ABSTRACT
Parasitic diseases continue to be a major worldwide health problem, and there is an urgent need for development of therapeutic drugs. This paper describes synthesis of dehydrodiferulic acid dilactone 1 and dehydrodisinapic acid dilactone 2 furofuran lignans by oxidative coupling of ferulic and sinapic acids, respectively. Their schistosomicidal, trypanocidal, and leishmanicidal activities were evaluated in vitro against Schistosoma mansoni adult worms, trypomastigote and amastigotes forms of Trypanosoma cruzi, and promastigote forms of Leishmania amazonensis. Compound 1 did not display significant schistosomicidal activity, but it presented potent trypanocidal activity, since it induced death of trypomastigotes and amastigotes with IC50/24h of 9.3µM and 7.3µM, respectively. Compound 2 had slight trypanocidal and schistosomicidal activities. None of the compounds were active against L. amazonensis. These results demonstrated that furofuran lignans are potentially useful for anti-parasitic drugs development and should be further investigated.
Subject(s)
Furans/chemical synthesis , Furans/pharmacology , Lignans/chemical synthesis , Lignans/pharmacology , Schistosomicides/chemical synthesis , Schistosomicides/pharmacology , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/pharmacology , Animals , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Furans/chemistry , Humans , Inhibitory Concentration 50 , Lactones/chemical synthesis , Lactones/chemistry , Leishmania/drug effects , Leishmania mexicana/drug effects , Lignans/chemistry , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Parasitic Sensitivity Tests , Schistosoma mansoni/drug effects , Schistosomicides/chemistry , Trypanocidal Agents/chemistry , Trypanosoma cruzi/drug effectsABSTRACT
The present study evaluates the in vitro and in vivo trypanocidal activity of ursolic acid and oleanolic acid against the Bolivia strain of Trypanosoma cruzi. Their acute toxicity is also assessed on the basis of median lethal dose (DL50) determination and quantification of biochemical parameters. Ursolic acid is the most active compound in vitro, furnishing IC50 of 25.5 microM and displaying 77% of trypomastigote lysis at a concentration of 128 microM. In agreement with in vitro assays, the results obtained for the in vivo assay reveals that ursolic acid (at a dose of 20 mg/Kg/day) provides the most significant reduction in the number of parasites at the parasitemic peak. Results concerning the LD50 assay and the biochemical parameters evaluated in the present study demonstrate that these substances can be safely used on an experimental basis.
Subject(s)
Chagas Disease/drug therapy , Triterpenes/pharmacology , Triterpenes/therapeutic use , Trypanocidal Agents/pharmacology , Trypanocidal Agents/therapeutic use , Trypanosoma cruzi/drug effects , Animals , Cell Survival/drug effects , Chagas Disease/parasitology , Humans , Inhibitory Concentration 50 , Lethal Dose 50 , Male , Parasitemia , Rats , Rats, Wistar , Triterpenes/administration & dosage , Triterpenes/toxicity , Trypanocidal Agents/toxicity , Ursolic AcidABSTRACT
Triterpene acids, including ursolic acid (1), urjinolic acid (4) and oleanoic acid (5) along with a mixture of 2alpha-hydroxyursolic acid (2) and maslic acid (3) were isolated from methylene chloride extracts of the Miconia sellowiana and M. ligustroides species and their activities against the trypomastigote blood forms of Trypanosoma cruzi were evaluated. The potassium salt derivative of ursolic acid (1a) was also tested. The in vitro assays showed that compounds 1, 5 and 1a were the most active (IC(50) 17.1 microm, 12.8 microm and 8.9 microm, respectively). In contrast, a mixture of 2 plus 3, that exhibit a hydroxyl at C-2 and C-3, is much less potent than a mixture of 1 and 5 (IC(50) 48.5 microm and 11.8 microm, respectively). In the same manner, compound 4, that differs from 5 by two additional hydroxyl groups (at C-2 and C-23) displayed weak trypanocidal activity (IC(50) 76.3 microm) when compared with the other triterpenes. These results suggest that the free hydroxyl at C-3 and the polarity of C-28 are the most influential structural features for determining the in vitro trypanocidal activity of triterpenes. In vivo assays were also undertaken for the most active compounds 1, 1a and the mixture of 1 plus 5. The most significant reduction in parasite number in the parasitemic peak were obtained for compound 1 and its salt derivative 1a (75.7% and 70.4%, respectively). Moreover, the survival time was increased for all the treated animals.
