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

Ewa Żesławska (1) , Aneta Kaczor (2) , Karolina Witek (3, 2) , Sabina Podlewska (2) , Joanna Czekajewska (4) , Annamaria Lubelska (2) , Wojciech Nitek (5) , Gniewomir Latacz , Sandrine Alibert (6) , Jean-Marie Pagès (6) , Elżbieta Karczewska (7) , Katarzyna Kieć-Kononowicz (2) , Jadwiga Handzlik (2)

1 Faculty of Chemistry - Jagiellonian University
2 Department of Technology and Biotechnology of Drugs
3 Jagiellonian University - Medical College
4 Department of Pharmaceutical Microbiology, Jagiellonian
5 Faculty of Chemistry
6 MCT - Membranes et cibles thérapeutiques
7 UJ - Uniwersytet Jagielloński w Krakowie = Jagiellonian University

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 (6) were performed. New compounds (7-17), with fused aromatic rings at position 5, were designed and synthesized. Crystallographic X-ray analysis proved that the final compounds (7-17) 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 Enterobacter aerogenes (EA289) were investigated in the real-time efflux (RTE) assay. Docking and molecular dynamics were applied to estimate an interaction of compounds 6-17 with penicillin binding protein (PBP2a). In vitro ADME-Tox properties were evaluated for compound 9. Most of the tested compounds reduced significantly (4-32-fold) oxacillin MIC in highly resistant MRSA HEMSA 5 strain. The anthracene-morpholine derivative (16) was the most potent (32-fold reduction). The tested compounds displayed significant EPI properties during RTE assay (37-97%). The naphthyl-methylpiperazine derivative 9 showed the most potent "dual action" of both oxacillin adjuvant (MRSA) and EPI (E. aerogenes). Molecular modeling results suggested the allosteric mechanism of action of the imidazolones, which improved binding of oxacillin in the PBP2a active site in MRSA.

Mots clés: multi-drug resistance; Efflux pump; MRSA; Staphylococcus aureus; Enterobacter aerogenes; 5-arylideneimidazolones; microdilution assays; RTE studies; allosteric modulation; ADMET in vitro

Domaines: Sciences du Vivant [q-bio]; Chimie

Ewa Żesławska, Aneta Kaczor, Karolina Witek, Sabina Podlewska, Joanna Czekajewska, et al.. molecules 5-Arylideneimidazolones with Amine at Position 3 as Potential Antibiotic Adjuvants against Multidrug Resistant Bacteria. Molecules, 2019, 24 (3), pp.438. ⟨10.3390/molecules24030438⟩. ⟨hal-02640618⟩