engleski

Computationally guided search for novel benzimidazole derivatives with enhanced antiproliferative activity

The experimental search for novel benzimidazole derivatives with enhanced antiproliferative activity was successfully guided by QSAR modelling. Robust 3D-QSAR models were derived using available database of the compounds with previously measured activities in the same laboratory, under the same conditions. Using the QSAR analysis of the obtained models, the molecular descriptors with the highest influence on the activity were identified. The QSAR analysis revealed that the antiproliferative activities against four cell lines, H460, HCT 116, MCF-7, and SW 620, 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. Novel amino and diamino substituted benzimidazo[1, 2-a]quinolines with introduced quarter amino groups and aliphatic chains were designed according to the QSAR analysis and their antiproliferative activities were computationally predicted. Using uncatalyzed microwave assisted amination, 14 novel compounds were synthesized and their antiproliferative activities were assessed against H460, HCT 116, MCF-7, and SW 620 tumor cell lines in vitro. Novel compounds showed antiproliferative activities in micromolar and submicromolar inhibition concentrations. Experimental measurements of antiproliferative activities enabled undisputed validation of QSAR models, very good agreement between experimentally measured activities and computational predictions was obtained. Based on the identified molecular descriptors with the highest influence on antiproliferative activity, possible mode of action is proposed.

QSAR ; benzimidazole derivatives ; antiproliferative activity

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