Planejamento, síntese e avaliação do potencial antileishmania de novos 2-aminotiofeno-3-carboxamidas obtidas por modificação molecular

Abstract

Leishmaniasis is considered a public health problem, most of the cases are registered in emerging countries and in low-income populations, being still neglected tropical diseases which are not prioritized in research investments by large pharmaceutical companies, which results in few treatment options, in which they have several adverse effects, and long periods of treatment. In view of this, it became necessary to search for new effective and less toxic drugs, which is initiated by the understanding of Medicinal Chemistry, which allows the synthesis or isolation of better compounds. In addition, among the compounds with activity described in the literature, the 2-amino-thiophene derivatives are a versatile class of sulfur-containing compounds and an immense capacity to offer ligands for different molecular targets, with anti-leishmania potential. replacement of carbonitrile, which showed low solubility, by carboxamide at position-3, which showed activity against L. amazonenses in other studies. Thus, the objective of this work was to synthesize new 2-aminothiophene-3 carboxamide derivatives that are candidates for antileishmanial drugs, by carrying out the molecular modification of substituted 3-carbonitrile prototypes, in order to verify the importance of the substitution pattern of the C-3 position of the thiophene ring. Fifteen compounds were synthesized, with color varying between yellow and orange, yields from 20 to 98%, with the same synthetic route for all molecules. The compounds had their structures confirmed by NMR1H and 13C, their antileishmanial activities evaluated against the promastigote forms of Leishmania amazonensis, L. braziliensis, L. infantum and L. major, and their toxicities evaluated against RAW 264.7 macrophages. The 6BOC2 compound showed the highest inhibitory activity with IC50 values lower than 8μM for all species tested, and a selectivity index (SI) higher than 37.6. The comparison of the inhibition values and SI of the 3-carboxamide derivatives in relation to the 3- carbonitrile derivatives allows us to affirm that the presence of the 3-carbonitrile radical is not essential for antileishmanial activity. Although the substitution by the 3- carboxamide group did not result in compounds with activity superior to the 3- carbonitrile derivatives, obtaining new compounds with this substitution pattern should be taken into account when planning new antileishmanial drug candidates for this class of compounds.