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

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. Three groups of amine derivatives of 5-aromatic imidazolidine-4-one (A-C) were tested for their potency to improve antibiotic efficacy against resistant strains of Staphylococcus aureus. Synthesis, docking and SAR-studies were performed. [Display omitted] •Three groups of amine derivatives of 5-aromatic imidazolidine-4-one were investigated.•New primary amines of 5-aromatic imidazolidine-2,4-diones were synthesized.•Compound's ability to improve efficacy of antibiotics against MRSA strain was tested.•New compounds able to overcome antibiotic resistance of MRSA were developed.•Docking and molecular dynamics study on compound's mechanism of action was performed.