Synthesis, characterization, antifungal and anti-HIV activities of metal(II) complexes of 4,6-di-tert-butyl-3-[(2-hydroxyethyl)thio]benzene-1,2-diol

doi:10.1016/j.ejmech.2007.09.024

European Journal of Medicinal Chemistry

Volume 43, Issue 7, July 2008, Pages 1536-1542

https://doi.org/10.1016/j.ejmech.2007.09.024 Get rights and content

Abstract

Co(II) and Ni(II) complexes with 4,6-di-tert-butyl-3-[(2-hydroxyethyl)thio]benzene-1,2-diol (L) have been synthesized and characterized by means of elemental analysis, TG/DTA, FT-IR, ESR, UV–vis, XRD, magnetic susceptibility, cyclic voltammetry and conductance measurements. According to the data obtained the organic compound acts as a bidentate O,S-coordinated ligand and yields Co(II) and Ni(II) complexes of the stoichiometry ML₂ which is characterized by square planar geometry. Antifungal and anti-HIV activities of the ligand and its metal(II) complexes were found to decrease in the sequence CuL₂ > CoL₂ ∼ NiL₂ > HL, along with their reducing ability (determined electrochemically).

Graphical abstract

Metal(II) complexes with 4,6-di-tert-butyl-3-[(2-hydroxyethyl)thio]benzene-1,2-diol have been synthesized and characterized by means of elemental analysis and various physico-chemical techniques. Antifungal and anti-HIV activities of the ligand and its metal(II) complexes have been determined.

Introduction

The new medical technologies introduced into clinical practice (transplantation of organs and tissues, immunosuppressive therapy), the HIV infection pandemic and wide employment of antibacterial pharmaceuticals resulting in an increased number of immunocompromised patients running a high risk of developing opportunistic infections like fungal, tuberculosis, viral and neoplastic diseases has become more and more important problem of the modern medicine [1], [2]. Invasive mycoses are the most common opportunistic infections in patients with AIDS. In this connection it is of interest to seek for bioactive compounds, exhibiting both anti-HIV and antifungal activities. Despite the fact that it is Candida spp. and Aspergillus spp. that remain the main causative pathogens, the number of cases of systemic fungal infections due to strains of Fusarium spp., Scedosporium spp., Mucor spp. and others, resistant to the most widely used antifungal polyene and azole drugs, is increasing [3], [4], [5]. In this connection a search for possible alternative antifungal agents by widening existing classes and producing new ones is a pressing task. Due to the possibility of their antifungal activity mode being different, metal complexes might provide the basis for novel antifungal agents, which could have potential applications as pharmaceuticals. Reports have appeared in the literature highlighting the fungicidal activity of transition metal complexes with 1,10-phenanthroline [6], [7], [8], [9], thiosemicarbazones [10], [11], [12], carboxylates [13], dithiocarbamates [14] and thiourea derivatives [15], [16], [17], [18]. Thus, the synthesis and characterization of metal complexes with organic bioactive ligands, in particular, of those with derivatives of sterically hindered o-diphenols (SHD), is one of the promising areas of the search for potential chemotherapeutic agents. An effective bioantioxidant has been found among them [19], moreover, a sulphurous derivative thereof exhibits a high antiviral activity [20], [21]. Although derivatives of SHD exhibit interesting biological properties [22], [23] and a great versatility as noninnocent ligands [24], [25], [26], [27], [28], [29], still there is virtually no pharmacological or coordinative information about their sulphurous derivatives. In this connection it is of interest to study various aspects of metal(II) coordination chemistry of these organic compounds and the biological activity of their metal complexes. Recently we have reported the synthesis, characterization and antimicrobial activities of some SHD derivatives as well as their Cu(II) complexes [30], [31]. Since our earlier work had revealed that Cu(II) complexation leads to enhancement of the antimicrobial activity of these ligands, we were motivated to explore whether there is a similar trend in the case of other transition metal(II) complexes of these organic compounds. We report here the synthesis and characterization of Co(II), Ni(II) complexes with one of the sulphurous derivatives of SHD, that is 4,6-di-tert-butyl-3-[(2-hydroxyethyl)thio]benzene-1,2-diol (L), in order to compare its coordinative behaviour in relation to Co(II), Ni(II) ions with the results obtained before for its Cu(II) complex [30], [31] and to assess the influence of complexation on antifungal and anti-HIV activities. The said o-diphenol derivative was chosen as the ligand to synthesize metal(II) complexes because it is relatively stable to oxidation, and its Cu(II) complex had previously demonstrated a promising activity against some fungi strains.

