Síntese e avaliação de atividade antituberculose de tiossemicarbazonas e 1,3,4-tiadiazol derivados do trans-cinamaldeído

Abstract

Tuberculosis remains one of the deadliest infectious diseases worldwide, a problem that has been further aggravated by the increasing number of cases resistant to conventional drugs, reinforcing the need for the development of new pharmacological agents. In this context, the present study aimed to synthesize and evaluate the antitubercular potential of six trans-cinnamaldehyde derivatives belonging to the thiosemicarbazone and 1,3,4-thiadiazole classes. Initially, an in silico screening was performed using the Way2Drug platform, involving several natural compounds, from which trans-cinnamaldehyde emerged as the most promising candidate for this study. Thiosemicarbazones were synthesized via a one-pot methodology, initially employing the reaction between hydrazine hydrate and three different isothiocyanates to form thiosemicarbazide intermediates, followed by condensation with trans-cinnamaldehyde. The 1,3,4-thiadiazoles were obtained in two steps, with the heterocyclization step carried out through FeCl₃-catalyzed oxidative cyclization. After synthesis, purification was performed by recrystallization to allow comparison of yields. In general, the thiadiazoles (TDZs) showed the highest crude yields as well as the best yields after recrystallization. Their purity was determined by melting point ranges. The synthesized compounds were characterized by infrared spectroscopy and by 1H and 13C nuclear magnetic resonance (NMR) spectroscopy. In silico analyses performed using the SwissADME and Osiris Prediction platforms demonstrated that all derivatives complied with Lipinski’s rule of five, suggesting good oral bioavailability. Thiosemicarbazones exhibited toxicological risk profiles similar to reference drugs, whereas thiadiazoles showed more favorable toxicological profiles. In in vitro assays against the standard H37Rv strain, thiosemicarbazones did not inhibit mycobacterial growth. However, thiadiazoles 1 and 2 showed promising activity against the standard Mycobacterium tuberculosis strain, with minimum inhibitory concentrations (MICs) of 1.95 and 0.97 μg·mL⁻¹, respectively, while the 1,3,4-tiadiazole 1 (TDZ-1) derivative also presented significant results against resistant strains. These findings demonstrate the potential of the trans-cinnamaldehyde-derived 1,3,4-thiadiazole heterocyclic system as a starting point for the development of new antitubercular agents.