Síntese, caracterização e potencial citotóxico e antituberculose de tiossemicarbazonas, seus complexos de gálio(III), bismuto(III), antimônio(III) e de bases de Schiff derivadas de p-nitrofeniletilenodiamina

Abstract

In the present work we describe the synthesis of thiosemicarbazones (TSCs) derived from pyrazinamide, its metal complexes of Ga3+, Bi3+ and Sb3+ as well as p-nitrophenylethylenediamine-derived Schiff bases. These compounds have been developed in order to investigate their potential as prototypes of antituberculosis and/or antitumor drugs. In this context, 2-pyrazineformamide thiosemicarbazone (HPzAm4DH, 1) and its derivatives substituted at N4 by methyl (HPzAm4M, 2), ethyl (HPzAm4E, 3), cyclohexyl (HPzAm4Cex, 4) and phenyl (HPzAm4Ph, 5) were prepared, whose data of melting point, IR and NMR spectroscopies and electrospray ionization mass spectrometry (ESI-MS) confirmed its purity and yield. Novel complexes were obtained with the thiosemicarbazones and the metal ions of interest. The Ga3+ complexes (610) have been prepared from TSC and gallium nitrate in the 2:1 ratio and exhibit the general formula [Ga(L)2]NO3, where L is the anionic thiosemicarbazone. Bi3+(1115) and Sb3+ (1620) complexes have been prepared from TSC and metal choride (1:1 ratio) and showed the general formula [M(L)Cl2] (where M = Bi3+ou Sb3+). All complexes were characterized, when possible, by melting point, conductivimetry, IR, electronic and NMR spectroscopies as well as ESI-MS. The biological action of all compounds has been investigated. The TSC haven t exhibit action against the tumor cell lines HCT116 (colon adenocarcinoma), OVCAR8 (ovarian cancer) and SF295 (glioblastoma multiforme) at 5g/mL and against Mycobacterium tuberculosis strain, the main bacterial species causing tuberculosis, in the concentration maximum of 100 g/mL. Ga3+ complexes (710) don t demonstrate significant cytotoxic effects against the tumor cell lines, except compound (9), which is more cytotoxic to MCF7, PC3 and HCT116 cells when compared to the reference drugs cisplatin and etoposide. In general, the activity of these complexes against M. tuberculosis bacteria is better than the free thiosemicarbazones, confirming that Ga3+ coordination resulted in compounds more potent against this bacterium. Bi3+ complexes (1115) have not shown significant activity against the tumor cells tested as well as against M. tuberculosis. The investigated Sb3+ complexes (1620) also have not shown activity against the tumor cells under study. Nonetheless, coordination to Sb3+ led to a significant increase in activity against M. tuberculosis, especially for complexes 17, 18 and 19, which show a minimum inhibitory concentration of 25 μg/mL. Twelve molecules containing the p-nitrobenzene group (2132) have also been synthesized and characterized by IR and NMR spectroscopies as well as ESI-MS. Among the compounds, 21, 29, 30 and 32 inhibit the growth of HCT116 cells by more than 90%. All compounds were inactive against M. tuberculosis at the concentrations tested, with the exception of 24 and 29