Structure-activity relationship of hybrids of Cinchona alkaloids and bile acids with in vitro antiplasmodial and antitrypanosomal activities
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...
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todo:paper_02235234_v100_n1_p10_Leverrier2023-10-03T15:11:12Z Structure-activity relationship of hybrids of Cinchona alkaloids and bile acids with in vitro antiplasmodial and antitrypanosomal activities Leverrier, A. Bero, J. Cabrera, J. Frédérich, M. Quetin-Leclercq, J. Palermo, J.A. 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 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 (IC<inf>50</inf>: 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: IC<inf>50</inf>: 36.1 nM to 8.72 μM), and the most active hybrids had IC<inf>50</inf>s comparable to that of artemisinin (IC<inf>50</inf>: 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 IC<inf>50</inf>s. © 2015 Published by Elsevier Masson SAS. Fil:Palermo, J.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_02235234_v100_n1_p10_Leverrier |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
| spellingShingle |
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 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 |
| topic_facet |
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 |
| description |
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 (IC<inf>50</inf>: 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: IC<inf>50</inf>: 36.1 nM to 8.72 μM), and the most active hybrids had IC<inf>50</inf>s comparable to that of artemisinin (IC<inf>50</inf>: 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 IC<inf>50</inf>s. © 2015 Published by Elsevier Masson SAS. |
| format |
JOUR |
| author |
Leverrier, A. Bero, J. Cabrera, J. Frédérich, M. Quetin-Leclercq, J. Palermo, J.A. |
| author_facet |
Leverrier, A. Bero, J. Cabrera, J. Frédérich, M. Quetin-Leclercq, J. Palermo, J.A. |
| author_sort |
Leverrier, A. |
| title |
Structure-activity relationship of hybrids of Cinchona alkaloids and bile acids with in vitro antiplasmodial and antitrypanosomal activities |
| title_short |
Structure-activity relationship of hybrids of Cinchona alkaloids and bile acids with in vitro antiplasmodial and antitrypanosomal activities |
| title_full |
Structure-activity relationship of hybrids of Cinchona alkaloids and bile acids with in vitro antiplasmodial and antitrypanosomal activities |
| title_fullStr |
Structure-activity relationship of hybrids of Cinchona alkaloids and bile acids with in vitro antiplasmodial and antitrypanosomal activities |
| title_full_unstemmed |
Structure-activity relationship of hybrids of Cinchona alkaloids and bile acids with in vitro antiplasmodial and antitrypanosomal activities |
| title_sort |
structure-activity relationship of hybrids of cinchona alkaloids and bile acids with in vitro antiplasmodial and antitrypanosomal activities |
| url |
http://hdl.handle.net/20.500.12110/paper_02235234_v100_n1_p10_Leverrier |
| work_keys_str_mv |
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| _version_ |
1807316914142183424 |