Synthesis and Antiplasmodial Activity of Betulinic Acid and Ursolic Acid Analogues

摘要

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).