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Molecules 2018, 23(5), 1212; https://doi.org/10.3390/molecules23051212

Novel Imidazole Aldoximes with Broad-Spectrum Antimicrobial Potency against Multidrug Resistant Gram-Negative Bacteria

1
Department of Biology, Faculty of Science, University of Split, R. Boškovića 33, HR-21 000 Split, Croatia
2
Department of Chemistry, Faculty of Science, University of Split, R. Boškovića 33, HR-21 000 Split, Croatia
3
Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, HR-10 000 Zagreb, Croatia
Present Address: Cargill Food Ingredients & Bio-Industrial, Cargill 84 Havenstraat, Vilvoorde, Vlaams-Brabant 1800, Belgium.
*
Authors to whom correspondence should be addressed.
Received: 3 April 2018 / Revised: 7 May 2018 / Accepted: 16 May 2018 / Published: 18 May 2018
(This article belongs to the Section Medicinal Chemistry)
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Abstract

In the search for a new class of potential antimicrobial agents, five novel N-substituted imidazole 2-aldoximes and their six quaternary salts were evaluated. The antimicrobial activity was assessed against a panel of representative Gram-positive and Gram-negative bacteria, including multidrug resistant bacteria. All compounds demonstrated potent in vitro activity against the tested microorganisms, with MIC values ranging from 6.25 to 50.0 μg/mL. Among the tested compounds, two quaternary compounds (N-but-3-enyl- and meta- (10) or para- N-chlorobenzyl (11) imidazolium 2-aldoximes) displayed the most potent and broad-spectrum activity against both Gram-positive and Gram-negative bacterial strains. The broth microdilution assay was also used to investigate the antiresistance efficacy of the both most active compounds against a set of Enterobacteriaceae isolates carried a multiple extended-spectrum β-lactamases (ESBLs) in comparison to eight clinically relevant antibiotics. N-but-3-enyl-N-meta-chlorobenzyl imidazolium 2-aldoxime was found to possess promising antiresistance efficacy against a wide range of β-lactamases producing strains (MIC 2.0 to 16.0 μg/mL). Best results for that compound were obtained against Escherichia coli and Enterobacter cloacae producing multiple β-lactamases form A and C molecular classes, which were 32- and 128-fold more potent than ceftazidime and cefotaxime, respectively. To visualize the results, principal component analysis was used as an additional classification tool. The mixture of ceftazidime and compound 10 (3 μg:2 μg) showed a strong activity and lower the necessary amount (up to 40-fold) of 10 against five of ESBL-producing isolates (MIC ≤ 1 µg/mL). View Full-Text
Keywords: imidazole 2-aldoximes; quaternary imidazolium salts; antimicrobial activity; extended-spectrum β-lactamase (ESBL); multivariate analysis; multidrug resistance imidazole 2-aldoximes; quaternary imidazolium salts; antimicrobial activity; extended-spectrum β-lactamase (ESBL); multivariate analysis; multidrug resistance
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Skočibušić, M.; Odžak, R.; Ramić, A.; Smolić, T.; Hrenar, T.; Primožič, I. Novel Imidazole Aldoximes with Broad-Spectrum Antimicrobial Potency against Multidrug Resistant Gram-Negative Bacteria. Molecules 2018, 23, 1212.

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