Antifungal promising agents of zinc(II) and copper(II) derivatives based on azole drug

J Inorg Biochem. 2021 Jun:219:111401. doi: 10.1016/j.jinorgbio.2021.111401. Epub 2021 Feb 20.

Abstract

A series of new metal complexes, [Zn(KTZ)2(Ac)2]·H2O (1), [Zn(KTZ)2Cl2]·0.4CH3OH (2), [Zn(KTZ)2(H2O)(NO3)](NO3) (3), [Cu(KTZ)2(Ac)2]·H2O (4), [Cu(KTZ)2Cl2]·3.2H2O (5), [Cu(KTZ)2(H2O)(NO3)](NO3)·H2O (6), were synthesized by a reaction of ketoconazole (KTZ) with their respective zinc or copper salts under mild conditions. Similarly, six corresponding metal-CTZ (clotrimazole) complexes [Zn(CTZ)2(Ac)2]·4H2O (7), [Zn(CTZ)2Cl2] (8), [Zn(CTZ)2(H2O)(NO3)](NO3)·4H2O (9), [Cu(CTZ)2(Ac)2]·H2O (10), [Cu(CTZ)2Cl2]·2H2O (11), [Cu(CTZ)2(H2O)(NO3)](NO3)·2H2O (12), were obtained. These metal complexes were characterized by elemental analyses, molar conductivity, 1H and 13C{1H} nuclear magnetic resonance, UV/Vis, and infrared spectroscopies. Further, the crystal structure for complexes 7 and 10 was determined by single-crystal X-ray diffraction. The antifungal activity of these metal complexes was evaluated against three fungal species of medical relevance: Candida albicans, Cryptococcus neoformans, and Sporothrix brasiliensis. Complexes 1 and 3 exhibited the greatest antifungal activity with a broad spectrum of action at low concentrations and high selectivity. Some morphological changes induced by these metal complexes in S. brasiliensis cells included yeast-hyphae conversion, an increase in cell size and cell wall damage. The strategy of coordination of clinic drugs (KTZ and CTZ) to zinc and copper was successful, since the corresponding metal complexes were more effective than the parent drug. Particularly, the promising antifungal activities displayed by Zn-KTZ complexes make them potential candidates for the development of an alternative drug to treat mycoses.

Keywords: Candida albicans; Clotrimazole; Cryptococcus neoformans; Ketoconazole; Metal complexes; Sporothrix brasiliensis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antifungal Agents / chemistry*
  • Antifungal Agents / pharmacology
  • Azoles / chemistry
  • Candida albicans / drug effects
  • Clotrimazole / chemistry*
  • Clotrimazole / pharmacology
  • Coordination Complexes / chemistry*
  • Coordination Complexes / pharmacology
  • Copper / chemistry*
  • Cryptococcus neoformans / drug effects
  • Ketoconazole / chemistry*
  • Ketoconazole / pharmacology
  • Microbial Sensitivity Tests / methods
  • Sporothrix / drug effects
  • X-Ray Diffraction / methods
  • Zinc / chemistry*

Substances

  • Antifungal Agents
  • Azoles
  • Coordination Complexes
  • Copper
  • Clotrimazole
  • Zinc
  • Ketoconazole

Supplementary concepts

  • Sporothrix brasiliensis