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Eco-friendly synthesis, in vitro anti-proliferative evaluation, and 3D-QSAR analysis of a novel series of monocationic 2-aryl/heteroaryl-substituted 6-(2-imidazolinyl)benzothiazole mesylates

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Abstract

Abstract

Herein, we describe the synthesis of twenty-one novel water-soluble monocationic 2-aryl/heteroaryl-substituted 6-(2-imidazolinyl)benzothiazole mesylates 3a–3u and present the results of their anti-proliferative assays. Efficient syntheses were achieved by three complementary simple two-step synthetic protocols based on the condensation reaction of aryl/heteroaryl carbaldehydes or carboxylic acid. We developed an eco-friendly synthetic protocol using glycerol as green solvent, particularly appropriate for the condensation of thermally and acid-sensitive heterocycles such as furan, benzofuran, pyrrole, and indole. Screening of anti-proliferative activity was performed on four human tumour cell lines in vitro including pancreatic cancer (CFPAC-1), metastatic colon cancer (SW620), hepatocellular carcinoma (HepG2), and cervical cancer (HeLa), as well as in normal human fibroblast cell lines. All tested compounds showed strong to moderate anti-proliferative activity on tested cell lines depending on the structure containing aryl/heteroaryl moiety coupled to 6-(2-imidazolinyl)benzothiazole moiety. The most potent cytostatic effects on all tested cell lines with \(\hbox {IC}_{50}\) values ranging from 0.1 to 3.70 \(\upmu \hbox {M}\) were observed for benzothiazoles substituted with naphthalene-2-yl 3c, benzofuran-2-yl 3e, indole-3-yl 3j, indole-2-yl 3k, quinoline-2-yl 3s, and quinoline-3-yl 3t and derivatives substituted with phenyl 3a, naphthalene-1-yl 3b, benzothiazole-2-yl 3g, benzothiazole-6-yl 3h, N-methylindole-3-yl 3l, benzimidazole-2-yl 3n, benzimidazole-5(6)-yl 3o, and quinolone-4-yl 3u with \(\hbox {IC}_{50}\) values ranging from 1.1 to 29.1 \(\upmu \hbox {M}\). Based on obtained anti-proliferative activities, 3D-QSAR models for five cell lines were derived. Molecular volume, molecular surface, the sum of hydrophobic surface areas, molecular mass, and possibility of making dispersion forces were identified by QSAR analyses as molecular properties that are positively correlated with anti-proliferative activity, while compound’s capability to accept H-bond was identified as a negatively correlated property. Comparison of molecular properties identified for different cell lines enabled assumptions about similarity of mode of action through which anti-proliferative activities against different cell lines are accomplished. Novel compounds that are predicted to have enhanced activities in comparison with herein presented ones were designed using 3D-QSAR analysis as guideline.

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Acknowledgements

This work has been supported by Croatian Science Foundation under the Project HRRZ-IP-2013-11-5596 (Synthesis and cytostatic evaluations of novel nitrogen heterocycles library). We greatly acknowledge the support of University of Rijeka research Grant 13.11.1.1.11 and the project “Research Infrastructure for Campus-based Laboratories at University of Rijeka”, co-financed by European Regional Development Fund (ERDF).

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Authors and Affiliations

  1. Department of Applied Chemistry, Faculty of Textile Technology, University of Zagreb, Prilaz baruna Filipovića 28a, 10000, Zagreb, Croatia

    Livio Racané & Lucija Ptiček

  2. Department of Biotechnology, Centre for High-Throughput Technologies, University of Rijeka, Radmile Matejčić 2, 51000, Rijeka, Croatia

    Mirela Sedić, Petra Grbčić & Sandra Kraljević Pavelić

  3. Division of Physical Chemistry, Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102A, 10000, Zagreb, Croatia

    Branimir Bertoša

  4. Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, 10000, Zagreb, Croatia

    Irena Sović & Grace Karminski-Zamola

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  1. Livio Racané
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Correspondence to Livio Racané or Sandra Kraljević Pavelić.

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Racané, L., Ptiček, L., Sedić, M. et al. Eco-friendly synthesis, in vitro anti-proliferative evaluation, and 3D-QSAR analysis of a novel series of monocationic 2-aryl/heteroaryl-substituted 6-(2-imidazolinyl)benzothiazole mesylates. Mol Divers 22, 723–741 (2018). https://doi.org/10.1007/s11030-018-9827-2

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