Síntese, avaliação biológica e estudos in silico de novos compostos Tiazólicos e Tiadiazínico com potencial frente ao Trypanosoma cruzi e Leishmania amazonensis

Abstract

The neglected diseases are a group of parasitic and infectious diseases that affect more than one billion people worldwide, affecting tropical and subtropical countries, mainly the population living in poverty. Chagas disease is part of this group of diseases. It is caused by the protozoan Trypanosoma cruzi, which is an anthropozoonosis of wide incidence both in Brazil and in the world. Despite having a high incidence, the treatment is limited to two drugs that have severe side effects and are ineffective in some cases, requiring investment in the research of new compounds that can be used as a therapeutic choice. Leishmaniasis is also part of the neglected diseases, presenting high rates of morbidity and mortality, being a public health problem in several countries of the world, with a limited therapeutic arsenal, justifying the need to discover new therapies. Studies point to thiazoles and thiadiazines as promising compounds for the treatment of these diseases, in which the compound 8c, recently published by our research group (consisting of a molecular hybrid of thiazole and thiophene), showed promising results against T. cruzi and that can be an important lead in the drug development. Based on this molecule, the objectives of this work were to make changes in compound 8c, synthesizing two new series of thiazoles and thiadiazines, to verify the influence on biological activity, as well as determining the inhibition mechanism through computational studies (docking, DFT, and molecular dynamics). The synthesis methodology proved to be efficient, obtaining 11 intermediate compounds and 99 final compounds, with satisfactory yields ranging from 50 - 95%. The HMBC and NOESY 2D NMR techniques were accurate in confirming the connectivity of the compounds, leading to structural confirmation of N-ethyl, N-allyl, and N-benzyl thiazoles by HMBC, and N-phenyl derivatives by NOESY. The density functional theory (DFT) method was efficient in explaining the regioselectivity observed for the substituted N-phenyl compounds, employing geometric optimization calculations and molecular orbitals, proposing the reaction mechanism and the formation of the main compounds. Regarding the assays against Leishmania amazonensis, 42 active compounds were found, with IC50 between 1.37 – 9.67 μM against amastigote forms, with low cytotoxicity and excellent selectivity index values. Among these compounds, 2f, 3f, 5c, and 11f were the most active (IC50 of 1.78, 1.37, 2.09, and 1.85 μM, respectively). Finally, molecular docking showed that the compounds can interact with critical residues of the enzyme (Cys153 and His289), similar to an inhibitor found in the literature. In addition, molecular dynamics simulations demonstrated the stability of compounds in complex with CPla. Furthermore, molecular docking in the cruzain showed important affinity and interactions (Cys25 and His159), showing that they are potential compounds against this target. The validation of Lipinski and Veber's rules through computational studies also showed that the compounds meet all the criteria and can present good biopharmaceutical properties.