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

ABSTRACT

In 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.

KEYWORDS:

• Antiproliferative activity in vitro
• benzimidazoles
• benzimidazo[1,2-a]quinolines
• fluorescence microscopy
• SAR

Additional information

Funding

This work has been supported by the Croatian Science Foundation under the projects 5596 (Synthesis and cytostatic evaluations of novel nitrogen heterocycles library) and 5660 (A multi-disciplinary approach to discover selective drugs targeting cancer stem cells: The role of potassium transport – Multi-CaST).