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Synthesis and antiproliferative activity of amino substituted benzimidazo[1,2-a]quinolines as mesylate salts designed by 3D-QSAR analysis

The experimental search for new benzimidazole derivatives with enhanced antiproliferative activity was successfully guided by QSAR modelling. Robust 3D-QSAR models were derived on the available database of the compounds with previously measured activities. The QSAR analysis revealed that the increase of the antiproliferative activities towards H460, HCT 116, MCF-7 cell lines and normal fibroblasts SW 620 cells will be obtained if new compounds are charged at a pH range from 5 to 7 and if their hydrophobicity is increased compared to the dataset compounds. Novel benzimidazo[1, 2- a]quinolines bearing quarter amino groups with corresponding aliphatic chains were designed and their antiproliferative activities were computationally predicted. Using uncatalyzed microwave assisted amination, 14 novel compounds were obtained to assess their antiproliferative activities towards H460, HCT 116, MCF-7, and SW 620 tumor cell lines in vitro. Novel compounds showed antiproliferative activities at micromolar and submicromolar inhibition concentrations. Experimental measurements of antiproliferative activities enabled validated the QSAR models showing very good agreement between experimentally measured activities and computational predictions. In an attempt to elucidate the mode of action through which benzimidazole derivatives accomplish their antiproliferative activities, thermal denaturation experiments were performed to test their DNA binding properties.

amines ; benzimidazo[1 ; 2-a]quinolines ; mesylate salts ; 3D-QSAR ; anticancer ; microwave

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