5-Amino-7-(trifluorometil)pirazolo[1,5-a]pirimidinas: síntese mediada por líquido iônico, estudo teórico e potencial antiglioma

Abstract

This work described the synthesis, theoretical study, in vitro antiglioma activity and cytotoxicity of a series pyrazolo[1,5-a]pyrimidines from three reaction steps. The first reaction step was the compound 1,1,1-trifluoro-4,4-diethoxy-3-buten-2-one by reaction with triethyl orthoacetate, trifluoroacetic anhydride, pyridine as base and in chloroform solvent. The second reaction step was through the above compound with substituted amines to obtain the β-enaminones (4-amino-4-ethoxy-1,1,1-trifluorobut 3-en-2-ones), precursors for the synthesis of the fused heterocycle. The third reaction step consists in obtaining the pyrazolo[1,5-a]pyrimidines from the synthesis using the β-enaminones with the 3-amino-5methylpyrazole in ionic liquid [BMIM][PF6] obtaining nine new compounds in the literature with good yields (42-86%). Gas chromatography–mass spectrometry (CG/MS) and nuclear magnetic resonance (NMR) 1H, 13C, 15N and two-dimensional (COSY, HMBC and HMQC) confirm the formation of the expected products. A theoretical study was performed aiming to propose a mechanism in which ionic liquid acting as a mediator generates a complex with β-enaminones and favors the formation reaction of pyrazolo[1,5-a]pyrimidines. The β-enaminone isomerization reaction and the identification of the enaminoester were based on 1H and 13C NMR and two-dimensional (COSY, HMQC, HMBC).The proposed mechanism was studied from computational tests. The study antiglioma demonstrated that four pyrazolo[1,5-a]pyrimidines had activity at a concentration of 100 µM. The compound 2-methyl-5-phenylamino-7-(trifluoromethyl)pyrazolo[1,5 a]pyrimidine, reducing the glioblastoma cell line by 20% at a concentration of 25 µM. The cytotoxicity study on astrocytes found that the four pyrazolo[1,5-a]pyrimidines are not cytotoxic tohealthy central nerve cells.