Avaliação da atividade antitumoral e inibição da atividade das enzimas acetilcolinesterase e adenosina desaminase por 4-tiazolidinonas derivadas do 4-(metiltio)benzaldeído e do 4-(metilsulfonil)benzaldeído

Abstract

The present study assessed the biological potential of fourteen 1,3-thiazolidin-4-ones through ADA and AChE inhibition effect, besides the potential anti glioma effect through decreasing of cell viability of glioblastoma multiform cells. In this work was applied the experience of the research group in thiazolidinone synthesis, in which was performed multicomponent and multicomponent one-pot reactions from reaction conditions already established for the group, besides determination of a new efficient reaction condition. The reactions occurs by seven different amine (2-(piperidin-1-yl)ethan-1-amine; 3-(piperidin-1-yl)propan-1-amine; N1,N1-diethylpropane-1,3- diamine; pyridin-2-ylmethanamine; pyridin-2-amine; 4-(methylthio)aniline; or benzo[d][1,3]dioxol-5-amine), two aldehydes (4-(methylthio)benzaldehyde ou 4- (methylsulfonyl)benzaldehyde) and the mercaptoacetic acid. The new compounds were efficient synthesized through used methodologies in moderate to good yields (22- 86%) and were identified by GC/MS and NMR. Five of them were also characterized by HRMS. The compounds 5b (65.9%), 5c (65.4%), 6a (34.3%), 6b (56.5%) and 6c (51.0%) presented inhibitory effect of lymphocytic AChE since 50 µM and the compound 5a (34.1%) present statistical difference since 100 µM. Only the same compounds presented ADA activity inhibition, however at high concentrations tested (250 and/or 500 µM). Assessing the cytotoxicity of these six compounds in CHO cell line (100, 250 e 500 µM in 48h), five of them presented safe already at 100 µM. Besides that, several compounds demonstrate significant difference from positive control TMZ in 72h and only one in 48h at 100 µM in C6 cell line MTT assay. The compounds 5b (52.2% in 48h; 78.0% in 72h), 5e (48.0%; 75.0%), 5g (61.2%; 81.7%) and 6e (47.2%; %) were the best results in the screening of inhibition of cell viability and were analyzed at different concentrations (5, 25, 50, 100 and 250 µM). The compounds 5b and 5e presented statistical difference at 5 µM, 6e at 25 µM and 5g at 50 µM in 72h of contact. Furthermore, the cytotoxicity study in primary astrocytes cells were evaluated and among fourteen compounds, eight of them were not cytotoxic at 250 µM, and none presented toxicity at 100 µM, both in 72h. Therefore, this work achieved fourteen new thiazolidinones, three of them (5c, 6b, 6c) considered potential acetylcholinesterase inhibitors and at least four (5b, 5e, 5g, 6e) with promising antitumor activity, with a good safety profile.