{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T17:53:32Z","timestamp":1788630812291,"version":"build-2803163510"},"reference-count":37,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2018,5,18]],"date-time":"2018-05-18T00:00:00Z","timestamp":1526601600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004488","name":"Hrvatska Zaklada za Znanost","doi-asserted-by":"publisher","award":["IP-2016-06-3775"],"award-info":[{"award-number":["IP-2016-06-3775"]}],"id":[{"id":"10.13039\/501100004488","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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 \u03bcg\/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 \u03b2-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 \u03b2-lactamases producing strains (MIC 2.0 to 16.0 \u03bcg\/mL). Best results for that compound were obtained against Escherichia coli and Enterobacter cloacae producing multiple \u03b2-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 \u03bcg:2 \u03bcg) showed a strong activity and lower the necessary amount (up to 40-fold) of 10 against five of ESBL-producing isolates (MIC \u2264 1 \u00b5g\/mL).<\/jats:p>","DOI":"10.3390\/molecules23051212","type":"journal-article","created":{"date-parts":[[2018,5,21]],"date-time":"2018-05-21T04:07:30Z","timestamp":1526875650000},"page":"1212","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Novel Imidazole Aldoximes with Broad-Spectrum Antimicrobial Potency against Multidrug Resistant Gram-Negative Bacteria"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4645-4513","authenticated-orcid":false,"given":"Mirjana","family":"Sko\u010dibu\u0161i\u0107","sequence":"first","affiliation":[{"name":"Department of Biology, Faculty of Science, University of Split, R. Bo\u0161kovi\u0107a 33, HR-21 000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2325-464X","authenticated-orcid":false,"given":"Renata","family":"Od\u017eak","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, University of Split, R. Bo\u0161kovi\u0107a 33, HR-21 000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6003-7241","authenticated-orcid":false,"given":"Alma","family":"Rami\u0107","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, HR-10 000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomislav","family":"Smoli\u0107","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, HR-10 000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomica","family":"Hrenar","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, HR-10 000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ines","family":"Primo\u017ei\u010d","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, HR-10 000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,5,18]]},"reference":[{"key":"ref_1","unstructured":"(2017). The Global Risks Report 2017, World Economic Forum. [12th ed.]."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1093\/cid\/cit152","article-title":"10 \u00d7 \u203220 Progress\u2014development of new drugs active against gram-negative bacilli: An update from the Infectious Diseases Society of America","volume":"56","author":"Boucher","year":"2013","journal-title":"Clin. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1128\/AAC.01009-09","article-title":"Updated functional classification of beta-lactamases","volume":"54","author":"Bush","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.mib.2006.08.011","article-title":"The CTX-M beta-lactamase pandemic","volume":"9","author":"Canton","year":"2006","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1128\/CMR.00037-09","article-title":"Three Decades of \u03b2-Lactamase Inhibitors","volume":"23","author":"Drawz","year":"2010","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1128\/AAC.00756-10","article-title":"Activities of NXL104 Combinations with Ceftazidime and Aztreonam against Carbapenemase-Producing Enterobacteriaceae","volume":"55","author":"Livermore","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2434","DOI":"10.1128\/AAC.01722-10","article-title":"Activity of NXL104 in Combination with \u03b2-Lactams against Genetically Characterized Escherichia coli and Klebsiella pneumoniae Isolates Producing Class A Extended-Spectrum \u03b2-Lactamases and Class C \u03b2-Lactamases","volume":"55","author":"Tailor","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1002\/med.21290","article-title":"Comprehensive review in current developments of imidazole-based medicinal chemistry","volume":"34","author":"Zhang","year":"2014","journal-title":"Med. Res. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"409","DOI":"10.2174\/1389557053544047","article-title":"Imidazole and benzimidazole derivatives as chemotherapeutic agents","volume":"5","author":"Boiani","year":"2005","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_10","first-page":"1","article-title":"Naturally occurring and synthetic imidazoles: Their chemistry and their biological activities","volume":"13","year":"2006","journal-title":"Curr. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s00044-015-1495-5","article-title":"Development of drugs based on imidazole and benzimidazole bioactive heterocycles: Recent advances and future directions","volume":"25","author":"Gaba","year":"2016","journal-title":"Med. Chem. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.ejmech.2015.12.013","article-title":"Imidazole-based pinanamine derivatives: Discovery of dual inhibitors of the wild-type and drug-resistant mutant of the influenza A virus","volume":"108","author":"Dong","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/978-1-4939-6515-1_5","article-title":"Systemic Antifungal Agents: Current Status and Projected Future Developments","volume":"1508","author":"Seyedmousavi","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1128\/JB.01047-13","article-title":"Response to Metronidazole and Oxidative Stress Is Mediated through Homeostatic Regulator HsrA (HP1043) in Helicobacter pylori","volume":"196","author":"Olekhnovich","year":"2014","journal-title":"J. Bacteriol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"12544","DOI":"10.1021\/ja051528c","article-title":"A Solid State 13C NMR, Crystallographic, and Quantum Chemical Investigation of Chemical Shifts and