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

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 four fluconazole molecules monodentately coordinated via the triazole nitrogen and two chlorido ligands. With respect to fluconazole, complex 2 showed significantly higher antifungal activity against Candida krusei and Candida parapsilosis. All tested compounds reduced the total amount of ergosterol at subinhibitory concentrations, indicating that the mode of activity of fluconazole was retained within the complexes, which was corroborated via molecular docking with cytochrome P450 sterol 14α-demethylase (CYP51) as a target. Electrostatic, steric and internal energy interactions between the complexes and enzyme showed that 2 has higher binding potency to this target. Both complexes showed strong inhibition of C. albicans filamentation and biofilm formation at subinhibitory 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 25% and to inhibit its biofilm formation by 20% in comparison to the untreated control. These results suggest that complex 2 may be further examined in the mixed Candida-P. aeruginosa infections.

Metal Complexes—A Promising Approach to Target Biofilm Associated Infections

“…The scientific literature reports a large diversity of species concerning both metal ions and ligands available for designing such effective anti-biofilm species ranging from simple to bulky ligands and acting as unidentate to multidentate species. A variety of complexes with anti-biofilm activity, ranging from species with known antibiotics or natural products to new synthetic ligands, mainly with low toxicity and chelating ability have been developed [ 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , <...>…”

“…A variety of complexes with anti-biofilm activity, ranging from species with known antibiotics or natural products to new synthetic ligands, mainly with low toxicity and chelating ability have been developed [ 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 ,…”

In vivo active organometallic-containing antimycotic agents

“…azole moieties, thiosemicarbazones, carboxamides, indoles) against several fungal strains or some organometallic moieties bound to active antifungal agents. [41][42][43][44][45][46][47][48][49][50][51][52][53] However, all these studies generally provided only MIC 50 values without any further biological investigation such as target engagement and toxicity. Willing to grasp this opportunity, we embarked on a research program to unveil potent complexes against fungal infections with an emphasis on addressing cellular targets and mode of action.…”

Metal complexes of azo mesalamine drug: Synthesis, characterization, and their application as an inhibitor of pathogenic fungi

“…[ 15 ] An alternative strategy to overcome resistance to fungi is the addition of metal ions to bioactive organic compounds that have shown antimicrobial properties. Also, metal complexes may be an untapped source of new compounds with the potential for antifungal substances, [ 16 ] and they considered eco‐friendly alternative strategies for fungicides. Moreover, there are no studies in which these compounds have been used on plant pathogenic fungi.…”