RESUMO
In the present study, a series of new esters of secochiliolide acid (SA), a diterpene isolated from Nardophyllum bryoides, were synthesized in good yield. All compounds were evaluated for their in vitro antiparasitic properties (on Plasmodium falciparum and Trypanosoma brucei brucei) and cytotoxicity (on WI38, normal mammalian cells). They displayed moderate antitrypanosomal activity with IC50 values between 2.55 and 18.14 µm, with selectivity indices >10, and low antiplasmodial effects with IC50 > 29 µm. The only exception was the n-hexyl ester of SA, which showed a strong and selective antiplasmodial activity (IC50 = 1.99 µm and selectivity index = 117.0). The in vivo antimalarial efficacy of this compound was then assessed according to the 4-day suppressive test of Peters in mice. An intraperitoneal treatment at 50 mg kg-1 day-1 induced a slight parasitaemia reduction by 56% which was statistically significant on day 4 post-infection and an increase in the survival time.
Assuntos
Antimaláricos/química , Antiprotozoários/química , Diterpenos/química , Ésteres/química , Propionatos/química , Antimaláricos/isolamento & purificação , Antimaláricos/farmacologia , Antiprotozoários/isolamento & purificação , Antiprotozoários/farmacologia , Asteraceae/química , Asteraceae/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Humanos , Extratos Vegetais/química , Plasmodium falciparum/efeitos dos fármacos , Propionatos/isolamento & purificação , Propionatos/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacosRESUMO
In this work, a series of hybrid compounds were tested as antiparasitic substances. These hybrids were prepared from bile acids and a series of antiparasitic Cinchona alkaloids by the formation of a covalent C-C bond via a decarboxylative Barton-Zard reaction between the two entities. The bile acids showed only weak antiparasitic properties, but all the hybrids exhibited high in vitro activities (IC50: 0.48-5.39 µM) against Trypanosoma brucei. These hybrids were more active than their respective parent alkaloids (up to a 135 fold increase in activity), and displayed good selectivity indices. Aditionally, all these compounds inhibited the in vitro growth of a chloroquine-sensitive strain of Plasmodium falciparum (3D7: IC50: 36.1 nM to 8.72 µM), and the most active hybrids had IC50s comparable to that of artemisinin (IC50: 36 nM). Some structure-activity relationships among the group of 48 hybrids are discussed. The increase in antiparasitic activity may be explained by an improvement in bioavailability, since the more lipophilic derivatives showed the lowest IC50s.
Assuntos
Antimaláricos/farmacologia , Ácidos e Sais Biliares/farmacologia , Alcaloides de Cinchona/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Antimaláricos/síntese química , Antimaláricos/química , Ácidos e Sais Biliares/química , Alcaloides de Cinchona/química , Relação Dose-Resposta a Droga , Conformação Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/químicaRESUMO
A series of 16 hybrids of Cinchona alkaloids and bile acids (4a-h, 5a-h) was prepared by means of a Barton-Zard decarboxylation reaction. Quinine, quinidine, cinchonine and cinchonidine were functionalized at position C-2 of the quinoline nucleus by radical attack of a norcholane substituent. The newly synthesized hybrids were evaluated in vitro for their antitrypanosomal, antileishmanial and antiplasmodial activities, along with their cytotoxicity against WI38, a normal human fibroblast cell line. Seven compounds (4d, 4f, 4h, 5b, 5d, 5f, 5h) showed promising trypanocidal activity with IC50 values in the same range as the commercial drug suramine. Moreover all the 16 hybrids showed antiplasmodial activity (IC50 ≤ 6 µg/ml), particularly those containing a nor-chenodeoxycholane moiety (4b, 4d, 4f, 4h, 5b, 5d, 5f, 5h) with IC50 values comparable to those of the natural alkaloids, and selectivity indices in the range of 5.6-15.7.