| Summary: | Antifungal <i>N</i>-phenacyl derivatives of 4,6- and 5,6-dibromobenzimidazoles are interesting substrates in the synthesis of new antimycotics. Unfortunately, their application is limited by the low synthesis yields and time-consuming separation procedure. In this paper, we present the optimization of the synthesis conditions and purification methods of <i>N</i>-phenacyldibromobenzimidazoles. The reactions were carried out in various base solvent-systems including K<sub>2</sub>CO<sub>3</sub>, NaH, KOH, <i>t-</i>BuOK, MeONa, NaHCO<sub>3</sub>, Et<sub>3</sub>N, Cs<sub>2</sub>CO<sub>3</sub>, DBU, DIPEA, or DABCO as a base, and MeCN, DMF, THF, DMSO, or dioxane as a solvent. The progress of the reaction was monitored using HPLC analysis. The best results were reached when the reactions were carried out in an NaHCO<sub>3</sub>–MeCN system at reflux for 24 h. Additionally, the cytotoxic activity of the synthesized compounds against MCF-7 (breast adenocarcinoma), A-549 (lung adenocarcinoma), CCRF-CEM (acute lymphoblastic leukemia), and MRC-5 (normal lung fibroblasts) was evaluated. We observed that the studied cell lines differed in sensitivity to the tested compounds with MCF-7 cells being the most sensitive, while A-549 cells were the least sensitive. Moreover, the cytotoxicity of the tested derivatives towards CCRF-CEM cells increased with the number of chlorine or fluorine substituents. Furthermore, some of the active compounds, i.e., 2-(5,6-dibromo-1<i>H</i>-benzimidazol-1-yl)-1-(3,4-dichlorophenyl)ethanone (<b>4f</b>), 2-(4,6-dibromo-1<i>H</i>-benzimidazol-1-yl)-1-(2,4,6-trichlorophenyl)ethanone (<b>5g</b>), and 2-(4,6-dibromo-1<i>H</i>-benzimidazol-1-yl)-1-(2,4,6-trifluorophenyl)ethanone (<b>5j</b>) demonstrated pro-apoptotic properties against leukemic cells with derivative <b>5g</b> being the most effective.
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