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Molecules 2014, 19(10), 16707-16723; doi:10.3390/molecules191016707

Evaluation of the Toxicity of 5-Aryl-2-Aminoimidazole-Based Biofilm Inhibitors against Eukaryotic Cell Lines, Bone Cells and the Nematode Caenorhabditis elegans

1
Centre of Microbial and Plant Genetics (CMPG), Department of Microbial and Molecular Systems, KU Leuven, Kasteelpark Arenberg 20, Box 2460, B-3001 Leuven, Belgium
2
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
3
Educell, Prevale 9, B-1236 Trzin, Slovenia
4
Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Department of Microbiology and Immunology, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
5
CELL/TRY Ltd., Levičnikova 34, B-8310 Šentjernej, Slovenia
6
Department of Biochemistry, Molecular and Structural Biology, Jožef Stefan Institute, Jamova 39, B-1000 Ljubljana, Slovenia
7
Department of Plant Systems Biology, VIB, Technologiepark 927, 9052 Ghent, Belgium
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 10 July 2014 / Revised: 22 August 2014 / Accepted: 15 September 2014 / Published: 16 October 2014
(This article belongs to the Section Medicinal Chemistry)
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Abstract

Previously, we have synthesized several series of compounds based on the 5-aryl-2-aminoimidazole scaffold, which showed a preventive activity against microbial biofilms. We here studied the cytotoxicity of the most active compounds of each series. First, the cytostatic activity was investigated against a number of tumor cell lines (L1210, CEM and HeLa). A subset of monosubstituted 5-aryl-2-aminoimidazoles showed a moderate safety window, with therapeutic indices (TIs) ranging between 3 and 20. Whereas introduction of a (cyclo-)alkyl chain at the N1-position strongly reduced the TI, introduction of a (cyclo-)alkyl chain or a triazole moiety at the 2N-position increased the TI up to 370. Since a promising application of preventive anti-biofilm agents is their use in anti-biofilm coatings for orthopedic implants, their effects on cell viability and functional behavior of human osteoblasts and bone marrow derived mesenchymal stem cells were tested. The 2N-substituted 5-aryl-2-aminoimidazoles consistently showed the lowest toxicity and allowed survival of the bone cells for up to 4 weeks. Moreover they did not negatively affect the osteogenic differentiation potential of the bone cells. Finally, we examined the effect of the compounds on the survival of Caenorhabditis elegans, which confirmed the higher safety window of 2N-substituted 5-aryl-2-aminoimidazoles. View Full-Text
Keywords: 5-aryl-2-aminoimidazole; biofilm inhibitor; toxicity; tumor cell lines; bone cells; Caenorhabditis elegans 5-aryl-2-aminoimidazole; biofilm inhibitor; toxicity; tumor cell lines; bone cells; Caenorhabditis elegans
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Steenackers, H.; Dubey, A.; Robijns, S.; Ermolat'ev, D.; Delattin, N.; Dovgan, B.; Girandon, L.; Fröhlich, M.; De Brucker, K.; Cammue, B.P.A.; Thevissen, K.; Balzarini, J.; Van der Eycken, E.V.; Vanderleyden, J. Evaluation of the Toxicity of 5-Aryl-2-Aminoimidazole-Based Biofilm Inhibitors against Eukaryotic Cell Lines, Bone Cells and the Nematode Caenorhabditis elegans. Molecules 2014, 19, 16707-16723.

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