title: Synthesis and antiplasmodial activity of betulinic acid and ursolic acid analogues.
abstract: 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).
authors.affiliation: 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.
authors.forename: Adrine M
authors.initials: AM
authors.lastname: Innocente
authors.forename: Gloria N S
authors.initials: GN
authors.lastname: Silva
authors.forename: Laura Nogueira
authors.initials: LN
authors.lastname: Cruz
authors.forename: Miriam S
authors.initials: MS
authors.lastname: Moraes
authors.forename: Myna
authors.initials: M
authors.lastname: Nakabashi
authors.forename: Pascal
authors.initials: P
authors.lastname: Sonnet
authors.forename: Grace
authors.initials: G
authors.lastname: Gosmann
authors.forename: Célia R S
authors.initials: CR
authors.lastname: Garcia
authors.forename: Simone C B
authors.initials: SC
authors.lastname: Gnoatto
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D021261:Parasitic Sensitivity Tests; D053978:Pentacyclic Triterpenes; D010963:Plasmodium falciparum / Q000187:drug effects*; D014315:Triterpenes / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D000094062:Betulinic Acid; D000097245:Ursolic Acid
chemical_list: D000962:Antimalarials; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D000094062:Betulinic Acid; D000097245:Ursolic Acid