Síntese e avaliação biológica de análogos de alcaloides 3- alquilpiridínicos e de análogos do ciclotetrapeptídeo FR235222

Abstract

This thesis is divided into two chapters. The chapter I refers to the synthesis and biological evaluation of oxygenated analogues of marine 3-alkylpyridine alkaloids. The chapter II deals with the synthesis and biological evaluation of analogues of the cyclic tetrapeptide FR235222. The marine alkaloids are a class of substances that have shown a variety of biological activities that make them potential drugs. In the present study, were obtained oxygenated analogues of 3-alkylpyridine alkaloids, which were tested for antimalarial, antileishmanial, antimicrobial and antitumor activities. In all the biological tests performed, some of the tested compounds showed to be active but also proved to be cytotoxic for human cells lines. The compounds obtained represent a promising matrix for the design of new non-cytotoxic analogues to human cells. The cyclic tetrapeptide FR235222, a natural product, and some of its synthetic derivatives have shown inhibitory activity of histone deacetylases. These inhibitors, by epigenetic mechanisms, presented potent and selective activity against Toxoplasma gondii and Plasmodium falciparum, both parasites of the phylum Apicomplexa, which cause toxoplasmosis and malaria, respectively. In this work, we synthesized a bifunctionalized cyclic tetrapeptide which can allow quick access to a large number of new analogues of FR235222. Additionally, we synthesized new analogues of FR235222 which were evaluated for anti-Toxoplasma gondii and antimalarial activity in vitro. One of the analogues obtained was active against Toxoplasma gondii at nanomolar concentrations, and cytotoxic to human cells. This same analogue can be used as a biological probe due to its high fluorescence and high penetration in the cystic form (bradyzoites) of the parasite Toxoplasma gondii.