Synthesis and antimicrobial profile of N-substituted imidazolium oximes and their monoquaternary salts against multidrug resistant bacteria Renata Odz ˇak a , Mirjana Skoc ˇibušic ´ b,⇑ , Ana Maravic ´ b a Department of Chemistry, Faculty of Science, University of Split, Teslina 12, 21 000 Split, Croatia b Department of Biology, Faculty of Science, University of Split, Teslina 12, 21 000 Split, Croatia article info Article history: Received 18 July 2013 Accepted 16 September 2013 Available online 25 September 2013 Keywords: Imidazolium oximes Monoquaternary salts Synthesis Antimicrobial activity b-Lactamase Multidrug resistance ESBL abstract Two different series of N-substituted imidazolium oximes and their monoquaternary salts were synthesized and biologically tested with respect to their ability to inhibit growth a diverse panel of anti- biotic susceptible Gram-positive and antibiotic resistant Gram-negative bacteria as well fungal strains. The newly synthesized compounds were analyzed by spectral studies to confirm their structure. The pre- liminary results showed that all compounds tested possess promising antimicrobial potential against both susceptible Gram-positive and antibiotic resistant Gram-negative isolates, exhibiting a wide range of MIC values from 0.14 to 100.0 lg/mL. The structure–activity relationship demonstrates that the p-methylphenyl and p-fluorophenyl groups in monoquaternary salts 6 and 7 attached directly to the imi- dazolium ring could be essential for observed remarkable inhibitory profiles against clinically important pathogens Pseudomonas aeruginosa (MIC = 0.14 lg/mL) and Klebsiella pneumoniae (MIC = 1.56 lg/mL). Furthermore, the broth microdilution assay was then used to investigate the antiresistance efficacy of compound 7 against fourteen extended-spectrum b-lactamase (ESBL)-producing strains in comparison to eight clinically relevant antibiotics. Compound 7 exhibited a remarkable antiresistance profiles ranging between 0.39 and 12.50 lg/mL against all of ESBL-producing strains, which leads to the suggestion that may be interesting candidate for development of new antimicrobials to combat multidrug resistant Gram-negative bacteria. Ó 2013 Elsevier Ltd. All rights reserved. 1. Introduction The therapeutic treatment of bacterial and fungal diseases with antimicrobial drugs has had a remarkable and profound impact on human health around the world. The current worldwide emergence of resistance to extended spectrum cephalosporins, monobactams, and carbapenems among Gram-negative patho- genic bacteria constitutes an important growing public health threat. Infections caused by extended-spectrum b-lactamase (ESBL) producing pathogens have become a clinical and therapeu- tic problem because these organisms are resistant not only to b-lactam antibiotics but also to many other antimicrobial agents. 1 The dominant mechanisms for resistance to the Gram-negative bacteria are the production of clinically relevant b-lactamases, par- ticularly extended-spectrum b-lactamases (ESBLs), such as class A TEM, SHV, and CTX-M b-lactamases. 2 Single amino acid substitu- tions in the SHV, TEM and CTX-M b-lactamases can drastically alter the substrate profiles of the enzymes and confer resistance to extended-spectrum cephalosporins and b-lactamase inhibitors. 1 Nonetheless, the recent increase and spread of acquired carbapen- ems resistance due to the production of metallo-b-lactamases (MBLs) such as SIM- and VIM-type enzymes already are starting to limit the clinical use of carbapenems. 3 In addition to the infection control challenges that have arisen, infections caused by these bacterial and fungal pathogens present clinicians with serious treatment challenges, due to limited antibi- otic options. 4 New strategies are therefore needed to identify and developed the next generation of drugs or agents with diverse chemical structures and novel mechanisms of action to control microbial infections. Thus, the search for effective molecules that have the ability to restore the susceptibility of multi-drug-resistant bacteria, such as clinical problematic ESBL- and MBL-containing strains, to clinically available antibiotics are a promising alterna- tive to the development of novel antimicrobials. In this regard, the prevention and treatment of these infectious diseases by applying heterocyclic imidazole derivatives as poten- tial and promising sources of antimicrobial agents have been a fo- cus of recent research for antibacterial drug discovery. 5,6 Among the numerous nitrogen heterocyclic compounds of biological and 0968-0896/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmc.2013.09.041 ⇑ Corresponding author. Tel.: +385 21 385 133; fax: +385 21 384 086. E-mail address: Mirjana.Skocibusic@pmfst.hr (M. Skoc ˇibušic ´). Bioorganic & Medicinal Chemistry 21 (2013) 7499–7506 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc