Síntese de derivados carbazólicos e beta-carbolínicos e avaliação da atividade antimalárica in vitro

Abstract

The steady increase in the number of current drug resistance cases used without malaria treatment has encouraged studies on a discovery of potentially active new drugs. In previous work by LAPAAM / INPA has revealed the in vitro and in vivo antimalarial activity of indole alkaloids, such as elipticine, olivacin and derivatives. The great challenge has been found other indolic structures, which are easier to obtain and which present similar or superior antimalarial activity as found in these structures. In this search, nucleic acid tricyclic derivatives obtained from carbazolic and -carbolinic skeletons were synthesized and attributes against in vitro assays. In total, twenty-three derivatives were synthesized, of which eighteen were evaluated in vitro biological assays against K1 P. falciparum strains and cytotoxicity in non-tumor cells (MRC-5). In addition were submitted to the tests five commercial substances harmine (24), harmane (25), harmaline (27) and carbazole (29). As the main reactions for the nitration, demethylation, formation of salts through hydrogen chloride bubbling, condensation reaction of Pictet-Splenger and alkylation, a quality formed by the unpublished compound in the 9-(2,3-dihydroxy)-harmano (25.1). Among the derivatives submitted antimalarial assays, 3-nitrocarbazole (29.4), O-acetyl-harmol (26.1) and the harmine salt HCl (24.4) were the most active with IC50 8,87 M, 12,2 M and IC50 19,31 M, respectively. The 8-nitroharmano (25.2) and the 9-(2,3-dihydropropyl)-harmane (25.1) had their activity potentiated with IC50 values lower than the harmane. And more active commercial substances harmaline with IC50 14,7 M and the norharman with IC50 17.67 M. According to the factory, there is no concentration of 50 g / mL, except for 6-nitro-harmano (25.3) and O-acetyl-harmol, whose lower viability is less than 25%.