Synthesis, crystal structure and anticancer activity of novel derivatives of ethyl 1-(4-oxo-8-aryl-4,6,7,8-tetrahydroimidazo[2,1- c][1,2,4]triazin-3-yl)formate

Abstract

Synthesis and anticancer activity of ethyl 1-(4-oxo-8-aryl-4,6,7,8-tetrahydroimidazo[2,1- c][1,2,4]triazin-3-yl)formates ( 7–12) are presented. The title compounds were obtained by two independent synthesis methods from 1-aryl-2-hydrazono-imidazolidines (1-aryl-2-hydrazino-imidazolines) ( 1–6) by cyclocondensation reaction with diethyl 2-(hydroxyimino)malonate ( A) and diethyl 2-oxomalonate ( B). Molecular structure of synthesized compounds was confirmed by IR, 1H NMR, EI-MS spectra, elemental analysis and X-ray crystallography for 12. Compounds 10 and 11 exhibited anticancer activity towards following cancer cells: LS180 (ECACC 87021202, human Caucasian colon adenocarcinoma cells), SiHa (ECACC 85060701, uterus cancer cells), T47D (ECACC 85102201, human breast carcinoma cells). Compound 10 was found to be the most active against SiHa cancer line; its GI was 41 and 52%, respectively in both examined concentrations (10 and 50 μg ml –1), whereas compound 11 had the highest potential to reduce the growth of LS180 and SiHa cancer lines, especially in a higher dose (50 μg ml –1). Moreover, the distinctly marked lower cytotoxicity of tested compounds against normal cell lines (HSF, human skin fibroblast cells and Vero African Green Monkey Kidney cells, GMK clone) and almost two-times higher against cancer cell lines was confirmed. Also antibacterial activity of starting 1-(2-chlorophenyl)-2-hydrazonoimidazolidine hydroiodide ( 4) is presented. Molecular structure of 4 was confirmed by IR, 1H NMR, 13C NMR, EI-MS spectra, elemental analysis and 1H– 1H COSY, HMBC and HMQC correlations. The marked antibacterial activity for this compound in relation to Staphylococcus aureus ATCC 25923 and Escherichia coli ATCC 25922 with equal minimal inhibitory concentration values of 15.62 and 15.62 μg ml –1 was found.