title: Evaluation of the toxicity of 5-aryl-2-aminoimidazole-based biofilm inhibitors against eukaryotic cell lines, bone cells and the nematode Caenorhabditis elegans.
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.
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), Department of Microbial and Molecular Systems, KU Leuven, Kasteelpark Arenberg 20, Box 2460, B-3001 Leuven, Belgium. Hans.Steenackers@biw.kuleuven.be.
authors.forename: Hans
authors.initials: H
authors.lastname: Steenackers
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), Department of Microbial and Molecular Systems, KU Leuven, Kasteelpark Arenberg 20, Box 2460, B-3001 Leuven, Belgium.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Dubey
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), Department of Microbial and Molecular Systems, KU Leuven, Kasteelpark Arenberg 20, Box 2460, B-3001 Leuven, Belgium.
authors.forename: Stijn
authors.initials: S
authors.lastname: Robijns
authors.affiliation: Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium.
authors.forename: Denis
authors.initials: D
authors.lastname: Ermolat'ev
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), Department of Microbial and Molecular Systems, KU Leuven, Kasteelpark Arenberg 20, Box 2460, B-3001 Leuven, Belgium.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Delattin
authors.affiliation: Educell, Prevale 9, B-1236 Trzin, Slovenia.
authors.forename: Barbara
authors.initials: B
authors.lastname: Dovgan
authors.affiliation: CELL/TRY Ltd., Levičnikova 34, B-8310 Šentjernej, Slovenia.
authors.forename: Lenart
authors.initials: L
authors.lastname: Girandon
authors.affiliation: Educell, Prevale 9, B-1236 Trzin, Slovenia.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Fröhlich
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), Department of Microbial and Molecular Systems, KU Leuven, Kasteelpark Arenberg 20, Box 2460, B-3001 Leuven, Belgium.
authors.forename: Katrijn
authors.initials: K
authors.lastname: De Brucker
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), Department of Microbial and Molecular Systems, KU Leuven, Kasteelpark Arenberg 20, Box 2460, B-3001 Leuven, Belgium.
authors.forename: Bruno P A
authors.initials: BP
authors.lastname: Cammue
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), Department of Microbial and Molecular Systems, KU Leuven, Kasteelpark Arenberg 20, Box 2460, B-3001 Leuven, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Thevissen
authors.affiliation: Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Department of Microbiology and Immunology, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.affiliation: Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium.
authors.forename: Erik V
authors.initials: EV
authors.lastname: Van der Eycken
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), Department of Microbial and Molecular Systems, KU Leuven, Kasteelpark Arenberg 20, Box 2460, B-3001 Leuven, Belgium.
authors.forename: Jozef
authors.initials: J
authors.lastname: Vanderleyden
mesh_terms: D000818:Animals; D018441:Biofilms / Q000187:drug effects*; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000254:growth & development*; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054697:Cytostatic Agents / Q000494:pharmacology; D005057:Eukaryotic Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects* / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D054697:Cytostatic Agents; D007093:Imidazoles; C014973:2-aminoimidazole