Imidazolidine-4-one derivatives in the search for novel chemosensitizers of Staphylococcus aureus MRSA: Synthesis, biological evaluation and molecular modeling studies

Anna Matys, Sabina Podlewska, Karolina Witek, Jagna Witek, Andrzej J. Bojarski, Jakub Schabikowski, Ewa Otrębska-Machaj, Gniewomir Latacz, Ewa Szymańska, Katarzyna Kieć-Kononowicz, Joseph Molnar, Leonard Amaral, Jadwiga Handzlik

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number7940
Pages (from-to)313-325
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume101
DOIs
Publication statusPublished - Jul 7 2015

Keywords

  • Arylideneimidazolidine-2,4-dione
  • Arylideneimidazolone
  • MRSA
  • MecR1
  • Naphthylhydantoin
  • PBP2a
  • Staphylococcus aureus

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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    Matys, A., Podlewska, S., Witek, K., Witek, J., Bojarski, A. J., Schabikowski, J., Otrębska-Machaj, E., Latacz, G., Szymańska, E., Kieć-Kononowicz, K., Molnar, J., Amaral, L., & Handzlik, J. (2015). Imidazolidine-4-one derivatives in the search for novel chemosensitizers of Staphylococcus aureus MRSA: Synthesis, biological evaluation and molecular modeling studies. European Journal of Medicinal Chemistry, 101, 313-325. [7940]. https://doi.org/10.1016/j.ejmech.2015.06.013