Hybrids of Cinchona Alkaloids and Bile Acids as Antiparasitic Agents Against Trypanosoma cruzi

Abstract

The current chemotherapy of Chagas disease needs to be urgently improved. With this aim, a series of 16 hybrids of Cinchona alkaloids and bile acids were prepared by functionalization at position C-2 of the quinoline nucleus by a radical attack of a norcholane substituent via a Barton–Zard decarboxylation reaction. The antitrypanosomal activity of the hybrids was tested on different stages and strains of T. cruzi. In particular, eight out of 16 hybrids presented an IC50 ≤1 μg/mL against trypomastigotes of the CL Brener strain and/or a selectivity index higher than 10. These promising hybrids yielded similar results when tested on trypomastigotes from the RA strain of T. cruzi (discrete typing unit—DTU—VI). Surprisingly, trypomastigotes of the Y strain (DTU II) were more resistant to benznidazole and to most of the hybrids than those of the CL Brener and RA strains. However, the peracetylated and non-acetylated forms of the cinchonine/chenodeoxycholic bile acid conjugate 4f and 5f were the most trypanocidal hybrids against Y strain trypomastigotes, with IC50 values of 0.5 and 0.65 μg/mL, respectively. More importantly, promising results were observed in invasion assays using the Y strain, where hybrids 5f and 4f induced a significant reduction in intracellular amastigotes and on the release of trypomastigotes from infected cells.

Lipase-Catalyzed Synthesis and Biological Evaluation of N-Picolineamides as Trypanosoma cruzi Antiproliferative Agents

“…Vero cells were infected with fluorescent parasites of the Y strain (Y-GFP). 57 After parasite removal, compounds were added to media in a concentration 10 times lower than their CC 50 . At 72 h postinfection, cells were lysed, and the fluorescence signal from parasites was measured (Figure 3a).…”

“…A screening of compounds was made in a T. cruzi infection model. Vero cells were infected with fluorescent parasites of the Y strain (Y-GFP) . After parasite removal, compounds were added to media in a concentration 10 times lower than their CC 50 .…”

Neglected Zoonotic Diseases: Advances in the Development of Cell-Penetrating and Antimicrobial Peptides against Leishmaniosis and Chagas Disease

“…A 10 µg/mL concentration is usually incubated at pH 7.2 in the presence of the candidate compound to be evaluated, and it is collected during the exponential growth phase. For T. cruzi , the most frequently used strains are the Tulahuen strain Discrete Typing Unit (DTU) VI clones C2 and C4, which express the beta-galactosidase gene [ 157 , 159 , 161 , 162 , 163 , 164 , 165 ] or the luciferase gene Luc2-Tulahuen [ 166 ]; Y strain DTU II (wild-type [ 167 , 168 ] or expressing the firefly luciferase gene [ 161 ]); Sylvio X10 strain DTU I [ 158 ]; Dm28c strain DTU I [ 165 ]; RA strain DTU VI [ 169 , 170 , 171 ]; and VD strain DTU VI [ 172 ].…”

Neglected Zoonotic Diseases: Advances in the Development of Cell-Penetrating and Antimicrobial Peptides against Leishmaniosis and Chagas

“…A 10 µg/mL concentration is usually incubated, at pH 7.2, in the presence of the candidate compound to be evaluated, and collected during the exponential growth phase. For T. cruzi, the most frequently used strains are Tulahuen strain Discrete Typing Unit (DTU) VI clone C2 and C4, expressing beta-galactosidase gene [155,157,[159][160][161][162][163] or luciferase gene Luc2-Tulahuen [164], Y strain DTU II wild type [165,166] or expressing the firefly luciferase gene [159], Sylvio X10 strain DTU I [156], Dm28c strain DTU I [163], RA strain DTU VI [167][168][169] and VD strain DTU VI [170].…”