Hydrogen Bonding in Histidine Dipeptides","volume":"127","author":"Cheng","year":"2005","journal-title":"J. Am. Chem. Soc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6095","DOI":"10.1021\/jm0702433","article-title":"Discovery of potent & selective inhibitors of activated thrombin-activatable fibrinolysis inhibitor for the treatment of thrombosis","volume":"50","author":"Bunnage","year":"2007","journal-title":"J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.ejmech.2015.04.003","article-title":"Novel imidazole derivatives as heme oxygenase-1 (HO-1) and heme oxygenase-2 (HO-2) inhibitors and their cytotoxic activity in human-derived cancer cell lines","volume":"96","author":"Salerno","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1021\/np400099m","article-title":"Anti-inflammatory and antinociceptive activity of epiisopiloturine, an imidazole alkaloid isolated from Pilocarpus microphyllus","volume":"76","author":"Silva","year":"2013","journal-title":"J. Nat. Prod."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5729","DOI":"10.1016\/j.tet.2016.07.068","article-title":"Synthesis, anti-proliferative activity, and toxicity of C4(C5) substituted N,N\u2032-bis(arylmethyl)imidazolium salts","volume":"72","author":"Shelton","year":"2016","journal-title":"Tetrahedron"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1016\/j.bmc.2016.11.051","article-title":"Discovery of biphenyl imidazole derivatives as potent antifungal agents: Design, synthesis, and structure-activity relationship studies","volume":"25","author":"Zhao","year":"2017","journal-title":"Bioorg. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6828","DOI":"10.1128\/AAC.03644-14","article-title":"Nitrotriazole- and imidazole-based amides and sulfonamides as antitubercular agents","volume":"58","author":"Papadopoulou","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/j.ejmech.2016.06.049","article-title":"Synthetic, enzyme kinetic, and protein crystallographic studies of C-beta-d-glucopyranosyl pyrroles and imidazoles reveal and explain low nanomolar inhibition of human liver glycogen phosphorylase","volume":"123","author":"Kantsadi","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Gong, K.K., Tang, X.L., Liu, Y.S., Li, P.L., and Li, G.Q. (2016). Imidazole Alkaloids from the South China Sea Sponge Pericharax heteroraphis and Their Cytotoxic and Antiviral Activities. Molecules, 21.","DOI":"10.3390\/molecules21020150"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"7499","DOI":"10.1016\/j.bmc.2013.09.041","article-title":"Synthesis and antimicrobial profile of N-substituted imidazolium oximes and their monoquaternary salts against multidrug resistant bacteria","volume":"21","year":"2013","journal-title":"Bioorg. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/0960-894X(95)00546-6","article-title":"Molecular shape analysis and activity of tautomycin, a protein phosphatase inhibitor","volume":"6","author":"Sugiyama","year":"1996","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1021\/cr00081a005","article-title":"Acetylcholinesterase: Enzyme structure, reaction dynamics, and virtual transition states","volume":"87","author":"Quinn","year":"1987","journal-title":"Chem. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1007\/s002040050504","article-title":"Quinuclidinium-imidazolium compounds: Synthesis, mode of interaction with acetylcholinesterase and effect upon Soman intoxicated mice","volume":"72","author":"Reiner","year":"1998","journal-title":"Arch. Toxicol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2649","DOI":"10.3891\/acta.chem.scand.20-2649","article-title":"Preparation of 2-imidazole- and 2-thiazolecarbaldehydes","volume":"20","author":"Iversen","year":"1966","journal-title":"Acta Chem. Scand."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.taap.2016.09.015","article-title":"A comprehensive evaluation of novel oximes in creation of butyrylcholinesterase-based nerve agent bioscavengers","volume":"310","author":"Baumann","year":"2016","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"7910","DOI":"10.1128\/JB.01147-08","article-title":"Genetic adaptation of Pseudomonas aeruginosa to the airways of cystic fibrosis patients is catalyzed by hypermutation","volume":"190","author":"Mena","year":"2008","journal-title":"J. Bacteriol."},{"key":"ref_31","first-page":"98","article-title":"Sulle funzioni bilineari","volume":"Volume 11","author":"Beltrami","year":"1873","journal-title":"Giornale di Matematiche ad Uso degli Studenti Delle Universita"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1080\/14786440109462720","article-title":"On lines and planes of closest fit to systems of points in space","volume":"2","author":"Pearson","year":"1901","journal-title":"Philos. Mag."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1037\/h0071325","article-title":"Analysis of a Complex of Statistical Variables into Principal Components","volume":"24","author":"Hotelling","year":"1933","journal-title":"J. Educ. Psychol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Jolliffe, I.T. (1986). Principal Component Analysis, Springer.","DOI":"10.1007\/978-1-4757-1904-8"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Smilde, A., Bro, R., and Geladi, P. (2004). Multi-Way Analysis with Applications in the Chemical Sciences, John Wiley & Sons Ltd.","DOI":"10.1002\/0470012110"},{"key":"ref_36","unstructured":"Hrenar, T. (2018). moonee, Program for Manipulation and Analysis of Multi- and Univariate Data, rev. 0.6827."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0003-2670(86)80028-9","article-title":"Partial least-squares regression, a tutorial","volume":"185","author":"Geladi","year":"1986","journal-title":"Anal. Chim. Acta"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/5\/1212\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:04:55Z","timestamp":1760195095000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/5\/1212"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5,18]]},"references-count":37,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2018,5]]}},"alternative-id":["molecules23051212"],"URL":"https:\/\/doi.org\/10.3390\/molecules23051212","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,5,18]]}}}