Aims and Background: In contrast to antibiotics, metal complexes can realize more than one mechanism of biocidal action to fight multidrug-resistant bacterial strains (due essentially to the metal ions), involving targets like functional groups in the walls of microbial cells and various enzymes. Among the potential antimicrobials are Bi(III) complexes with diphenols. Objective: The present work aimed at synthesizing and investigating novel Bi(III) complexes with Schiff bases as potential antimicrobial and antioxidant agents. Methods: Bi(III) complexes were characterized by means of elemental analysis, FT-IR, UV-Vis, 1H NMR spectroscopy, XRD, cyclic voltammetry and conductivity measurements as well as biological methods. Results: The complexes are characterized by the formula Bi(L)2Cl and pyramidal geometry of their coordination cores BiO2N2Cl, wherein the Bi(III) cation is coordinated by hydroxyl and azomethine moieties. The ligands coordinate in their monoanionic forms. The complexes are more lipophilic and more bioactive against the bacteria tested than the ligands. Both the ligands and their complexes exhibited the capability for the Fe(III)-Cyt c reduction and displayed comparable reducing rates. All the compounds are characterized by the DPPH and ABTS radical scavenging activity, and they are more active reductants than Trolox in the CUPRAC assay too. The peculiarities of the interaction of the complexes with BSA suggest that Cys-34 of BSA is not a major binding site for these complexes. According to molecular docking studies, the complexes bind to BSA via non-covalent interactions. Conclusion: Bi(III) complexation with Schiff bases plays an important role in their antimicrobial and antioxidant activities as well as in their interaction with BSA.

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.

Free radicals are ubiquitous in biological systems, being responsible for pathogenesis of degenerative diseases and participating in vitally important biochemical processes, which are mediated by radical regulatory agents. The effects of the aliphatic amine substituents in the catechol-derived Mannich bases on their antioxidant and pro-oxidant activity were investigated. It has been found that the presence of catechol moiety in the structure of Mannich bases allows them to act as Cu(II) reductants, efficient Fe(II) chelators and potent DPPH radical scavengers. It has been found that the plausible mechanism of the DPPH radical scavenging proceeds via quinone formation, followed by their interaction with ethanol via the Michael addition reaction. In the neutrophil respiratory burst assay, several compounds have demonstrated a weak antioxidant activity at the micromolar level (0.1-10 mu M), whereas at the millimolar level (0.1 m & Mcy;) a strong pro-oxidant effect has been observed. Additionally, at the highest used concentrations a pronounced cytotoxicity against dermal fibroblasts DF-2 and an immunosuppressive effect against T-lymphocytes have been observed for all the synthesized compounds. It has been demonstrated that the oxidation of catechols in the presence of low-molecular thiols results in the formation of covalent adducts, which provides an insight into their cytotoxicity and detoxification pathways.

The effect of aminophenol, amino acids and their derivatives on the level of •NO and its intermediates (•NO2, N2O3) in an aqueous aerobic media (pH = 7.4) was studied using nitroprusside as a •NO donor. It was found that the highest NOx scavenging activity is exhibited by 3-aminophenol (IC50 = 0.11 mM), 2-aminophenol (IC50 = 0.195 mM) and 4,6-di-tert-butyl-2-aminophenol (IC50 = 0.12 mM), standards: trolox (IC50 = 0.19 mM) and ascorbate (IC50 = 4.88 mM). Methylation of the OH group reduced the effectiveness of aminophenol. In the studied concentration range (0–70 mM), Tyr-Ala (IC50 = 5.0 mM) and β-Ala-His (IC50 = 35.0 mM) were more active than Phe-Ala (IC50 50 mM) and Gly-Gly (IC50 50 mM). Complexes Cu(Gly)2 and Cu(Gly-Gly)2 at low concentrations (0.05–0.5 mM) are 1.4–1.8 times more effective than Gly and Gly-Gly.

The effect of N-acyl derivatives of 2-amino-4,6-di-tert-butylphenolon the functions of neutrophils was studied. It has been established that these derivatives with a free hydroxyl group in the benzene ring, in contrast to O-methylated ones, modify the properties of cells, which is expressed in a decrease in hypochlorous acid generation during the “respiratory burst” formation. These compounds are scavengers of HOCl/OCl– generated by activated neutrophils and reduce the secretion of myeloperoxidase (MPO) from cells. N-(3,5-di-tert-butyl-2-hydroxyphenyl)acetamide has been shown to be the most effective hypochlorous acid scavenger. This substance significantly suppresses the secretory degranulation of neutrophils and has a cytoprotective effect under conditions of halogenating stress.

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.