It should be noted that the effect of some transition metal complexes on the structure of fungal and mammalian cell organelles has been studied, and the general conclusion is that they have the potential to damage mitochondrial function and to uncouple respiration [9]. In this connection it may be expected that metal complexes which are able to participate in redox processes and affect the electron-transport cell systems will be promising in the search for antifungal agents. This encouraged us to examine redox properties of the ligand and its metal(II) complexes by cyclic voltammetry to find out whether there is a correlation between antifungal activities of the compounds under study and their redox properties.

Section snippets

Materials and methods

Chemicals were purchased from commercial sources and were used without further purification. The SHD derivative was prepared according to Refs. [20], [21], [32]. Elemental analyses were carried out according to the standard methods by Microanalytical Laboratory, Bioorganic Chemistry Institute, National Academy of Sciences, Belarus. Metal and sulfur determination was carried out using an atomic emission spectrometer with an inductively coupled plasma excitation source (Spectroflame Modula).

Antifungal assays

Antifungal activities of the compounds were tested against the following test microorganisms (the collection of Department of Microbiology, Belarusian State University): yeasts (Pichia pastoris, Lypomyces lipofer, Saccharomyces cerevisiae, Cryptococcus laurentiive, Candida utilis, Candida boidinii) and fungi (Aspergillus niger, Fusarium spp., Mucor spp., Penicillium lividum, Botrytis cinerea, Alternaria alternata, Sclerotinia sclerotiorum, Monilia spp.).

Bioactivities of the compounds against

Results and discussion

The solid products resulting from the interaction of metal(II) ions with the ligand were well characterized by means of elemental analysis, TG/DTA, FT-IR, UV–vis, ESR, magnetic susceptibility and conductance measurements. These complexes were insoluble in water, ethanol, diethyl ether, nitromethane and chloroform, but they were soluble in acetonitrile and dimethyl sulfoxide. The conductivity data indicate their being essentially non-electrolytes in acetonitrile [38], and suggest that the two

Acknowledgement

This work was supported by International Science and Technology Center (ISTC grant B-984). We are grateful to Dr. R. Zheldakova (Belarusian State University) for the antifungal testing.

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Short communicationSynthesis, characterization, antifungal and anti-HIV activities of metal(II) complexes of 4,6-di-tert-butyl-3-[(2-hydroxyethyl)thio]benzene-1,2-diol

Abstract

Graphical abstract

Introduction

Section snippets

Materials and methods

Antifungal assays

Results and discussion

Acknowledgement

J. Infect.

Polyhedron

Toxicol. In Vitro

Polyhedron

J. Inorg. Biochem.

Eur. J. Med. Chem.

J. Inorg. Biochem.

J. Inorg. Biochem.

J. Inorg. Biochem.

Coord. Chem. Rev.

Coord. Chem. Rev.

Polyhedron

J. Virol. Methods

Coord. Chem. Rev.

J. Inorg. Biochem.

Eur. J. Clin. Microbiol. Infect. Dis.

Br. J. Biomed. Sci.

J. Antimicrob. Chemother.

Clin. Infect. Dis.

Biometals

Met. Based Drugs

Met. Based Drugs

Short communication
Synthesis, characterization, antifungal and anti-HIV activities of metal(II) complexes of 4,6-di-tert-butyl-3-[(2-hydroxyethyl)thio]benzene-1,2-diol