Amino substituted benzimidazo[1,2-a]quinolines: Antiproliferative potency, 3D QSAR study and DNA binding properties

Abstract

We describe the synthesis, 3D-derived quantitative structure-activity relationship (QSAR), antiproliferative activity and DNA binding properties of a series of 2-amino, 5-amino and 2,5-diamino substituted benzimidazo[1,2-a]quinolines prepared by environmentally friendly uncatalyzed microwave assisted amination. The antiproliferative activities were assessed in vitro against colon, lung and breast carcinoma cell lines; activities ranged from submicromolar to micromolar. The strongest antiproliferative activity was demonstrated by 2-amino-substituted analogues, whereas 5-amino and or 2,5-diamino substituted derivatives resulted in much less activity. Derivatives bearing 4-methyl- or 3,5-dimethyl-1-piperazinyl substituents emerged as the most active. DNA binding properties and the mode of interaction of chosen substituted benzimidazo[1,2-a]quinolines prepared herein were studied using melting temperature studies, a series of spectroscopic studies (UV/Visible, fluorescence, and circular dichroism), and biochemical experiments (topoisomerase I-mediated DNA relaxation and DNase I footprinting experiments). Both compound 36 and its bis-quaternary iodide salt 37 intercalate between adjacent base pairs of the DNA helix while compound 33 presented a very weak topoisomerase I poisoning activity. A 3D-QSAR analysis was performed to identify hydrogen bonding properties, hydrophobicity, molecular flexibility and distribution of hydrophobic regions as these molecular properties had the highest impact on the antiproliferative activity against the three cell lines.

Keywords: 3D-QSAR; Antiproliferative activity; Benzimidazo[1,2-a]quinolines; Benzimidazoles; DNA binding properties.