Thiosemicarbazone scaffold for the design of antifungal and antiaflatoxigenic agents: evaluation of ligands and related copper complexes

Abstract

The issue of food contamination by aflatoxins presently constitutes a social emergency, since they represent a severe risk for human and animal health. On the other hand, the use of pesticides has to be contained, since this generates long term residues in food and in the environment. Here we present the synthesis of a series of chelating ligands based on the thiosemicarbazone scaffold, to be evaluated for their antifungal and antiaflatoxigenic effects. Starting from molecules of natural origin of known antifungal properties, we introduced the thio- group and then the corresponding copper complexes were synthesised. Some molecules highlighted aflatoxin inhibition in the range 67–92% at 100 μM. The most active compounds were evaluated for their cytotoxic effects on human cells. While all the copper complexes showed high cytotoxicity in the micromolar range, one of the ligand has no effect on cell proliferation. This hit was chosen for further analysis of mutagenicity and genotoxicity on bacteria, plants and human cells. Analysis of the data underlined the importance of the safety profile evaluation for hit compounds to be developed as crop-protective agents and at the same time that the thiosemicarbazone scaffold represents a good starting point for the development of aflatoxigenic inhibitors.

Copper(II) Thiosemicarbazone Complexes and Their Proligands upon UVA Irradiation: An EPR and Spectrophotometric Steady-State Study

“…Aromatic and heteroaromatic thiosemicarbazones (TSCs) and their transition metal complexes have gained considerable attention due to their coordination chemistry and broad range of biological activities [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. The biological actions of thiosemicarbazones are often related to the chelation of metal ions, especially regarding coordination with biologically relevant transition metal ions [ 10 , 11 , 12 , 13 , 14 , 15 ]. For example, Cu(II)-TSC complexes are effective anticancer agents, and act as strong inhibitors of DNA synthesis via the inhibition of ribonucleotide reductase [ 16 , 17 , 18 ].…”

Synthesis, characterization, antifungal and antibacterial activities evaluation of copper (II), zinc (II) and cadmium (II) chloride and bromide complexes with new (E)‐1‐(3,4‐dimethoxybenzylidene)‐4‐methylthiosemicarbazone ligand

“…Efficient evaluation of the antimicrobial properties of metal complexes has increased in measure over the last decade, with diverse reports displaying the activity and potential modes of action of metal‐based antibiotics. [ 43–48 ] As previously reported, [ 10,34,38 ] the complexes of thiosemicarbazones and their metal complexes are among the most widely studied compounds because of their potential therapeutic use as antifungal, antibacterial or antiviral agents. In our study, we confirmed the antifungal and antibacterial potential of these molecules, especially when the complexation concerns the metals cadmium, zinc and copper.…”

“…Thiosemicarbazone (TSC) derivatives can adopt various coordination modes as N , S ‐donors, and their transition metal complexes have been studied because of their biological [ 1–3 ] and pharmaceutical [ 4,5 ] activities. TSCs and their metal complexes have been demonstrated to exhibit high biological activity against malarial, [ 6–8 ] bacterial [ 9 ] and fungal infections, [ 9,10 ] and displayed promising antitumor activity against various cancer cell lines. [ 11–13 ] The biological behavior of the TSCs is enhanced upon binding metal ions through a synergic effect; [ 14–16 ] it was verified that TSCs’ tendency to cross biological membranes can be adapted by coordination.…”

(E)-2-(2-Hydroxy-3-methylbenzylidene)-N-methylhydrazine-1-carbothioamide: supramolecular assemblies in two-dimensions mediated by N—H...S and C—H...π interactions

“…Metal complexes of thiosemicarbazones have also received much attention. The metal chelation typically improves the lipophilicity of the ligand and facilitates the penetration of the complexes into bacterial membranes (Lobana et al, 2009;Rogolino et al, 2017). Thiosemicarbazones have multi-donor characteristics because of the presence of nitrogen and sulfur atoms in their molecular backbone.…”