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Copper(II) and Zinc(II) Complexes with the Clinically Used Fluconazole: Comparison of Antifungal Activity and Therapeutic Potential

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Copper(II) and Zinc(II) Complexes with the Clinically Used Fluconazole: Comparison of Antifungal Activity and Therapeutic Potential pharmaceuticals Article Copper(II) and Zinc(II) Complexes with the Clinically Used Fluconazole: Comparison of Antifungal Activity and Therapeutic Potential Nevena Lj. Stevanovi´c 1 , Ivana Aleksic 2, Jakob Kljun 3 , Sanja Skaro Bogojevic 2 , Aleksandar Veselinovic 4, Jasmina Nikodinovic-Runic 2,* , Iztok Turel 3,* , Miloš I. Djuran 5,* and Biljana Ð. Gliši´c 1,* 1 Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovi´ca12, 34000 Kragujevac, Serbia; [email protected] 2 Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade, Serbia; [email protected] (I.A.); [email protected] (S.S.B.) 3 Faculty of Chemistry and Chemical Technology, University of Ljubljana, Veˇcnapot 113, SI-1000 Ljubljana, Slovenia; [email protected] 4 Department of Chemistry, Faculty of Medicine, University of Niš, Blvd. Dr Zorana Djindjica 81, 18108 Niš, Serbia; [email protected] 5 Department of Chemical and Biological Sciences, Serbian Academy of Sciences and Arts, Knez Mihailova 35, 11000 Belgrade, Serbia * Correspondence: [email protected] (J.N.-R.); [email protected] (I.T.); [email protected] (M.I.D.); [email protected] (B.Ð.G.); Tel.: +381-11-397-6034 (J.N.-R.); +386-1-47-98-525 (I.T.); +381-34-300-251 (M.I.D.); +381-34-336-223 (B.Ð.G.) Abstract: Copper(II) and zinc(II) complexes with clinically used antifungal drug fluconazole (fcz), . · {[CuCl2(fcz)2] 5H2O}n, 1, and {[ZnCl2(fcz)2] 2C2H5OH}n, 2, were prepared and characterized by spectroscopic and crystallographic methods. The polymeric structure of the complexes comprises Citation: Stevanovi´c,N.L.; Aleksic, I.; four fluconazole molecules monodentately coordinated via the triazole nitrogen and two chlorido Kljun, J.; Skaro Bogojevic, S.; ligands. With respect to fluconazole, complex 2 showed significantly higher antifungal activity Veselinovic, A.; Nikodinovic-Runic, J.; against Candida krusei and Candida parapsilosis. All tested compounds reduced the total amount of Turel, I.; Djuran, M.I.; Gliši´c,B.Ð. ergosterol at subinhibitory concentrations, indicating that the mode of activity of fluconazole was Copper(II) and Zinc(II) Complexes retained within the complexes, which was corroborated via molecular docking with cytochrome with the Clinically Used Fluconazole: α Comparison of Antifungal Activity P450 sterol 14 -demethylase (CYP51) as a target. Electrostatic, steric and internal energy interactions and Therapeutic Potential. between the complexes and enzyme showed that 2 has higher binding potency to this target. Both Pharmaceuticals 2021, 14, 24. complexes showed strong inhibition of C. albicans filamentation and biofilm formation at subin- https://doi.org/10.3390/ph14010024 hibitory concentrations, with 2 being able to reduce the adherence of C. albicans to A549 cells in vitro. Complex 2 was able to reduce pyocyanin production in Pseudomonas aeruginosa between 10% and Received: 11 December 2020 25% and to inhibit its biofilm formation by 20% in comparison to the untreated control. These results Accepted: 25 December 2020 suggest that complex 2 may be further examined in the mixed Candida-P. aeruginosa infections. Published: 30 December 2020 Keywords: copper(II) complex; zinc(II) complex; fluconazole; antifungal agents; anti-biofilm activity Publisher’s Note: MDPI stays neu- tral with regard to jurisdictional clai- ms in published maps and institutio- nal affiliations. 1. Introduction Over the last few decades, fungal strains causing invasive infections present not only a serious threat to human health worldwide, but also causing devastating effect for Copyright: © 2020 by the authors. Li- agriculture and the environment [1–3]. An estimated 1.5–2 million people die of a fungal censee MDPI, Basel, Switzerland. infection each year and this mortality is mainly caused by Aspergillus, Candida, Cryptococcus, This article is an open access article and Pneumocystis species [4]. Immunocompromised patients, such as recipients of solid distributed under the terms and con- organ transplants or hematopoietic stem cells, and those infected with HIV are most ditions of the Creative Commons At- susceptible to these pathogens [5]. Four classes of organic compounds classified based tribution (CC BY) license (https:// on their mode of action are currently used for the treatment of fungal infections: the creativecommons.org/licenses/by/ polyenes (including amphotericin B and nystatin), azoles, echinocandins (caspofungin and 4.0/). Pharmaceuticals 2021, 14, 24. https://doi.org/10.3390/ph14010024 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, x FOR