Semicarbazonas e tiossemicarbazonas análogas à tioacetazona: síntese, estudos in silico e avaliação de atividade antituberculose

Abstract

Mycobacterium tuberculosis is the bacillus responsible for tuberculosis desease, a worldwide high-impact infectious disease, especially in immunodeficient patients. Polichemotherapy treatment has drugs of first and second choice, however they have severe adverse effects and a long treatment, which increases the chance of patients abandoning treatment. This fact became a huge problem, since it started the manifestation of multi-resistant and extensively resistant strains to one or more antibiotics. As a result of this situation, it is necessary to develop new safe and effective bioactive molecules with potential anti-Mycobacterium tuberculosis activity. Thiosemicarbazones and semicarbazones have a wide pharmacological profile, in addition to being effective in inhibiting the ribonucleotide reductase enzyme, further enhancing the interest in studying these compounds. In this sense, the present work presents a synthesis of a series of thiosemicarbazones and semicarbazones with structures analogues to the drug thioacetazone, focusing on the evaluation of the anti- Mycobacterium tuberculosis activity and on the prediction studies of physical-chemical parameters in silico. The yield compounds were obtained with yield range of 26.2 to 89.4%. Structural characterization was performed by 1H and 13C nuclear magnetic resonance spectroscopy and infrared spectroscopy (FT-IR). The in silico parameter studies were carried out with the aid of the OSIRIS Property Explorer®, SwissADME®, PASS Online® and Molinspiration® software, in which physical-chemical properties- attributed to the ability of oral bioavailability, toxicological action, predictions of pharmacological activities and bioactivity were obtained and the analyzes indicated that the substances may have a good bioavailability profile. Thiosemicarbazones 4, 5, 3 and 2 were the most active substances against a standard H37Rv strain of M. tuberculosis, with MICs of 7,8, 15,6, 15,6 and 31,25 µg.mL-1, respectively. Finally, although the mechanism of action or the molecular targets for the proposed molecules is not known, it was observed that when halogen substituents were inserted as electron withdrawing groups in the para position of the aromatic ring linked to the lipophilic effect of the sulfur atom of thiosemicarbazones, results in an improvement in activity.