Lupeol, a triterpene frequently found in Asteraceae plant species, showed moderate to low activity in different strains of Plasmodium falciparum, the most virulent malaria etiological agents. In this work, lupeol was isolated from Parahancornia fasciculata, a plant that is used to treat malaria in the Amazonia region. In the search of more activity lupeol derivatives, five new 1,2,3-triazole hybrid molecules were synthetized by copper-catalyzed azide-alkyne cycloaddition. The antiplasmodial activity of the semi-synthetic compounds were evaluated by the lactate dehydrogenase assay; the lupeol propargyl ether was the only one to disclosing increased activity (half maximal inhibitory concentration-IC50-62.0 ± 1.92 µmol L-1) in relation to lupeol (IC50 117.00 µmol L-1). Therefore, this work revealed a new class of interesting lupeol derivatives that can be obtained by linking electron donors to the hydroxy group at C-3.

Derivatives of steviol, isosteviol and betulinic acid were prepared and tested in vitro against Plasmodium falciparum W2 (chloroquine-resistant) and Trypanosoma cruzi. The best results against P. falciparum were found for the betulinic acid derivatives 3-[(2,4-dinitrophenyl)hydrazono]lup-20(29)-en-28-oic acid and 3-hydroxy-20-[(2,4-dinitrophenyl)hydrazono]-29-norlupan-28-oic acid (values concentration in that the growth of the parasites is 50% inhibited, IC50 = 9.96, 6.45 and 21.06 µg mL-1, respectively). Isosteviol was inactive but its 4-nitro- and 2,4-dinitrophenylhydrazone showed moderate activity (IC50 = 17.50-22.58 µg mL-1). The derivatives of betulinic acid were more selective to the parasite when compared with hepatoblastoma HepG2 A16 cells. The results showed that nitrophenylhydrazone derivatives of lupane and beyerane terpenes are promising prototypes of antimalarial agents. Among the compounds tested against T. cruzi the oxime of isosteviol was active against both epimastigote and trypomastigote forms of the parasite.

We herein report the synthesis of hybrid kauranoid molecules of type 1,2,3-triazole-1,4-disubstituted aiming to improve the antimalarial activity of kaurenoic and xylopic acids. The CuI-catalyzed cycloaddition of azides and kauranoid terminal alkynes was explored as a hybridization strategy. Kauranoid terminal alkynes were prepared from kaurenoic and xylopic acids that were isolated from Wedelia paludosa D. C. (Asteraceae) and Xylopia frutescens Aubl. (Annonaceae). A total of 15 kauranoid derivatives, including nine new triazoles, were obtained and five out of these were more active than the original diterpenes. Interestingly, an increased activity was observed for a kauranoid propargyl ether. Interaction between ent-kaurane diterpene derivatives and Ca2+-ATPase (PfATP6) was investigated. Synthesis of diterpene derivatives emerges as a possible route to be explored in the quest of potentially new inhibitors of PfATP6.