engleski

Computationally guided search for novel benzimidazole derivatives with enhanced antiproliferative activity

Novel amino and diamino substituted benzimidazo[1, 2-a]quinolines were designed using 3D-QSAR analysis, synthetized and their antiproliferative activities were assessed against H460, HCT 116, MCF-7 and SW 620 tumor cell lines in vitro. Robust 3D-QSAR models were derived on the available database of the compounds with already measured antiproliferative activities against H460, HCT 116, MCF-7 and SW 620 tumor cell lines. For each cell line, 3D-QSAR model was derived using Volsurf based procedure and its predictive ability was tested by internal and external validation. The QSAR analysis was conducted for the models with the highest predictive ability for each cell line. The results of QSAR analysis identified molecular properties with the highest influence on antiproliferative activity. It was revealed that antiproliferative activities against all four cell lines should be increased if the new compounds are charged at pH range from 5 to 7 and if their hydrophobicity is increased comparing to the dataset compounds. Therefore, new amino and diamino substituted benzimidazo[1, 2-a]quinolines with introduced quarter amino groups and aliphatic chains were designed and their antiproliferative activities were predicted by 3D-QSAR models. Using uncatalyzed microwave assisted amination 14 new compounds that were designed by QSAR modeling were synthesized. The structures of prepared compounds were determined by the NMR analysis based on the analysis of H-H coupling constants as well as chemical shifts and by mass spectroscopy. Their antiproliferative activities in vitro on four human tumor cells (H460, HCT 116, MCF-7, and SW) were assessed. Experimental values enabled undisputed validation of QSAR models, very good agreement between experimental activities and computational predictions was obtained. As computationally predicted, the designed compounds showed antiproliferative activities in micromolar and submicromolar inhibition concentrations.

3D-QSAR, Heteroaromatic Amides

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