5-Arylideneimidazolones with Amine at Position 3 as Potential Antibiotic Adjuvants against Multidrug Resistant Bacteria

Searching for new chemosensitizers of bacterial multidrug resistance (MDR), chemical modifications of (Z)-5-(4-chlorobenzylidene)-2-(4-methylpiperazin-1-yl)-3H-imidazol-4(5H)-one ( ) were performed. New compounds ( ⁻ ), with fused aromatic rings at position 5, were designed and synthesized. Crystallographic X-ray analysis proved that the final compounds ( ⁻ ) were substituted with tertiary amine-propyl moiety at position 3 and primary amine group at 2 due to intramolecular Dimroth rearrangement. New compounds were evaluated on their antibiotic adjuvant properties in either Gram-positive or Gram-negative bacteria. Efflux pump inhibitor (EPI) properties towards the AcrAB-TolC pump in (EA289) were investigated in the real-time efflux (RTE) assay. Docking and molecular dynamics were applied to estimate an interaction of compounds ⁻ with penicillin binding protein (PBP2a). In vitro ADME-Tox properties were evaluated for compound . Most of the tested compounds reduced significantly (4-32-fold) oxacillin MIC in highly resistant MRSA HEMSA 5 strain. The anthracene-morpholine derivative ( ) was the most potent (32-fold reduction). The tested compounds displayed significant EPI properties during RTE assay (37⁻97%). The naphthyl-methylpiperazine derivative showed the most potent "dual action" of both oxacillin adjuvant (MRSA) and EPI ( ). Molecular modeling results suggested the allosteric mechanism of action of the imidazolones, which improved binding of oxacillin in the PBP2a active site in MRSA.