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Molecules 2012, 17(10), 12003-12014;

Synthesis and Antiplasmodial Activity of Betulinic Acid and Ursolic Acid Analogues

Laboratório de Fitoquímica e Síntese Orgânica, Faculdade de Farmácia, Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul. Av. Ipiranga, 2752, Porto Alegre 90610-000, RS, Brazil
Laboratório de Biologia Celular e Molecular de Plasmodium, Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, USP. Rua do Matão, travessa 14, 321, São Paulo 05508-900, SP, Brazil
Laboratoire des Glucides, FRE CNRS 3517, UFR de Pharmacie Université de Picardie Jules Verne1, Rue des Louvels, 80037 Amiens cedex 1, France
Author to whom correspondence should be addressed.
Received: 17 September 2012 / Revised: 24 September 2012 / Accepted: 7 October 2012 / Published: 12 October 2012
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More than 40% of the World population is at risk of contracting malaria, which affects primarily poor populations in tropical and subtropical areas. Antimalarial pharmacotherapy has utilised plant-derived products such as quinine and artemisinin as well as their derivatives. However, worldwide use of these antimalarials has caused the spread of resistant parasites, resulting in increased malaria morbidity and mortality. Considering that the literature has demonstrated the antimalarial potential of triterpenes, specially betulinic acid (1) and ursolic acid (2), this study investigated the antimalarial activity against P. falciparum chloroquine-sensitive 3D7 strain of some new derivatives of 1 and 2 with modifications at C-3 and C-28. The antiplasmodial study employed flow cytometry and spectrofluorimetric analyses using YOYO-1, dihydroethidium and Fluo4/AM for staining. Among the six analogues obtained, compounds 1c and 2c showed excellent activity (IC50 = 220 and 175 nM, respectively) while 1a and b demonstrated good activity (IC50 = 4 and 5 μM, respectively). After cytotoxicity evaluation against HEK293T cells, 1a was not toxic, while 1c and 2c showed IC50 of 4 μM and a selectivity index (SI) value of 18 and 23, respectively. Moreover, compound 2c, which presents the best antiplasmodial activity, is involved in the calcium-regulated pathway(s). View Full-Text
Keywords: triterpenes; betulinic acid; ursolic acid; malaria; P. falciparum; cytotoxicity; calcium triterpenes; betulinic acid; ursolic acid; malaria; P. falciparum; cytotoxicity; calcium

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Innocente, A.M.; Silva, G.N.S.; Cruz, L.N.; Moraes, M.S.; Nakabashi, M.; Sonnet, P.; Gosmann, G.; Garcia, C.R.S.; Gnoatto, S.C.B. Synthesis and Antiplasmodial Activity of Betulinic Acid and Ursolic Acid Analogues. Molecules 2012, 17, 12003-12014.

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