Natalia V. Loginova

Phytophthora spp. is recognized as one of the most widespread and destructive fungal pathogens of agricultural crops. Consequently, the discovery, development and rational application of chemical crop protection agents against this pathogen represent a matter of considerable urgency. In this context, hydrazones and their metal complexes, particularly those of copper(II), rank among the most promising candidates for antifungal screening. Owing to their straightforward synthesis, a wide range of substrates, and the ability to tailor structures with predefined physicochemical properties to diverse biological activities, copper(II) complexes of hydrazones are actively explored as antifungal agents. The biochemical mechanisms underlying the prominent antifungal properties of these compounds involve the overproduction of reactive oxygen species (ROS) and the induction of mitochondrial depolarization. A series of hydrazones derived from 4,6-di-tert-butyl-2,3-dihydroxybenzaldehyde (2-(4,6-di-tert-butyl-2,3-dihydroxybenzylidene)hydrazine-1-carboxamide and 4,6-di-tert-butyl-2,3-dihydroxybenzylidene-4-hydroxybenzohydrazide), along with their corresponding copper(II) complexes, have been synthesized and fully characterized by the methods of NMR, ESR, FT-IR and UV–visible absorption spectroscopy, complemented by elemental analysis, powder X-ray diffraction and electrochemical studies. The resulting binuclear copper(II) complexes were found to adopt a [Cu₂L₂] coordination motif (where L denotes the ligand). The synthesized compounds have demonstrated reducing properties, with the copper(II) complexes undergoing electrochemical oxidation more readily than the parent ligands, which could be the prerequisite for cellular redox cycling leading to ROS overproduction. Antifungal activity assays against Phytophthora infestans revealed that complexation with copper(II) affects the bioactivity of the hydrazone ligands differently depending on their structure: Cu(II) complexation reduced the activity of HL^I, whereas HL^II and its corresponding Cu(II) complex displayed comparable inhibitory activity.

With radical scavenging and reduction potential assays, cyclic voltammetry and density functional theory calculations, we have revealed structure–activity relationships that challenge the conventional understanding of antioxidant mechanisms.

Biological activity of hydrazones and thiasemicarbazones is well-described: thiosemicarbazide moiety is present in the structure of an antibacterial drug thioacetazone, hydrazone derivatives of isoniazid demonstrate a high activity against Mycobacterium spp., whereas 5-nitrofuran-2-carbaldehyde-derived hydrazones have proven effective in the treatment of urinary tract infections. Such compounds are also known to readily form Cu(II) complexes with a high antimicrobial activity attributed to ROS generation and subsequent caspase-dependent apoptotic cell death. Antifungal properties of thiosemicarbazone ligands and their Cu(II) complexes have been linked to alteration of ergosterol biosynthesis and membrane damage. 4,6-di-tert-butyl-2,3-dihydroxybenzaldehyde-derived hydrazones, thiosemicarbazones, and their Cu(II) complexes have been synthesized and characterized by NMR, ESR, FT-IR, UV-visible absorption spectroscopy, mass spectrometry, as well as elemental, XRD powder diffraction and thermogravimetric analysis studies. The obtained binuclear Cu(II) complexes have been found to possess the coordination polyhedron of [Cu₂L₂], HL being the formula of the corresponding ligand. Microbiological screening of the synthesized compounds against Gram-positive (Bacillus subtilis, Staphylococcus saprophyticus) and Gram-negative (Escherichia coli, Pseudomonas putida) bacteria has demonstrated a markedly enhanced antibacterial activity of hydrazone and thiosemicarbazone derivatives upon their complexation with the Cu(II) ion. Interestingly, antifungal activity of the 4,6-di-tert-butyl-2,3-dihydroxybenzaldehyde-derived hydrazones and thiosemicarbazones against Phytophthora spp. has been found to slightly decrease upon Cu(II) complexation. Due to tautomerism and metal chelation via anionic or neutral forms, biological activity of hydrazone and thiosemicarbazone derivatives can be controllably tuned by the formation of Cu(II) complexes of various coordination cores and nuclearities, rendering them promising basic structures for further modification.

Displaying versatile biological activity, Schiff bases are known to possess prominent optical, thermal, and metal coordination properties, rendering them prospective for the design of dyes, photonic devices, ion sensors, molecular probes, etc. Furthermore, azomethine compounds bearing a phenolic moiety may exert antioxidant action. In this work, the antioxidant activity of the bis-substituted and mono-substituted phenolic azomethine dyes derived from 4,6-di-tert-butyl-2,3-dihydroxybenzaldehyde was determined in DPPH radical and ABTS cation radical scavenging assays, FRAP and CUPRAC metal reducing assays, and ferrous iron chelating activity assay. The effects of aliphatic amine substituents, steric factors, and the coordination behavior of the compounds on their antioxidant activity were studied. Experimental results of the antioxidant activity assays and plausible mechanisms of antioxidant action were elucidated with reference to the reaction parameters and global reactivity descriptors calculated for the DFT-optimized compound structures. The studied phenolic Schiff bases were characterized by spectroscopic and quantum chemical methods. Solvatochromic properties of the compounds were investigated in terms of the influence of solvent nature and the acidity and basicity of the medium on their catechol imine/quinone methide tautomerism.

