Síntese de derivados indólicos e avaliação frente ao Plasmodium falciparum

Abstract

Malaria is an infectious disease that leads to an acute, life-threatening condition. It is caused by protozoa of the genus Plasmodium and transmitted by the bite of female mosquitoes of the genus Anopheles. N-heterocycles are common in pharmaceutical industry, such as the indole nucleus, present in several drugs and occupying a notable position with respect to the generation of new antimalarial agents. Indole derivatives functionalized at the C-2 position are among the most active compounds against P. falciparum. C-H activation protocols at C-2 of indole with electron withdrawing groups have been widely studied and, through them, direct functionalization of the ring is achieved without the use of drastic reaction conditions. Nitrocompounds are a window of opportunity in organic synthesis and enable rapid access, for example, to amines via reduction, which can be trapped in situ to lead to functionalized products in a one pot fashion, a strategy commonly applied in the synthesis of Ugi adducts. This work aimed to synthesize 2-nitroalkylindoles through the development of a protocol for alkylation of indole at C-2 with nitrostyrenes via C-H activation and subsequent synthetic modification - Ugi reduction and condensation - of the nitro derivatives for the synthesis of peptidomimetics, towards the search for active compounds against the 3D7 strain of P. falciparum. Regarding the C-H activation reaction, a method was developed for the synthesis of (2-(2-nitro-1-phenylethyl)-1H-indol-1-l)(pyrrolidin-1-yl)methanones, catalysed by Rh( III), obtaining a total of 18 compounds, with yields between 39 and 80%. Next, the reduction of nitroalkylindoles to the corresponding amines was studied. Once the optimal condition for reduction was found, studies of the Ugi reaction began, which culminated in the synthesis of 14 compounds, with overall yields between 22 and 71%. Finally, the antiplasmodial activity of the synthesized compounds was performed against P. falciparum, and promising results were obtained with the peptidomimetics, motivating the synthesis of new adducts to contribute with the structure-activity relationship studies. Based on the skeleton of the most active compound, twenty-one compounds were prepared in 37 - 94% yield.