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

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Abstract

An experimental search for new benzimidazole derivatives with enhanced antiproliferative activity was successfully guided by QSAR modelling. Robust 3D-QSAR models were derived on an available database of compounds with previously measured activities. Our QSAR analysis revealed that an increase of the antiproliferative activities towards H460, HCT 116, MCF-7 and 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 quarternary amino groups with corresponding aliphatic chains were designed, and their antiproliferative activities were computationally predicted. Using uncatalysed microwave-assisted amination reactions, 14 novel compounds were obtained to assess their antiproliferative activities towards H460, HCT 116, MCF-7, and SW 620 tumour cell lines in vitro. Novel compounds showed antiproliferative activities at micromolar and submicromolar inhibition concentrations. Experimental measurements of antiproliferative activities validation 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.

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Acknowledgements

We greatly appreciate the financial support of the Croatian Science Foundation under the projects: 5596 (Synthesis and cytostatic evaluations of novel nitrogen heterocycles library), 5660 (A multidisciplinary approach to discover selective drugs targeting cancer stem cells: The role of potassium transport—MultiCaST) and IP-2014-09-7309 (SupraCAR).

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Author notes

  1. Darko Vušak and Nataša Perin have contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, 10000, Zagreb, Croatia

    Darko Vušak & Branimir Bertoša

  2. Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, P. O. Box 177, 10000, Zagreb, Croatia

    Nataša Perin, Grace Karminski-Zamola & Marijana Hranjec

  3. Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, P. O. Box 180, 10000, Zagreb, Croatia

    Irena Martin-Kleiner & Marijeta Kralj

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  1. Darko Vušak
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  2. Nataša Perin
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  7. Branimir Bertoša
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Correspondence to Marijana Hranjec or Branimir Bertoša.

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Vušak, D., Perin, N., Martin-Kleiner, I. et al. Synthesis and antiproliferative activity of amino-substituted benzimidazo[1,2-\({\varvec{a}}\)]quinolines as mesylate salts designed by 3D-QSAR analysis. Mol Divers 21, 621–636 (2017). https://doi.org/10.1007/s11030-017-9753-8

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  • DOI: https://doi.org/10.1007/s11030-017-9753-8

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