N-Phenacyldibromobenzimidazoles—Synthesis Optimization and Evaluation of Their Cytotoxic Activity

Abstract

Antifungal N-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 N-phenacyldibromobenzimidazoles. The reactions were carried out in various base solvent-systems including K2CO3, NaH, KOH, t-BuOK, MeONa, NaHCO3, Et3N, Cs2CO3, 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 NaHCO3–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-1H-benzimidazol-1-yl)-1-(3,4-dichlorophenyl)ethanone (4f), 2-(4,6-dibromo-1H-benzimidazol-1-yl)-1-(2,4,6-trichlorophenyl)ethanone (5g), and 2-(4,6-dibromo-1H-benzimidazol-1-yl)-1-(2,4,6-trifluorophenyl)ethanone (5j) demonstrated pro-apoptotic properties against leukemic cells with derivative 5g being the most effective.

Promiscuous Lipase-Catalyzed Knoevenagel–Phospha–Michael Reaction for the Synthesis of Antimicrobial β-Phosphono Malonates

“…The toxic effect on bacterial cells after the analysis of the MIC and MBC tests for all 14 analyzed compounds, for which the MIC values were observed in the range of 0.2–1.4 µg/mL, and 2–82 µg/mL for MBC values in the analyzed model strains K12, R2, R3 and R4) ( Figure 4 and Figure 5 ), which had specific functional groups in the structure of the aromatic ring located at the beta position. It is worth noting that the introduction of a halogen atom into the structure of the tested compounds had a significant effect on the activity of compinds 6 and 7, which is often observed for various types of compounds exhibiting antibacterial activity [ 58 , 59 , 60 ]. Similar enhanced antimicrobial activity was observed for methyl and methoxy groups located in the aromatic ring of the studied compounds 5 and 12 ( Figure 4 , Figure 5 and Figure 6 ).…”