Structure-activity relationship of hybrids of Cinchona alkaloids and bile acids with in vitro antiplasmodial and antitrypanosomal activities.

作者: Aurélie Leverrier , Joanne Bero , Julián Cabrera , Michel Frédérich , Joëlle Quetin-Leclercq

DOI: 10.1016/J.EJMECH.2015.05.044

关键词:

摘要: In this work, a series of hybrid compounds were tested as antiparasitic substances. These hybrids prepared from bile acids and Cinchona alkaloids by the formation covalent C-C bond via decarboxylative Barton-Zard reaction between two entities. The showed only weak properties, but all exhibited high in vitro activities (IC50: 0.48-5.39 μM) against Trypanosoma brucei. more active than their respective parent (up to 135 fold increase in activity), displayed good selectivity indices. Aditionally, these inhibited growth chloroquine-sensitive strain Plasmodium falciparum (3D7: IC50: 36.1 nM 8.72 μM), most had IC50s comparable that artemisinin 36 nM). Some structure-activity relationships among group 48 are discussed. activity may be explained an improvement bioavailability, since lipophilic derivatives lowest IC50s.

参考文章(31)
Roberta C.N.R. Corrales, Nicolli B. de Souza, Liliane S. Pinheiro, Clarice Abramo, Elaine S. Coimbra, Adilson David Da Silva, Thiopurine derivatives containing triazole and steroid: Synthesis, antimalarial and antileishmanial activities Biomedicine & Pharmacotherapy. ,vol. 65, pp. 198- 203 ,(2011) , 10.1016/J.BIOPHA.2010.10.013
W Trager, J. Jensen, Human malaria parasites in continuous culture Science. ,vol. 193, pp. 673- 675 ,(1976) , 10.1126/SCIENCE.781840
Derek H.R. Barton, Joseph Cs. Jaszberenyi, Dagang Tang, Photolytic generation of carbon radicals from barton esters: Recent developments Tetrahedron Letters. ,vol. 34, pp. 3381- 3384 ,(1993) , 10.1016/S0040-4039(00)79161-1
Joanne Bero, Michel Frédérich, Joëlle Quetin-Leclercq, Antimalarial compounds isolated from plants used in traditional medicine. Journal of Pharmacy and Pharmacology. ,vol. 61, pp. 1401- 1433 ,(2009) , 10.1211/JPP/61.11.0001
Bernard Meunier, Hybrid molecules with a dual mode of action: dream or reality? Accounts of Chemical Research. ,vol. 41, pp. 69- 77 ,(2008) , 10.1021/AR7000843
Alfons Enhsen, Werner Kramer, Günther Wess, Bile acids in drug discovery Drug Discovery Today. ,vol. 3, pp. 409- 418 ,(1998) , 10.1016/S1359-6446(96)10046-5
R HO, R KIM, Transporters and drug therapy: implications for drug disposition and disease. Clinical Pharmacology & Therapeutics. ,vol. 78, pp. 260- 277 ,(2005) , 10.1016/J.CLPT.2005.05.011
Francis W. Muregi, Akira Ishih, Next-Generation Antimalarial Drugs: Hybrid Molecules as a New Strategy in Drug Design. Drug Development Research. ,vol. 71, pp. 20- 32 ,(2009) , 10.1002/DDR.20345
Marta P. Carrasco, Ana S. Newton, Lídia Gonçalves, Ana Góis, Marta Machado, Jiri Gut, Fátima Nogueira, Thomas Hänscheid, Rita C. Guedes, Daniel J.V.A. dos Santos, Philip J. Rosenthal, Rui Moreira, Probing the aurone scaffold against Plasmodium falciparum: design, synthesis and antimalarial activity. European Journal of Medicinal Chemistry. ,vol. 80, pp. 523- 534 ,(2014) , 10.1016/J.EJMECH.2014.04.076
Ricardo Augusto Massarico Serafim, José Eduardo Gonçalves, Felipe Pereira de Souza, Ana Paula de Melo Loureiro, Silvia Storpirtis, Renata Krogh, Adriano Defini Andricopulo, Luiz Carlos Dias, Elizabeth Igne Ferreira, Design, synthesis and biological evaluation of hybrid bioisoster derivatives of N-acylhydrazone and furoxan groups with potential and selective anti-Trypanosoma cruzi activity. European Journal of Medicinal Chemistry. ,vol. 82, pp. 418- 425 ,(2014) , 10.1016/J.EJMECH.2014.05.077