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Abstract:

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. © 2015 Published by Elsevier Masson SAS.

Registro:

Documento: Artículo
Título:Structure-activity relationship of hybrids of Cinchona alkaloids and bile acids with in vitro antiplasmodial and antitrypanosomal activities
Autor:Leverrier, A.; Bero, J.; Cabrera, J.; Frédérich, M.; Quetin-Leclercq, J.; Palermo, J.A.
Filiación:UMYMFOR, Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pab. 2, Buenos Aires, 1428, Argentina
Pharmacognosy Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Avenue E. Mounier B1.72.03, Brussels, B-1200, Belgium
Laboratory of Pharmacognosy, Drug Research Center (CIRM), University of Liège, Avenue de l'Hôpital 1, B36, Liège, B-4000, Belgium
Palabras clave:Antiparasitic activity; Barton-Zard reaction; Bile acids; Cinchona alkaloids; Hybrids; artemisinin; bile acid; camptothecin; chloroquine; Cinchona alkaloid; suramin; antimalarial agent; antitrypanosomal agent; bile acid; Cinchona alkaloid; antimalarial activity; antiplasmodial activity; antiprotozoal activity; antitrypanosomal activity; Article; controlled study; drug bioavailability; drug cytotoxicity; drug synthesis; fibroblast; heteronuclear multiple bond correlation; human; human cell; hybrid; IC50; in vitro study; lipophilicity; nonhuman; nuclear magnetic resonance spectroscopy; Plasmodium falciparum; structure activity relation; Trypanosoma brucei; chemistry; conformation; dose response; drug effects; drug sensitivity; structure activity relation; synthesis; Trypanosoma brucei brucei; Antimalarials; Bile Acids and Salts; Cinchona Alkaloids; Dose-Response Relationship, Drug; Molecular Conformation; Parasitic Sensitivity Tests; Plasmodium falciparum; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma brucei brucei
Año:2015
Volumen:100
Número:1
Página de inicio:10
Página de fin:17
DOI: http://dx.doi.org/10.1016/j.ejmech.2015.05.044
Título revista:European Journal of Medicinal Chemistry
Título revista abreviado:Eur. J. Med. Chem.
ISSN:02235234
CODEN:EJMCA
CAS:artemisinin, 63968-64-9; camptothecin, 7689-03-4; chloroquine, 132-73-0, 3545-67-3, 50-63-5, 54-05-7; suramin, 129-46-4, 145-63-1; Antimalarials; Bile Acids and Salts; Cinchona Alkaloids; Trypanocidal Agents
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_02235234_v100_n1_p10_Leverrier

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Citas:

---------- APA ----------
Leverrier, A., Bero, J., Cabrera, J., Frédérich, M., Quetin-Leclercq, J. & Palermo, J.A. (2015) . Structure-activity relationship of hybrids of Cinchona alkaloids and bile acids with in vitro antiplasmodial and antitrypanosomal activities. European Journal of Medicinal Chemistry, 100(1), 10-17.
http://dx.doi.org/10.1016/j.ejmech.2015.05.044
---------- CHICAGO ----------
Leverrier, A., Bero, J., Cabrera, J., Frédérich, M., Quetin-Leclercq, J., Palermo, J.A. "Structure-activity relationship of hybrids of Cinchona alkaloids and bile acids with in vitro antiplasmodial and antitrypanosomal activities" . European Journal of Medicinal Chemistry 100, no. 1 (2015) : 10-17.
http://dx.doi.org/10.1016/j.ejmech.2015.05.044
---------- MLA ----------
Leverrier, A., Bero, J., Cabrera, J., Frédérich, M., Quetin-Leclercq, J., Palermo, J.A. "Structure-activity relationship of hybrids of Cinchona alkaloids and bile acids with in vitro antiplasmodial and antitrypanosomal activities" . European Journal of Medicinal Chemistry, vol. 100, no. 1, 2015, pp. 10-17.
http://dx.doi.org/10.1016/j.ejmech.2015.05.044
---------- VANCOUVER ----------
Leverrier, A., Bero, J., Cabrera, J., Frédérich, M., Quetin-Leclercq, J., Palermo, J.A. Structure-activity relationship of hybrids of Cinchona alkaloids and bile acids with in vitro antiplasmodial and antitrypanosomal activities. Eur. J. Med. Chem. 2015;100(1):10-17.
http://dx.doi.org/10.1016/j.ejmech.2015.05.044