The effects of azomethine derivatives of 4,6-di- tert -butyl-2,3-dihydroxybenzaldehyde on the formation of radiolysis products of deaerated n -hexane and ethanol have been studied. It was shown that the catechol moiety in the tested compounds did not significantly affect their reactions with carbon-centered radicals. The aldimine group exhibited high activity as an α-hydroxyalkyl radical scavenger and low activity as a scavenger of alkyl radicals. The introduction of additional radical-inhibiting groups –OH, –SH, –NO 2 , and =N–NH– into the side fragment of a molecule led to a significant increase in the antiradical activity with respect to various types of carbon-centered radicals.

The influence of cycloaminomethyl derivatives of 4-tert-butyl-1,2-dihydroxybenzene, 3,5-di-tert-butyl-1,2-dihydroxybenzene, and 4,6-di-tert-butyl-1,3-dihydroxybenzene with different substituent ring sizes on the formation of n-hexane radiolysis products in the presence and absence of oxygen was studied. It was shown that the activity of sterically hindered diphenol derivatives toward alkyl radicals increased with the ring size in the side substituent, while the activity toward peroxyl radicals remained at the same level.

Novel Ag(I) complexes (2a–2c) with phenolic Schiff bases were synthesized using 4,6-di-tert-butyl-3-(((5-mercapto-1,3,4-thiadiazol-2-yl)imino)methyl)benzene-1,2-diol (1a), 4,6-di-tert-butyl-3-(((4-mercaptophe­nyl­)­imino)­methyl)benzene-1,2-diol (1b), and 4,6-di-tert-butyl-3-(((3-mercaptophenyl)imino)methyl)­benzene-1,2-diol (1c). They were examined by elemental analysis, FT-IR, UV-Vis, 1H-NMR spectroscopy, XRD, cyclic voltammetry, conductivity measurements, and biological methods. The complexes are characterized by distorted geometry of the coordination cores AgN2S2 (2c), AgNS (2b) and AgS2 (2a). These stable complexes were not typified by the intramolecular redox reaction in organic solvents resulting in the formation of silver nanoparticles (AgNPs). Antibacterial activity of 1a–1c and 2a–2c was evaluated in comparison with AgNPs and commonly used antibiotics. All the complexes were more active than the ligands against the bacteria tested (14), but they were less active than AgNPs and commonly used antibiotics. Both 1a–1c and their complexes 2a–2c exhibited the capability for the bovine heart Fe(III)-Cyt c reduction. The ligands 1b and 1c were characterized by the highest reduction rate among the compounds under study, and they showed a higher reducing ability (determined by cyclic voltammetry) as compared with that of their Ag(I) complexes 2b and 2c.

The fundamental importance of copper as a redox-active metal essential to the functioning of several metabolic enzymes provides a wide range of its biological activity pathways. Copper(II) coordination compounds are known to exhibit potent antiproliferative, antibacterial, nuclease, anti-inflammatory and antimycobacterial activities. Hydrazones are organic ligands commonly used for complexation with copper(II) that possess antibacterial, antiviral and antifungal properties. Copper–ligand interaction might facilitate charge delocalization and increase net hydrophobicity of the system, resulting in its enhanced pharmacological activity. Coordination compounds of Cu(II) with 4,6-di-tert-butyl-2,3-dihydroxybenzaldehyde derived hydrazone, nitrofurantoin and ftivazide have been synthesized, characterized by means of elemental and XRD analysis, FT-IR, UV-Vis and NMR spectroscopy and tested for antibacterial activity in vitro on Gram-positive and Gram-negative bacteria.

Исследована возможность совместного применения модифицированных пространственно- затрудненных 1,2-дигидроксибензолов и промышленного противостарителя аминного типа (6PPD) в рецептурах наполненных эластомерных композиций на основе комбинации непредельных натурального и синтетического полибутадиенового каучуков. Установлено влияние комбинаций противостарителей фенольного и аминного типов на упруго-прочностные свойства резин, стойкость вулканизатов к воздействию повышенных температур, а также на усталостную выносливость образцов при многократном растяжении. Модифицированные стабилизаторы различаются типом, количеством и пространственным расположением заместителей в бензольном кольце. Исследуемые ингредиенты вводились в резиновые смеси в дозировке 2,0 мас. ч. на 100,0 мас. ч. каучука. В качестве образца сравнения использовались эластомерные композиции, содержащие комбинацию промышленных стабилизаторов фенольного 2,6-ди-трет-бутил-4-метилфенол (ионол) и аминного N-(1,3-диметилбутил)-N'-фенил-п-фенилендиамин (6PPD) типов в дозировке по 2,0 мас. ч. Определено, что замена промышленного стабилизатора ионола на модифицированные производные 1,2-дигидроксибензолов позволяет получать резины, не уступающие или превосходящие по физико-механическим характеристикам вулканизаты с комбинацией промышленных стабилизаторов. Выявлено, что применение в резиновых смесях стабилизатора с азепанильным циклом совместно с 6PPD обеспечивает наиболее существенное улучшение упруго-прочностных свойств резин как до, так и после теплового старения, а также позволяет получать вулканизаты с наибольшей усталостной выносливостью.

