title: Synthesis, antimicrobial evaluation and molecular modeling of 5-hydroxyisoquinolinium salt series; the effect of the hydroxyl moiety.
abstract: In the present paper, we describe the synthesis of a new group of 5-hydroxyisoquinolinium salts with different lengths of alkyl side-chain (C10-C18), and their chromatographic analysis and biological assay for in vitro activity against bacterial and fungal strains. We compare the lipophilicity and efficacy of hydroxylated isoquinolinium salts with the previously published (non-hydroxylated) isoquinolinium salts from the point of view of antibacterial and antifungal versatility and cytotoxic safety. Compound 11 (C18) had to be excluded from the testing due to its low solubility. Compounds 9 and 10 (C14, C16) showed only moderate efficacy against G+ bacteria, notably with excellent potency against Staphyloccocus aureus, but no effect against G- bacteria. In contrast, non-hydroxylated isoquinolinium salts showed excellent antimicrobial efficacy within the whole series, particularly 14 (C14) against G+ strains and 15 (C16) against fungi. The electronic properties and desolvation energies of 5-hydroxyisoquinolinium and isoquinolinium salts were studied by quantum-chemistry calculations employing B3LYP/6-311++G(d,p) method and an implicit water-solvent simulation model (SCRF). Despite the positive mesomeric effect of the hydroxyl moiety reducing the electron density of the quaternary nitrogen, it is probably the higher lipophilicity and lower desolvation energy of isoquinolinium salts, which is responsible for enhanced antimicrobial versatility and efficacy.
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. Electronic address: ondrej.soukup@fnhk.cz.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Soukup
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; Center for Basic and Applied Research, Faculty of Informatics and Management, University of Hradec Kralove, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic.
authors.forename: Rafael
authors.initials: R
authors.lastname: Dolezal
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; Department of Cybernetics and Biomedical Engineering, Faculty of Electrical Engineering and Computer Science, VSB-Technical University of Ostrava, 17. Listopadu 15, 708 33 Ostrava-Poruba, Czech Republic.
authors.forename: David
authors.initials: D
authors.lastname: Malinak
authors.affiliation: Department of Epidemiology, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic; Department of Surgical Studies, Faculty of Medicine, University of Ostrava, Syllabova 19, 700 30 Ostrava, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Marek
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
authors.forename: Sarka
authors.initials: S
authors.lastname: Salajkova
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; Department of Epidemiology, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
authors.forename: Marketa
authors.initials: M
authors.lastname: Pasdiorova
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Honegr
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Korabecny
authors.affiliation: Department of Biological and Medical Sciences, Faculty of Pharmacy, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Nachtigal
authors.affiliation: Departement de Toxicologie et Risque Chimique, Institut de Recherche Biomédicale des Armées, BP73, F-91223 Brétigny-sur-Orge, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Nachon
authors.affiliation: Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
authors.forename: Daniel
authors.initials: D
authors.lastname: Jun
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D005658:Fungi / Q000187:drug effects / Q000254:growth & development; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000254:growth & development; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000254:growth & development; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D011789:Quantum Theory; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D007546:Isoquinolines
keywords: 5-Hydroxyisoquinolinium salts; Antimicrobial activity; Isoquinolinium salts; Lipophilicity; Synthesis