Schiff bases bearing a sterically hindered phenolic moiety and their Bi(III) complexes were synthesized and characterized by physicochemical, quantum chemical, and biological methods. The compounds were screened in vitro against bacterial and yeast strains. It was found that Bi(III) complexes demonstrate higher antimicrobial activity compared to the parent ligands as well as to the commonly used drug (De-Nol®). Moreover, the antibacterial activity of investigated compounds did not directly correlate with their hemolytic activity, indicating that the antimicrobial effect of Bi(III) complexes cannot be explained solely by their membranolytic properties. Spectrofluorometric studies of the interaction of the Bi(III) complexes with plasma proteins indicate their moderate to high affinity toward BSA and hemoglobin, which is crucial for the determination of their pharmacological profile as well as toxicity assessment. Additionally, molecular docking was performed to predict the possible interaction modes and binding energies of the tested compounds at the molecular level. The results obtained may provide the basis for the design and development of novel Bi(III)-based antimicrobial agents.

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Nanoparticles are known to have a high specific surface area, which accounts for an increased probability of their interaction with bacterial cells. Therefore, the application of silver(I) nanoparticles (AgNPs) and their nanocomposites as antimicrobial agents against drug-resistant bacterial strains appears to be prospective. A critical point for the advancement of AgNPs into clinical practice is a fundamental understanding of their behavior in biological systems, including protein binding and interaction with blood components, which reflects their toxicity. The latter is primarily determined by the physicochemical properties of AgNPs, namely their size, shape, surface chemistry, etc. Therefore, nanotoxicity may be substantially reduced through the manipulation of certain physicochemical characteristics of AgNPs, increasing their biocompatibility and hence paving the way for possible biomedical applications. In this study we have focused on estimating the binding affinity of the synthesized Ag(I) complexes of 2-(4,6-di-tert-butyl-2,3-dihydroxyphenylsulfanyl)-acetic acid and 4,6-di-tert-butyl-2,3-dihydroxybenzaldehyde isonicotinoyl hydrazone, as well as AgNPs derived thereof to bovine serum albumin (BSA) and hemoglobin by the fluorimetric method. Furthermore, cellular toxicity of the AgNPs towards human erythrocytes was measured in a hemolysis assay. Organosols formed by the Ag(I) complexes upon their reduction to AgNPs in acetonitrile and DMSO were characterized by the transmission electron microscopy (TEM) method and atomic force microscopy (AFM).

Schiff bases represent a class of biologically active and structurally diverse organic compounds that may be involved in copper(II) coordination as N,O-donor ligands. A redox-active biometal, copper is known to play a significant role in cellular metabolism and accounts for a wide range of biological activities exhibited by its compounds, namely antibacterial, antiproliferative, antifungal, antiinflammatory, etc. 4,6-Di-tert-butyl-2,3-dihydroxybenzaldehyde-derived Schiff bases and their Cu(II) complexes have been synthesized and characterized by means of FT-IR, UV-Vis, NMR and ESR spectroscopy, mass-spectrometry, elemental, XRD and thermogravimetric analysis, electrochemical measurements, quantum chemical calculations and molecular docking studies. The compounds were tested in vitro for antibacterial activity on Gram-positive and Gram-negative bacteria, bovine serum albumin and haemoglobin binding, as well as for hemolytic activity and for antioxidant activity in DPPH and ABTS assays. The synthesized ligands and their copper(II) complexes have been found to possess low cell toxicity and exhibit antioxidant activity higher than that of Trolox. Furthermore, several copper(II) complexes have demonstrated antibacterial activity comparable to those of tetracycline and streptomycin. The results obtained have been corroborated by molecular docking studies and interpreted in terms of the effects of copper(II) coordination by the organic ligand on radical-scavenging and bactericidal properties, protein affinity and toxicity of the latter.

Inhibition of quorum sensing is considered to be an effective strategy of control and treatment of a wide range of acute and persistent infections. Pseudomonas aeruginosa is an opportunistic bacterium with a high adaptation potential that contributes to healthcare-associated infections. In the present study, the effects of the synthesized hybrid structures bearing sterically hindered phenolic and heterocyclic moieties in a single scaffold on the production of virulence factors by P. aeruginosa were determined. It has been shown that the obtained compounds significantly reduce both pyocyanin and alginate production and stimulate the biosynthesis of siderophores in vitro, which may be attributed to their iron-chelating properties. The results of docking-based inverse high-throughput virtual screening indicate that transcription regulator LasR and Cu-transporter OPRC could be potential molecular targets for these compounds. Investigation of the impact small molecules exert on the molecular mechanisms of the production of bacterial virulence factors may pave the way for the design and development of novel antibacterial agents.

Current research on synthetic and naturally occurring phenolic compounds is centered around their prominent antioxidant properties. Since reactive oxygen (ROS) and nitrogen (RNS) species cause considerable damage to cellular components upon their overproduction, associated with the pathogenesis of degenerative, cardiovascular and oncological diseases, antioxidants may reduce the risk of developing such conditions. Because hydroxyl, amino and sulfhydryl groups present in their structure, antioxidants may function as hydrogen atom and electron donors, as well as metal-reducing and metal-chelating agents. We synthesized phenolic Schiff bases from 4,6-di-tert-butyl-2,3-dihydroxybenzaldehyde; ortho-, meta- and para-mercaptoanilines; and 2,2′- and 4,4′-disulfanediyldianilines. Their antioxidant properties were studied in a 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging assay.