Síntese e avaliação do potencial antimicrobiano de novos derivados 2-amino-tiofênicos obtidos a partir de 1,4-ditiano-2,5-diol

Abstract

2-Aminothiophene derivatives are important synthetic intermediates for medicinal chemistry, allowing to obtaining several bioactive compounds, with emphasis on antifungal and antibacterial agents. Previous studies carried out by the Laboratory of Synthesis and Vectorization of Molecules have identified promising antimicrobial activity of cycloalquil[b]thiophene derivatives, yet theoretical studies have demonstrated that their high LogP values are one of the main factors limiting their biological potential. Thus, the aim of the present work was to synthesize novel 2-amino-thiophenic derivatives using 1,4-dithiane-2,5-diol as precursor, in order to obtain unsubstituted thiophene at C-4 and C-5 positions, and also to determine the in vitro antimicrobial activity of these compounds. 25 new thiophene derivatives were obtained through two methods using diferente energy sources: heating and microwave irradiation. The use of the microwave was more adequate for the synthesis, resulting in compounds with better yields (60-89%). The compounds had their structures confirmed by nuclear magnetic resonance, infrared spectroscopy and mass spectrometry. In the evaluation of the antimicrobial activity strains of Staphylococcus, Candida, Cryptococcus and Aspergillus were used. The assays were performed by the susceptibility test using the broth microdilution technique (CLSI, 2002) to determine the Minimum Inhibitory Concentration (MIC) of the substances on the strains. The most active compounds were those who presented as substituting groups the indole (CN11, CN15) and pyridine (CN25), inhibiting the fungal growth of most Candida, Cryptococcus and Aspergillus strains, respectively, following the compounds with presence of Cl, F and Br (CN02, CN03 and CN21) and 3-OEt-4-OH (CN26) for phenyl substituted derivatives which inhibited only the growth of Candida and Cryptococcus strains. The new derivatives obtained do not present an increase in antimicrobial activity when compared to their cycloaquil[b]thiophene analogs, demonstrating that substitutions at thiophene ring positions 4 and 5 are not essential for the antimicrobial activity of 2-aminothiophene derivatives, but the decrease of the derivatives LogP results in molecules with better pharmacokinetic profile, which encourages us to continue searching for more active compounds. Keywords: Gewald reaction, dithiane, antimicrobial activity.