Síntese e avaliação da atividade tripanocida de novos azóis, derivados da β-lapachona

Abstract

After more than 100 years since its discovery, Chagas disease still represents a challenge for humanity, since its treatment has serious gaps. In addition to not being satisfactorily effective in the chronic phase of the disease, the drugs used worldwide for its treatment, nifurtimox and benznidazole, cause severe side effects to patients treated with them. Thousands of people die each year due to this disease, which mainly affects tropical regions, such as Brazil. In Brazil, only benznidazole is authorized for the treatment of Chagas disease, by the National Health Surveillance Agency (ANVISA). Thus, the search for new drugs for the treatment of Chagas disease is essential. In this sense, -lapachone derivatives have emerged as promising compounds, especially the azole derivatives. -lapachone is a naphthoquinone, found in several tree and shrub species of the Bignoniaceae family, among them, ipê. In the last decades, several research groups, especially in Brazil, have been dedicated to the synthesis of -lapachone derivatives, to combat several pathogens, including Trypanosoma cruzi (T. cruzi), which causes Chagas disease. In addition to these efforts in the search for new trypanocidal agents, in this work 26 imidazole derivatives and 2 oxazole derivatives of -lapachone were synthesized, among which 21 are unpublished (compounds 8 to 26 and compound 28), in addition to a 2- amino-oxazole derived from 1,10-phenanthroline-5,6-dione (27). Among the synthesized compounds, 16 were evaluated in vitro for trypanocidal activity, in addition to -lapachone, against the amastigote and trypomastigote forms of T. cruzi. Under the conditions tested, four of the evaluated compounds for the first time (compounds 7, 10, 12 and 22) were more active than -lapachone against the trypomastigote form of the parasite, among which two (compounds 7 and 22) were also more active than the reference drug itself, benznidazole. Against the amastigote form, three (22, 23 and 24) of the novel compounds were more active than -lapachone, among which two (22 and 23) were more active than benznidazole. It was also possible to verify that compounds 22 and 23 had greater selectivity for the parasite than for the host cells. The mechanism of action of compound 22 under the parasite was investigated, and it was found that the mitochondria is its main target of action, causing its swelling and a washing aspect in the organelle; morphological changes were also observed in the structures of the parasite's cells. By these investigations, it was possible to verify damages caused in complexes II, III and IV of mitochondrial electron transport systems. In addition to the valuable results of trypanocidal activity, this work also enabled the development of a new method of synthesis of the 2-amino-oxazole derived from β-lapachone, compound 24, and the improvement of the reaction conditions of the 2-amino-imidazole derived from β-lapachone, the compound 7.