Исследована эффективность применения новых производных пространственно-затрудненных пирокатехинов в качестве противостарителей в рецептурах наполненных эластомерных композиций на основе комбинации синтетических полиизопренового и полибутадиенового каучуков. Установлено влияние производных пирокатехинов на упруго-прочностные свойства вулканизатов, стойкость резин к термическому старению в среде воздуха, а также их сопротивление разрастанию трещин при многократном изгибе. Исследуемые стабилизаторы различаются типом, количеством и пространственным расположением заместителей в бензольном кольце. Данные ингредиенты вводились в резиновые смеси в дозировках 1,0 и 2,0 мас. ч. на 100,0 мас. ч. каучука. В качестве образца сравнения использовались эластомерные композиции, содержащие промышленный стабилизатор 2,6-ди-трет-бутил-4-метилфенол (ионол, BHT). Определено, что опытные противостарители имеют более низкую летучесть по сравнению с наиболее известным и эффективным промышленным стабилизатором ионолом. Выявлено, что характер изменения упруго-прочностных свойств эластомерных композиций, содержащих синтезированные противостарители, определяется природой и дозировкой стабилизаторов. Показано, что применение в резиновых смесях новых стабилизирующих добавок приводит к получению вулканизатов, обладающих повышенной стойкостью к воздействию повышенных температур и к разрастанию трещин при продольном изгибе.

Background: In this review article, a brief overview of novel metallotherapeutic agents (with an emphasis on the complexes of essential biometals) promising for medical application is presented. We have also focused on the recent work carried out by our research team, specifically the development of redox-active antimicrobial complexes of sterically hindered diphenols with some essential biometals (copper, zinc, nickel). Results: The complexes of essential metals (manganese, iron, cobalt, nickel, copper, zinc) described in the review show diverse in vitro biological activities, ranging from antimicrobial and anti-inflammatory to antiproliferative and enzyme inhibitory. It is necessary to emphasize that the type of organic ligands in these metal complexes seems to be responsible for their pharmacological activities. In the last decades, there has been a significant interest in synthesis and biological evaluation of metal complexes with redox-active ligands. A substantial step in the development of these redox-active agents is the study of their physicochemical and biological properties, including investigations in vitro of model enzyme systems, which can provide evidence on a plausible mechanism underlying the pharmacological activity. When considering the peculiarities of the pharmacological activity of the sterically hindered diphenol derivatives and their nickel(II), copper(II) and zinc(II) complexes synthesized, we took into account the following: (i) all these compounds are potential antioxidants and (ii) their antimicrobial activity possibly results from their ability to affect the electron-transport chain. Conclusion: We obtained novel data demonstrating that the level of antibacterial and antifungal activity in the series of the above-mentioned metal-based antimicrobials depends not only on the nature of the phenolic ligands and complexing metal ions, but also on the lipophilicity and reducing ability of the ligands and metal complexes, specifically regarding the potential biotargets of their antimicrobial action - ferricytochrome c and the superoxide anion radical. The combination of antibacterial, antifungal and antioxidant activity allows one to consider these compounds as promising substances for developing therapeutic agents with a broad spectrum of activities.

The redox-activity of novel bioactive Ni(II) complexes with ortho-and meta-diphenols was investigated.Amorphous water insoluble complexes with general formula NiL2 were synthesized according to the authorial method.It was found that the complexes are highly lipophilic (lgPow= 2.5÷3.5),stable in water-organic media (stability constants logarithm lgβ=15-18) and have a non-electrolyte nature.Voltammetry analysis was used to determine the first oxidation peak (Epa 1 , V) as a thermodynamic criterion of compounds' reducing ability.It was found that complexes with ortho-diphenol derivatives possess stronger reducing ability then the complexes with meta-diphenol.Antimicrobial activity of Ni(II) complexes against Mycobacterium smegmatis and Candida albicans were evaluated.Intricate dependence between reducing ability and bactericidal activity was found.

