RESUMEN
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.
Asunto(s)
Antiparasitarios/farmacología , Ácidos y Sales Biliares/farmacología , Alcaloides de Cinchona/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Chlorocebus aethiops , Concentración 50 Inhibidora , Espacio Intracelular/parasitología , Ratas , Células VeroRESUMEN
In this work, a series of hybrid compounds were tested as antiparasitic substances. These hybrids were prepared from bile acids and a series of antiparasitic Cinchona alkaloids by the formation of a covalent C-C bond via a decarboxylative Barton-Zard reaction between the two entities. The bile acids showed only weak antiparasitic properties, but all the hybrids exhibited high in vitro activities (IC50: 0.48-5.39 µM) against Trypanosoma brucei. These hybrids were more active than their respective parent alkaloids (up to a 135 fold increase in activity), and displayed good selectivity indices. Aditionally, all these compounds inhibited the in vitro growth of a chloroquine-sensitive strain of Plasmodium falciparum (3D7: IC50: 36.1 nM to 8.72 µM), and the most active hybrids had IC50s comparable to that of artemisinin (IC50: 36 nM). Some structure-activity relationships among the group of 48 hybrids are discussed. The increase in antiparasitic activity may be explained by an improvement in bioavailability, since the more lipophilic derivatives showed the lowest IC50s.
Asunto(s)
Antimaláricos/farmacología , Ácidos y Sales Biliares/farmacología , Alcaloides de Cinchona/farmacología , Plasmodium falciparum/efectos de los fármacos , Tripanocidas/farmacología , Trypanosoma brucei brucei/efectos de los fármacos , Antimaláricos/síntesis química , Antimaláricos/química , Ácidos y Sales Biliares/química , Alcaloides de Cinchona/química , Relación Dosis-Respuesta a Droga , Conformación Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Tripanocidas/síntesis química , Tripanocidas/químicaRESUMEN
A series of 16 hybrids of Cinchona alkaloids and bile acids (4a-h, 5a-h) was prepared by means of a Barton-Zard decarboxylation reaction. Quinine, quinidine, cinchonine and cinchonidine were functionalized at position C-2 of the quinoline nucleus by radical attack of a norcholane substituent. The newly synthesized hybrids were evaluated in vitro for their antitrypanosomal, antileishmanial and antiplasmodial activities, along with their cytotoxicity against WI38, a normal human fibroblast cell line. Seven compounds (4d, 4f, 4h, 5b, 5d, 5f, 5h) showed promising trypanocidal activity with IC50 values in the same range as the commercial drug suramine. Moreover all the 16 hybrids showed antiplasmodial activity (IC50 ≤ 6 µg/ml), particularly those containing a nor-chenodeoxycholane moiety (4b, 4d, 4f, 4h, 5b, 5d, 5f, 5h) with IC50 values comparable to those of the natural alkaloids, and selectivity indices in the range of 5.6-15.7.
Asunto(s)
Antiparasitarios/química , Antiparasitarios/farmacología , Ácidos y Sales Biliares/química , Alcaloides de Cinchona/química , Alcaloides de Cinchona/farmacología , Antiparasitarios/toxicidad , Línea Celular , Alcaloides de Cinchona/toxicidad , Humanos , Concentración 50 InhibidoraRESUMEN
Three known Cinchona alkaloids of the quinine type, quinine (1), cupreine (2), cinchonine (3), and the possible artifact cinchonine-HCl (3-HCl), along with two new ones, acetylcupreine (4) and N-ethylquinine (5), have been isolated from the bark of Remijia peruviana (Rubiaceae). Their stereochemical structures were established by high resolution NMR spectroscopy. Alkaloids 2-4 had antifeedant effects on Leptinotarsa decemlineata with varying potencies. Compound 4 was cytotoxic to both insect Sf9 and mammalian CHO cells after 48 h of incubation, while 3-HCl had stronger and selective cytotoxicity to Sf9. Quinine 1 had a moderate to low effect on Trypanosoma cruzi. Tumoral cells were also affected by these alkaloids, with 4 and 3-HCl being the most cytotoxic to all the cell lines tested. Overall, the 8R, 9S configurations, as in 3 and 3-HCl, as well as the C-6'acetylated alkaloid 4, with an 8S, 9R configuration, showed stronger biological effects.