PEER REVIEW 2 of 21 Pharmaceuticals 2021, 14, 24 2 of 20 their mode of action are currently used for the treatment of fungal infections: the polyenes (including amphotericin B and nystatin), azoles, echinocandins (caspofungin and mica- fungin), and antimetabolites (such as 5-fluorocytosine) [6]. Among them, azoles are the micafungin),most commonly and antimetabolitesused antifungal (such agents, as 5-fluorocytosine)due to the fact that [6]. they Among have them, broad-spectrum azoles are theantifungal most commonly activity, usedbetter antifungal effectiveness agents, and due an ac toceptable the fact thattoxicity they profile have broad-spectrum [7]. This class of antifungalantifungal activity, agents inhibits better effectiveness the enzymes and (cytoc anhrome acceptable P450), toxicity included profile in the [7]. synthesis This class of ofergosterol, antifungal which agents is inhibits a component the enzymes of the (cytochromefungal cell membrane P450), included [8,9]. Fluconazole in the synthesis (fcz), ofwhich ergosterol, belongs which to the is afirst-generation component of theazoles, fungal is cella triazole membrane (Figure [8, 91),]. Fluconazoledeveloped for (fcz), the whichtreatment belongs of Candida to the first-generationinfections, including azoles, C. albicans is a triazole, C. tropicalis (Figure,1 C.), developedparapsilosis, forand the der- treatmentmatophytes of Candida[8]. On theinfections, other hand, including AspergillusC. albicans spp. or, otherC. tropicalis hyphomycetes, C. parapsilosis and C., krusei and dermatophytesare intrinsically [8 ].resistant On the otherto fluconazole, hand, Aspergillus while C.spp. glabrata or other, occasionally hyphomycetes shows and aC. reduced krusei aresensitivity intrinsically [8]. resistantMoreover, to fluconazole,the number whileof fluconazole-resistantC. glabrata, occasionally strains shows has arapidly reduced in- sensitivitycreased with [8]. the Moreover, excessive the use number of this of antifu fluconazole-resistantngal agent [10]. strainsConsidering has rapidly the limited increased anti- withfungal the spectrum excessive of use fluconazole, of this antifungal as well agentas resistance [10]. Considering development the and limited its other antifungal draw- spectrum of fluconazole, as well as resistance development and its other drawbacks, the backs, the identification of novel compounds capable to overcome these problems is identification of novel compounds capable to overcome these problems is highly urgent. highly urgent. FigureFigure 1. 1. StructuralStructural formula of of fluconazole fluconazole (fcz). (fcz). Th Thee numbering numbering of atoms of atoms was was used used for NMR for NMR as- assignationsignation and and does does not not match match the the one one applied applied in in the the X-ray X-ray study study of of the the complexes complexes 11 andand 22.. DueDue to to the the favorable favorable properties properties and and proven proven application application in in medicine medicine [ 11[11],], metal metal com- com- plexesplexes could could representrepresent anan untapped source of of novel novel compounds compounds having having antifungal antifungal poten- po- tential.tial. It is It well is well known known that that the the presence presence of me of metaltal ions ions is essential is essential for formany many biological biological pro- processescesses in inliving living organisms, organisms, such such as as metabolism, metabolism, respiration, photosynthesis,photosynthesis, growth growth and and reproduction,reproduction, muscle muscle contraction contraction and and respiration, respiration, nerve nerve signal signal transmission transmission and and nitrogen nitrogen fixationfixation [ 12[12].]. Without Without the the presence presence of of metal metal ions, ions, most most enzymes enzymes would would not not be be able able to to con- con- ductduct their their impressively impressively fine-tuned fine-tuned transformations transformations [13 [13].]. As As was was mentioned mentioned above, above, besides besides thethe essential essential role role of of metal metal ions ions in in biological biological systems, systems, many many metal-based metal-based drugs drugs and and imaging imag- agentsing agents are extensively are extensively used in used medicine in medicine for the treatmentfor the treatment and diagnosis and diagnosis of a wide of range a wide of diseasesrange of [ 11diseases]. The main[11]. The advantage main advantage of the medicinal of the medicinal use of metal use compoundsof metal compounds with respect with torespect purely to organic purely drugs organic is a drugs different is a mode different of action, mode including of action, ligand including exchange ligand or exchange release, reactiveor release, oxygen reactive species oxygen (ROS) species generation,
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