Desenvolvimento de métodos alternativos para a síntese de n-acilidrazonas derivadas de isatinas

Abstract

Isatin is a heterocyclic compound widely known for its applications in medicinal chemistry. N-acylhydrazone derivatives of isatin constitute an important class of molecules with broad pharmacological action. In parallel, indole alkaloids containing the prenyl group have shown activity in tumor cells. Taking these aspects into consideration, the objective of this work was to develop alternative methods for the synthesis of new N-acylhydrazones derivatives of N-prenylated isatins. The N-prenylated derivatives of isatin, 5-fluoro-isatin, 5-bromo-isatin and 5-methyl-isatin were synthesized using prenyl bromide as the alkylating agent and K2CO3 as the base in dimethylformamide medium, obtaining these intermediates with yields ranging from 79% to 94%. In the investigation process, the method that stood out was the one that used the deep eutectic solvent of choline chloride:acetic acid as solvent/catalyst in the synthesis of the twelve N-acylhydrazones, eleven of which were new, obtaining reaction times between 3 and 17 minutes and yields that varied between 82% and 97%. All compounds were fully characterized by physical methods (infrared, 1H and 13C nuclear magnetic resonance and mass spectrometry), with the formation of syn/antiperiplanar conformation being observed in the compounds substituted o-chloro in the benzohydrazide moiety. Most of the compounds were evaluated for anticancer activity in the K562 (chronic myeloid leukemia), NCI-H1299 (lung carcinoma) and HCT116 (human colon cancer) cell lines. The compound (Z)-2-chloro-N’-(5-fluoro-1-(3-methylbut-2-en-1-yl)-2-oxoindolin-3-ylidene)benzohydrazide (5k) was the only one that presented a growth inhibition percentage above 60% in the K562 and HCT116 strains. Therefore, it was possible to develop an efficient method using the deep eutectic solvent as a solvent/catalyst to obtain new N-acylhydrazones compounds.