Dados do Trabalho

Título

Antimalarial agent derived from gold-amodiaquine complex with activity in multiple stages of the Plasmodium life cycle

Introdução

Malaria is the one of the deadest infectious diseases worldwide. Chemically, quinolines are excellent ligands for metal coordination and are deployed as drugs for malaria treatment. There is a growing body of evidence indicating that metal complexes can be conjugated with antimalarial quinolines, as amodiaquine, to be used as chemical tools to overcome the disadvantages of quinolines, improving their bioactive speciation, cellular distribution, and subsequently broadening the spectrum of activity to multiple stages of the complex Plasmodium life cycle.

Objetivo (s)

To evaluate the in vitro antiparasitic potency of a new gold-amodiaquine complex (complex 4) against different stages of the plasmodium life cycle and the in vivo efficacy as an antiplasmodial agent.

Material e Métodos

The antiplasmodial activity of the gold complex (4) was first evaluated in vitro against three different strains of P. falciparum at the asexual blood stages, followed by an evaluation of in vitro activity against the sexual blood stages of P. falciparum (stage V gametocytes). Its efficacy as a blood schizonticidal agent was assessed in P. berghei-infected mice using a standard 4-day regime. The lowest dose capable of ensuring 50 % survival in mice was set at 30 μmol amodiaquine (AQ) treatment per kg of animal weight (20.5 mg/kg), given intraperitoneally, while 15 μmol/kg is known to suppress parasitemia, but does not provide a cure.

Resultados e Conclusão

We compared the potency of the antiplasmodial activity of AQ and the metal complex (4). We observed that complex (4) was approximately twice as potent as AQ. While the asexual blood stages are quite susceptible to heme detoxification suppressors like AQ and CQ, the sexual blood stages (gametocytes) are much less susceptible to this class of drugs. Neither AQ nor the metal complex (4) displayed gametocidal activity in low nanomolar concentrations, as observed for the asexual blood stages. At 15 μmol/kg the compound (4) was effective in reducing parasitemia and in increasing animal survival in comparison to the untreated infected group. When complex (4) was increased to 30 μmol/kg, it was able to cure 70 % of mice from a pool of two independent experiments, compared to the 50 % cured after AQ treatment. Based on this, the efficacy displayed by complex (4) was twice as high as that of AQ treatment.

Palavras-chave

Malaria, organometallics, gold, quinoline, amodiaquine.

Agradecimentos

CNPq, FAPERGS, FAPESP, Fondazione Cariplo, Fiocruz CAPES-Print, FAPESB.