title: Imidazolidine-4-one derivatives in the search for novel chemosensitizers of Staphylococcus aureus MRSA: synthesis, biological evaluation and molecular modeling studies.
abstract: A series of amine derivatives of 5-aromatic imidazolidine-4-ones (7-19), representing three subgroups: piperazine derivatives of 5-arylideneimidazolones (7-13), piperazine derivatives of 5-arylideneimidazolidine-2,4-dione (14-16) and primary amines of 5-naphthyl-5-methylimidazolidine-2,4-diones (17-19), was evaluated for their ability to improve antibiotics effectiveness in two strains of Gram-positive Staphylococcus aureus: ATCC 25923 (a reference strain) and MRSA (methicillin resistant S. aureus) HEMSA 5 (a resistant clinical isolate). The latter compounds (17-19) were obtained by 4-step synthesis using Bucherer-Bergs condensation, two-phase bromoalkylation and Gabriel reactions. The naphthalen derivative: (Z)-5-(naphthalen-2-ylmethylene)-2-(piperazin-1-yl)-3H-imidazol-4(5H)-one (10) was the most potent in combination with β-lactam antibiotics and ciprofloxacin against the resistant strain. The high potency to increase efficacy of oxacillin was noted for (Z)-5-(anthracen-10-ylmethylene)-2-(piperazin-1-yl)-3H-imidazol-4(5H)one (12) too. In order to explain the mechanism of action of the compounds 10 and 12, docking studies with the use of crystal structures of a penicillin binding protein (PBP2a) and MecR1 were carried out. Their outcomes suggested that the most probable mechanism of action of the active compounds is the interaction with MecR1. Molecular dynamic experiments performed for the active compounds and compound 13 (structurally similar to 12) supported this hypothesis and provided possible explanation of activity dependencies of the tested compounds in terms of the restoration of antibiotic efficacy in S. aureus MRSA HEMSA 5.
authors.affiliation: Department of Technology and Biotechnology of Drugs Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Matys
authors.affiliation: Department of Medicinal Chemistry Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland; Faculty of Chemistry Jagiellonian University, Ingardena 3, PL 30-060 Kraków, Poland.
authors.forename: Sabina
authors.initials: S
authors.lastname: Podlewska
authors.affiliation: Department of Technology and Biotechnology of Drugs Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Witek
authors.affiliation: Department of Medicinal Chemistry Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland.
authors.forename: Jagna
authors.initials: J
authors.lastname: Witek
authors.affiliation: Department of Medicinal Chemistry Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland.
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Bojarski
authors.affiliation: Department of Technology and Biotechnology of Drugs Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Schabikowski
authors.affiliation: Department of Technology and Biotechnology of Drugs Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Otrębska-Machaj
authors.affiliation: Department of Technology and Biotechnology of Drugs Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
authors.forename: Gniewomir
authors.initials: G
authors.lastname: Latacz
authors.affiliation: Department of Technology and Biotechnology of Drugs Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Szymańska
authors.affiliation: Department of Technology and Biotechnology of Drugs Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kieć-Kononowicz
authors.affiliation: Institute of Medical Microbiology and Immunobiology, University of Szeged, Szeged, Hungary.
authors.forename: Joseph
authors.initials: J
authors.lastname: Molnar
authors.affiliation: Travel Medicine of the Centro de Malaria & Otra Doencas Tropicais (CMDT), Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Rua da Junqueira 100, 1349-008 Lisbon, Portugal.
authors.forename: Leonard
authors.initials: L
authors.lastname: Amaral
authors.affiliation: Department of Technology and Biotechnology of Drugs Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland. Electronic address: j.handzlik@uj.edu.pl.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Handzlik
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D048289:Imidazolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D048289:Imidazolidines
keywords: Arylideneimidazolidine-2,4-dione; Arylideneimidazolone; MRSA; MecR1; Naphthylhydantoin; PBP2a; Staphylococcus aureus