Synthesis and Antiproliferative Activity of Novel 2-Substituted N-Methylated Benzimidazoles and Tetracyclic Benzimidazo [1,2-a]Quinolines

Abstract

ABSTRACTIn this paper, the synthesis, antiproliferative activity in vitro and structure–activity relationship of N-methylated 2-benzimidazoles related to 2,3-acrylonitriles and benzimidazo [1,2-a]quinolines bearing halogeno or amino substituent is described. Amino-substituted N-methylated benzimidazo[1,2-a]quinolines were prepared by using microwave-assisted amination from corresponding halogeno-substituted precursors. All newly prepared compounds were tested against tree human cancer cells to assess their antiproliferative activity in vitro. Compounds 4a and 4b display certain selective activity against MCF-7 cells together with the N,N-dimethylamino-substituted derivative 4e with IC50 0.4 µM. Cyclic derivatives 7a, 7b, and 8 were more active with IC50 in micromolar range of concentrations but without any selectivity among tested cells. Among the most active compounds, 2-amino-substituted derivatives 9a and 9b were also selective against HCT116 cells with IC50 values 0.2 µM and 0.4 µM, respectively. The influence of compounds 9a and 9b on the cell cycle of HCT 116 revealed that both compounds induced a strong reduction of the percentage of cells in S phase, along with the induction of cell death.