Síntese e avaliação da atividade antibacteriana e antitumoral de derivados indólicos e arilfuranos.

Abstract

The importance of heterocyclic compounds in medicinal chemistry is undeniable, since they are part of the structure of several bioactive molecules, whether of natural or synthetic origin. Several drugs used in the clinic have one or more heterocycles in their chemical structure, which, in most cases, are essential for the therapeutic activity and/or modulation of the pharmacokinetic properties. In view of the relevance of these nucleus in the development of new drugs, the present work proposes the synthesis and evaluation of the antibacterial and antitumor activity of a series of indole and arylfuran derivatives. The key step to obtain the most promising compounds was a reductive amination reaction. For the synthesis of the indole ring, the methodology described by Fischer was used, in which it was possible to synthesize the indole substituted at position 2 by an ester group. From this compound, 27 indole derivatives were synthesized with yields ranging from 14 to 96%. Twenty-one furan derivatives were obtained from furfural with yields between 37 and 93%. Among these two classes of compounds, six hybrids were designed based on the structure of AFN-1252 and curcumin, inhibitors of bacterial FabI that is an important molecular target for the development of new antibacterial agents. The ability of the synthesized compounds to inhibit bacterial growth, as well as their antitumor activity were evaluated in vitro and the results obtained revealed very promising substances. The amine N-((5-(4-chlorophenyl)furan-2-yl)methyl)-3-phenylpropan1-amine 20j demonstrated an interesting result in both assays: it was active against Gramnegative bacteria (E. coli, MIC = 49 µM) and Gram-positive (S. aureus, MIC = 98 µM), in addition to showing significant activity against the proliferation of breast cancer cells (MDAMB-231, IC50 = 3.21 µM) , acute monocytic leukemia (THP-1, IC50 = 8.92 µM) and chronic myeloid leukemia (K-562, IC50 = 10.3 µM). Indolamine N-((1H-indol-2-yl)methyl)-3- phenylpropan-1-amine 6i was also active against the proliferation of leukemic cell lines, presenting an IC50 = 1.61 µM (THP-1) and 18.12 µM (K-562). Both amines showed an appropriated selectivity index (>2), indicating a lower toxicity of these compounds to normal cells. In this context, the relevance of these results in the search for new potential heterocyclic compounds for the treatment of bacterial infections and human cancer is considered.