5-Arylideneimidazolones with Amine at Position 3 as Potential Antibiotic Adjuvants against Multidrug Resistant Bacteria.
Aneta Kaczor, Karolina Witek, Sabina Podlewska, Joanna Czekajewska, Annamaria Lubelska, Ewa Żesławska, Wojciech Nitek, Gniewomir Latacz, Sandrine Alibert, Jean-Marie Pagès, Elżbieta Karczewska, Katarzyna Kieć-Kononowicz, Jadwiga Handzlik
Author Information
Aneta Kaczor: Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, 30-688 Cracow, Poland. aneta.kaczor@student.uj.edu.pl.
Karolina Witek: Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, 30-688 Cracow, Poland. karolina.witek@uj.edu.pl.
Sabina Podlewska: Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, 30-688 Cracow, Poland. smusz@if-pan.krakow. ORCID
Joanna Czekajewska: Department of Pharmaceutical Microbiology; Jagiellonian University, Medical College, Medyczna 9, 30-688 Cracow, Poland. j.czekajewska@uj.edu.pl.
Annamaria Lubelska: Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, 30-688 Cracow, Poland. annamarialubelska@outlook.com.
Ewa Żesławska: Department of Chemistry, Institute of Biology, Pedagogical University of Cracow, Podchorążych 2, 30-084 Cracow, Poland. ewa.zeslawska@up.krakow.pl. ORCID
Wojciech Nitek: Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Cracow, Poland. nitek@chemia.uj.edu.pl.
Gniewomir Latacz: Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, 30-688 Cracow, Poland. glatacz@cm-uj.krakow.pl. ORCID
Sandrine Alibert: Aix Marseille Univ, INSERM, SSA, MCT, FAC PHARM, 27 Bd Jean Moulin, 13005 Marseille, France. sandrine.alibert@univ-amu.fr. ORCID
Jean-Marie Pagès: Aix Marseille Univ, INSERM, SSA, MCT, FAC PHARM, 27 Bd Jean Moulin, 13005 Marseille, France. Jean-Marie.PAGES@univ-amu.fr.
Elżbieta Karczewska: Department of Pharmaceutical Microbiology; Jagiellonian University, Medical College, Medyczna 9, 30-688 Cracow, Poland. elzbieta.karczewska@uj.edu.pl.
Katarzyna Kieć-Kononowicz: Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, 30-688 Cracow, Poland. mfkonono@cyf-kr.edu.pl.
Jadwiga Handzlik: Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, 30-688 Cracow, Poland. j.handzlik@uj.edu.pl.
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.
