title: Synthesis and structure-activity relationship of amidine derivatives of 3,4-ethylenedioxythiophene as novel antibacterial agents.
abstract: Current antibacterial chemotherapeutics are facing an alarming increase in bacterial resistance pressuring the search for novel agents that would expand the available therapeutic arsenal against resistant bacterial pathogens. In line with these efforts, a series of 9 amidine derivatives of 3,4-ethylenedioxythiophene were synthesized and, together with 18 previously synthesized analogs, evaluated for their relative DNA binding affinity, in vitro antibacterial activities and preliminary in vitro safety profile. Encouraging antibacterial activity of several subclasses of tested amidine derivatives against Gram-positive (including resistant MRSA, MRSE, VRE strains) and Gram-negative bacterial strains was observed. The bis-phenyl derivatives were the most antibacterially active, while compound 19 from bis-benzimidazole class exhibited the widest spectrum of activity (with MIC of 4, 2, 0.5 and ≤0.25 μg/ml against laboratory strains of Staphyloccocus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Moraxella catarrhalis, respectively and 4-32 μg/ml against clinical isolates of sensitive and resistant S. aureus, Staphylococcus epidermidis and Enterococcus faecium) and also demonstrated the strongest DNA binding affinity (ΔTm of 15.4 °C). Asymmetrically designed compounds and carboxamide-amidines were, in general, less active. Molecular docking indicated that the shape of the 3,4-ethylenedioxythiophene derivatives and their ability to form multiple electrostatic and hydrogen bonds with DNA, corresponds to the binding modes of other minor-groove binders. Herein reported results encourage further investigation of this class of compounds as novel antibacterial DNA binding agents.
authors.affiliation: University of Zagreb, Faculty of Veterinary Medicine, Department of Chemistry and Biochemistry, Heinzelova 55, 10000 Zagreb, Croatia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Stolić
authors.affiliation: University of Zagreb School of Medicine, Center for Translational and Clinical Research, Department for Intercellular Communication, Šalata 2, 10000 Zagreb, Croatia.
authors.forename: Hana
authors.initials: H
authors.lastname: Čipčić Paljetak
authors.affiliation: University of Zagreb School of Medicine, Center for Translational and Clinical Research, Department for Intercellular Communication, Šalata 2, 10000 Zagreb, Croatia. Electronic address: mihaela.peric@mef.hr.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Perić
authors.affiliation: University of Zagreb School of Medicine, Center for Translational and Clinical Research, Department for Intercellular Communication, Šalata 2, 10000 Zagreb, Croatia.
authors.forename: Mario
authors.initials: M
authors.lastname: Matijašić
authors.affiliation: Rudjer Bošković Institute, Division of Molecular Medicine, Laboratory for Epigenomics, Bijenička 54, 10000 Zagreb, Croatia.
authors.forename: Višnja
authors.initials: V
authors.lastname: Stepanić
authors.affiliation: University of Zagreb School of Medicine, Center for Translational and Clinical Research, Department for Intercellular Communication, Šalata 2, 10000 Zagreb, Croatia.
authors.forename: Donatella
authors.initials: D
authors.lastname: Verbanac
authors.affiliation: University of Zagreb, Faculty of Veterinary Medicine, Department of Chemistry and Biochemistry, Heinzelova 55, 10000 Zagreb, Croatia. Electronic address: mbajic@vef.hr.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Bajić
mesh_terms: D000578:Amidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000601652:3,4-ethylenedioxythiophene; D000578:Amidines; D000900:Anti-Bacterial Agents; D013876:Thiophenes
keywords: Amidine; Antibacterial activity; DNA binding; Minimum inhibitory concentration; Minor groove binders; Thiophene