,5-a]pyrimidine derivatives

“…Triazolopyrimidines represent a pharmaceutically important class of compounds because of their diverse range of biological activities, such as antitumor [1], cytotoxicity [2], therapeutic potentiality [3], potent and selective ATP site directed inhibition of the EGF-receptor protein tyrosine kinase [4] and cardiovascular [5] activities. In addition, they have been found in DNA-interactive drugs [6] and as useful building blocks in the synthesis of herbicidal drugs, e.g.…”