Busca de novos fármacos para o tratamento da malária humana através de diferentes abordagens

Abstract

The human malaria remains one of the major parasitic diseases in the world, affecting millions of people each year and causing severe morbidity and mortality, especially in children in Africa. The disease causes poverty in countries with high prevalence, including Brazil, in the Amazon Region. Due to the spread of Plasmodium falciparum resistance to available antimalarial drugs and of P. vivax to chloroquine, including in Brazil, new therapies are needed, as drug treatment remains the main strategy to control the disease. The search for new drugs has the erythrocytic stages of Plasmodium as the main target, but the interest in reducing malaria transmission and eradicating the disease includes eliminating sexual forms, which requires the development of drugs against gametocytes. In this study the main proposal was to search for new compounds with dual activity of blood schizonticidal activity evaluated in vitro and in vivo, as well as transmission blocking activity, in vitro. The compound selection for screening was performed by different approaches: (i) docking studies having the enzymes as specific targets lactate dehydrogenase (atorvastatin, itraconazole, posaconazole) and topoisomerase I (pterocarpanquinones and derivatives) of P. falciparum; (ii) the popular knowledge about the use of infusions of the medicinal plant Aspidosperma nitidum against malaria in the Brazilian Amazon, and, (iii) the development of hybrid compounds, derived from artesunate with mefloquine (MEFAS) or primaquine (PRIMAS). The results showed that: (i) the commercially available drugs atorvastatin, itraconazole, posaconazole, and the extracts and fractions of A. nitidum stem bark were active in vitro against P. falciparum; (ii) atorvastatin, posaconazole and the compounds isolated from A. nitidum, also inhibited the parasitemia of mice experimentally infected with P. berghei, and, (iii) MEFAS and PRIMAS showed a dual activity against P. falciparum asexual forms and gametocytes. It can be concluded that scientific knowledge generated in this study may contribute to the development of new drugs with dual and selective antimalarial activity.