Síntese, caracterização estrutural e relação estrutura-atividade de novos compostos cíclicos tiazolidínicos e tiazinicos derivados de tiossemicarbazonas planejados como protótipo de fármaco leishmanicida

Abstract

Neglected diseases are a group of parasites and bacterial diseases that most lead to death worldwide, especially leishmaniasis, being a parasite of high incidence in Brazil, related to several cases of death. The choice of therapeutic regimen for treatment is based on a small therapeutic arsenal, with drugs discovered more than 50 years ago, having several adverse effects and, in many cases, not leading to complete cure of the patients. Antimonial complexes are the main choice for therapy, however, there are cases where patients are resistant to responding to treatment, using amphotericin B as a second-choice treatment and pentamidine as a third alternative. Thiazolidinic and thiazine compounds and also indoles are frequently reported in the literature as being active against the amastigote and promastigote forms of Leishmania spp. Among the various compounds present in the chemistry library of the Laboratory of Medicinal Chemistry (LQM), compounds LQM 17.1 and LQM 05 are Those that present more promising results, with potential leishmanicidal effect. The aim of the project is to carry out structural modifications from the compounds LQM 17.1, LQM18.1 and LQM 05, in order to develop a series of new molecular rigid derivatives derived from the class of thioazolidines and thiazines, and using the indolic nucleus, Synthesize a new series of molecular hybrid compounds by two methodologies in order to optimize the method. Initially, the planned compounds were obtained by condensation between three different benzaldehydes, the indole nucleus and thiosemicarbazide. Subsequently, the intermediates were cyclized with different dielectrophiles, yielding the desired final derivatives. Molecular hybrids showed better yields in a shorter reaction time using the sonication method. All compounds, both intermediate and final, were suitably characterized by the Nuclear Magnetic Resonance (NMR) spectroscopic method of hydrogen (1H) and carbon thirteen (13C). The cytotoxicity evaluation (MTT) showed that the molecular stiffness of the compounds LQM05.1, LQM17.1 and LQM18.1 did not increase the toxicity of the compounds, however, when replacing the thiazolidine ring, there was an increase in toxicity, excerpt for compound LQM122 . On the other hand, the molecular hybrids presented toxicity, with only LQM167 compound consisting of a dihydrothiazole being non-toxic. In the assays against amastigote forms, a decrease in activity was observed when compared to the starting compounds for both the molecular rigid and the molecular hybrids, and further structural drug modification studies were necessary to identify new compounds leads and hits with activity more promising than LQM17.1 that may in future be used in the treatment of leishmaniasis.