Derivatives of 2-amino-4,6-di-tert-butylphenol exhibit antiviral properties and radical regulatory activity against various types of organic radicals which determines the actuality of their further investigation. But the question of aminophenol derivatives immunomodulatory activity remains open. In this regard, the aim of the study was to assess the effects of 2-amino-4,6-di-tert-butylphenol derivatives on the viability and functional potential of human peripheral blood lymphocytes. As a result of the studies, it was shown that aminophenol compounds at concentrations of 10–5–10–7 mol did not exert a toxic effect while at a concentration of 10–4 mol showed a cytotoxic effect due to the induction of secondary necrosis. Compounds N-(2-hydroxy-3,5-di-tert-butylphenyl)-4-methylbenzenesulfonamide and 2,4-di-tert-butyl-6-morpholinophenol at a concentration of 10–6 mol stimulated the extracellular production of α-interferon by peripheral blood mononuclear cells and intracellular production of γ-interferon by CD3+T-lymphocytes. An immunosuppressive effect (more than 50 %) of N-(2-hydroxy-3,5-di-tert-butylphenyl)-4-methylbenzenesulfonamide and 2,4-di-tert-butyl-6-morpholinophenol compounds at a concentration of 10–5 mol was revealed to the mitogen-induced proliferation of T-lymphocytes.

Исследована возможность применения пространственно-затрудненных дифенолов и аминофенолов в качестве стабилизаторов в рецептурах резиновых смесей на основе неполярного синтетического полиизопренового каучука. Установлено влияние новых стабилизирующих добавок на реологические характеристики эластомерных композиций. Исследуемые добавки различаются типами заместителей в бензольном кольце и их пространственным расположением. Данные ингредиенты вводились в резиновые смеси в дозировках 0,5 и 1,5 мас. ч. на 100 мас. ч. каучука. Образцом сравнения являлись эластомерные композиции, не содержащие стабилизаторов, а также композиции с промышленными химическими противостарителями 2,6-ди-трет-бутил-4-метил-фенолом (ионол, BHT) и N-(1,3-диметилбутил)-N'-фенил-n-фенилендиамином (дусантокс 6PPD) в аналогичных дозировках. Выявлено, что введение в ненаполненные резиновые смеси на основе синтетического полиизопренового каучука определенных типов новых полифункциональных стабилизирующих добавок на основе пространственно-затрудненных дифенолов и аминофенолов оказывает незначительное влияние на вязкость по Муни и релаксацию напряжений сдвига композиций, что не потребует корректировки составов рецептур резиновых смесей и технологических режимов их переработки. Показано, что эластомерные композиции с новыми стабилизирующими добавками по вязкостным и релаксационным характеристикам не уступают композициям с промышленными стабилизаторами, что подтверждает возможность применения новых соединений в качестве стабилизаторов эластомерных композиций.

The object of the work is to develop optimal composition of a gel with wound­healing ability based on Ag(I) complex with 2­(4,6­di­tert­butyl­2,3­dihydroxyphenylsulphanyl)acetic acid to produce a novel effective remedy. It was found that propylene glycol (PG) favours the formation of more fine suspension of Ag(I) complex, and introduction of polyvinylpyrrolidone (PVP) hinders aggregation of the particles of the complex, thus providing optimal dispersity of the gel suspension. The gels based on methyl cellulose (MC) are characterized by an acceptable degree of release of Ag(I) complex. It is the gels containing PG and PVP that are characterized by the most complete release of the active substance, which is in agreement with the data on the optimal dispersity. It was found that PG and PVP being introduced into the gel composition increase the osmotic activity of the gel considerably. The optimal composition of the ointment base was determined, %: MC – 3.5; PVP – 5.0; 0.1 mol/L citric acid solution – 5.0; PG – 20.0; water for injections – up to 100.0. The gel obtained was shown to surpass «Dermazin» cream and «Levomecol» ointment in wound­healing ability, while the content of the active substance was significantly lower (0.5 %), and to promote wounds to be cleansed of microorganisms fast and completely too. No accumulation of silver in the liver was found when the gel was used medicinally.

Experiments on cell cultures addressed the antiviral properties of 2-anilino-4,6-di- tert -butylphenol and N-(3,5-di- tert -2-hydroxyphenyl)acetamide, both of which are o -aminophenol derivatives, and 3,4-dihydroxy-benzoic acid against herpes simplex virus and in experimental cutaneous herpes in white mice. Assessment of the data obtained here indicates that all three study compounds were significantly less active than acyclovir in cell cultures. In experiments on laboratory animals, the efficacy of ointment containing N-(3,5-di- tert -2-hydroxyphenyl) acetamide was comparable with that of acyclovir ointment, while ointments containing 2-anilino-4,6-di- tert -butylphenol and 3,4-dihydroxybenzoic acid were less active.

C 6 -Substituted derivatives of 3,5-di- tert -butyl-1,2-dihydroxybenzene have been synthesized, and their effect on radiation-induced free-radical oxidation of n -hexane and production of reactive oxygen and chlorine forms in neutrophils have been studied. It has been shown the introduction of the phenylhydrazone and phenylazomethine groups significantly increases the antioxidant activity of pyrocatechol derivatives. For six compounds, the ability to prevent the development of oxidative stress due to hyperproduction of active oxygen intermediates and HOCl/OCl − in neutrophils has been revealed.