PMID- 34023457 OWN - NLM STAT- MEDLINE DCOM- 20210802 LR - 20210802 IS - 1878-7568 (Electronic) IS - 1742-7061 (Linking) VI - 129 DP - 2021 Jul 15 TI - Development of di-methacrylate quaternary ammonium monomers with antibacterial activity. PG - 138-147 LID - S1742-7061(21)00320-2 [pii] LID - 10.1016/j.actbio.2021.05.012 [doi] AB - Nine antibacterial di-methacrylate monomers based on bis-quaternary ammonium salts (bis-QAMs) were synthesized and structurally characterized. The biological activity of the bis-QAMs was tested in terms of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) on different bacterial strains achieving promising results and, in most cases, a complete bactericidal effect using a bis-QAM concentration lower than 1 mg/mL. Two of the structures showed comparable and superior activity against S. mutans than the commercial monomer 12-methacryloyloxydodecyl pyridinium bromide (MDBP). All the bis-QAMs here described were able to inhibit S. mutans biofilm formation at a concentration equal to the MIC value. From the analysis of the obtained data, some correlation regarding the structure and the antibacterial activity of the bis-QAMs could be drawn: a flexible alkyl C(12) spacer between the two quaternary ammonium moieties increased the monomer antibacterial effect in comparison to the aromatic ones; the equilibrium between hydrophobic and hydrophilic moieties was directly correlated to the bactericidal range of action; the increase of the steric hindrance of the ammonium side groups might be both advantageous or disadvantageous to the antibacterial efficacy depending on the whole monomer chemical structure. Even though the possible correlation between the monomer structures and their bacteriostatic or bactericidal effect is under investigation, the monomers exhibited low cytotoxicity on human dental pulp stem cells, confirming their promising potential in the dental materials' field. STATEMENT OF SIGNIFICANCE: The use of dental resins with antibacterial monomers might prevent the formation of secondary caries at the restoration margins. For this purpose, a series of di-methacrylate bis-quaternary ammonium monomers (QAMs) was developed. Unlike antibacterial mono-methacrylate monomers already described in the literature, the synthesized di-methacrylate monomers have the potential of acting as cross-linkers stabilizing the polymeric network and bear two quaternary ammonium groups that increase their antibacterial ability. The QAMs exert bactericidal activity on both Gram(+) and Gram(-) bacterial strains maintaining at the same time good biocompatibility with the oral environment. Some structural elements of the monomers were clearly related to high antibacterial properties, and this can help design new active structures and better understand their mechanism of action. CI - Copyright (c) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. FAU - Fanfoni, Lidia AU - Fanfoni L AD - University of Trieste, Department of Medical Sciences, Piazza dell'Ospitale 1, 34125, Trieste, Italy. FAU - Marsich, Eleonora AU - Marsich E AD - University of Trieste, Department of Medical Sciences, Via L. Giorgieri 5, 34127, Trieste, Italy. Electronic address: emarsich@units.it. FAU - Turco, Gianluca AU - Turco G AD - University of Trieste, Department of Medical Sciences, Piazza dell'Ospitale 1, 34125, Trieste, Italy. Electronic address: gturco@units.it. FAU - Breschi, Lorenzo AU - Breschi L AD - University of Bologna, Department of Biomedical and Neuromotor Science, Via San Vitale 59, 40125 Bologna, Italy. Electronic address: lorenzo.breschi@unibo.it. FAU - Cadenaro, Milena AU - Cadenaro M AD - University of Trieste, Department of Medical Sciences; Institute for Maternal and Child Health Burlo Garofolo, Via dell'Istria, 65, 34137, Trieste, Italy. Electronic address: mcadenaro@units.it. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210520 PL - England TA - Acta Biomater JT - Acta biomaterialia JID - 101233144 RN - 0 (Ammonium Compounds) RN - 0 (Anti-Bacterial Agents) RN - 0 (Methacrylates) RN - 0 (Quaternary Ammonium Compounds) SB - IM MH - *Ammonium Compounds MH - Anti-Bacterial Agents/pharmacology MH - Biofilms MH - Humans MH - *Methacrylates/pharmacology MH - Quaternary Ammonium Compounds/pharmacology MH - Streptococcus mutans OTO - NOTNLM OT - Antibacterial monomer OT - Cytotoxicity OT - MIC/MBC OT - Structure-activity relationship OT - bis-quaternary ammonium salt OT - di-methacrylate monomer COIS- Declaration of Competing Interest The authors declare to be also the inventors of the patent presenting the structures and activity of the newly synthesized monomers. All authors disclose any financial and personal relationships with other people or organizations that could inappropriately influence (bias) their work. The authors confirm that there has been no significant financial support for this work that could have influenced its outcome. EDAT- 2021/05/24 06:00 MHDA- 2021/08/03 06:00 CRDT- 2021/05/23 20:40 PHST- 2021/01/26 00:00 [received] PHST- 2021/05/07 00:00 [revised] PHST- 2021/05/11 00:00 [accepted] PHST- 2021/05/24 06:00 [pubmed] PHST- 2021/08/03 06:00 [medline] PHST- 2021/05/23 20:40 [entrez] AID - S1742-7061(21)00320-2 [pii] AID - 10.1016/j.actbio.2021.05.012 [doi] PST - ppublish SO - Acta Biomater. 2021 Jul 15;129:138-147. doi: 10.1016/j.actbio.2021.05.012. Epub 2021 May 20.