Planejamento e avaliação de novos derivados 2-iminotiofen-tiazolidínicos como inibidores de cisteína proteases de Trypanosoma cruzi e Leishmania amazonensis

Abstract

The term neglected diseases refers to a set of pathologies that affect about 1 billion individuals worldwide, who live in social exclusion and poverty, resulting in a major global public health problem. In this sense, pharmacotherapy against trypanosomiasis, leishmaniasis and Chagas disease remains ineffective, especially when faced with their chronic forms. Thus, in a study recently reported by our research group, the LQM83 derivative was obtained, a thiophene-thiazolidine molecular hybrid, in which it showed potential inhibition against cruzin, with IC50 = 2.4 μM. Based on this, intending to contribute directly to the improvement of the anti-chagasic and leishmanicidal therapeutic arsenal, it obtained 47 new derivatives, with yields between 58-95% and a purity in range of 99%. Evaluation against the amastigote forms of Leishmania amazonensis showed the promising compounds 5f and 7c, being more potent than the standard drug Meglumine Antimoniate and less cytotoxic than Amphotericin B. In addition, 5f was more selective than both, where 7c showed greater selectivity than this last drug. Molecular docking simulations against the proposed target cruzain suggest that derivatives 1f and 7e have potential interactions to the detriment of LQM83, such as carbon-hydrogen and π-alkyl interactions with Ala159 and conventional hydrogen bonding with Asp140 residue, respectively. Such residues may be the key to obtain more potent activities, where biological assays against trypomastigote and amastigote forms are in progress. Finally, studies involving the design and obtaining of promising compounds contribute to the development of new effective derivatives, with low cost and toxicity against leishmaniasis and Chagas disease, mainly targeting the most underserved population.