Two series of new diorganotin complexes 1-10, with abiraterone acetate and abiraterone, were synthesized and characterized using 1H, 13C, 119Sn NMR, IR spectroscopy, ESI-MS, and elemental analysis. The anti-inflammatory activity of compounds was evaluated by their inhibition ability toward lipoxygenase. The most active compounds were dibutyltin complexes 4 and 9. Antiproliferative activity in vitro was studied on HCT-116, MCF-7, and PC-3 cancer cell lines, as well as on primary rat skin fibroblasts. Compounds with dibutyltin and diphenyltin moieties (4, 9 and 5, 10, respectively) demonstrated the highest antiproliferative effect, significantly inducing apoptosis in HCT-116 and PC-3 cells and causing the cell cycle arrest at the G2/M phase. These complexes also exhibited significant antibacterial activity comparable to that of ciprofloxacin against the Bacillus subtilis strain. Complex 5 showed antifungal activity against Candida albicans, although it was weaker than metronidazole.

New vitamin E hydrazone analogues bearing (2-hydroxyaryl) methylene moieties were obtained from Trolox hydrazide and the corresponding 2-hydroxyarenecarbaldehydes. The compounds demonstrated effective antioxidant activity and selective action against cancer cells, suggesting their potential as supportive pharmacological agents in oncology.

In this study, the analgesic activity of the Cl-Ala-OH-AR compound was evaluated in various models of somatogenic somatic pain. The results showed that the Cl-Ala-OH-AR compound significantly increases the latency of the reaction in tests of the formation of thermal somatic pain, such as "Hot plate" and "Tail Twitching", however, its effectiveness was lower than that of tramadol and adenosine. In the algogen-induced somatic pain model evaluated in the formalin test, Cl-Ala-OH-AR demonstrated more pronounced analgesic properties, especially in the inflammatory phase, where the reduction in pain reactions was 3.4 times greater than the effect of adenosine. These results indicate a significant analgesic potential of Cl-Ala-OH-AR in the context of somatogenic somatic pain caused by algogens, which opens up prospects for further study.

Aim: To study the potential of the melatonin isostere, the compound K-165, to reduce intraocular pressure in old animals with elevated ophthalmotonus, and to evaluate its local irritant effect and cytotoxic properties. Materials and methods: The study was conducted in old rats over two years of age with intraocular pressure (IOP) above 16 mmHg. The level of ophthalmotonus was measured using a portable contact tonometer Tonovet ICare (Finland). The presence of IOP-lowering activity of the tested substance was assessed by the maximum reduction in ophthalmotonus compared to baseline pressure levels. The assessment of local irritant effects was conducted using a three-point scale after applying the substance to the eye tissues of the laboratory animal. Cytotoxicity was studied on HepG2 cell lines (human hepatocellular carcinoma) (CLS Cell Lines Service). Result: The compound K-165 reduces the level of intraocular pressure (IOP) in old animals, outperforming melatonin comparator. K-165 decreases ophthalmotonus by 21 % from baseline by the third hour and does not have a local irritating effect on the eye conjunctiva. It is shown that the mean cytotoxic concentration exceeds 100 μM for the compound K-165 (R² = 0.9), indicating low cytotoxicity. Conclusion: The compound K-165 significantly reduces IOP, does not have a local irritating effect, and is classified as a compound with low cytotoxicity.

In this work, stable chemical precursors (3,5-DTBC) and alkylated derivatives were synthesized through strategic modifications guided by the redox and chelation properties of catechol. Leveraging the molecular principle that fusing two bioactive components often yields synergistic effects, catechol — a polyphenol with broad biological activities — was integrated into the nitrogen-containing heterocyclic core structure, imidazolidine-2,4-dione, to design a novel class of hybrid compounds (7a–q) with diverse pharmacological profiles. The primary objective was to explore efficient synthetic routes, characterize structures via physicochemical analyses, and possible evaluate cytotoxicity and AT1-inhibitory activity in vitro.

Objective: Synthesis of new compounds, melatonin isosters, and study of their ability to reduce intraocular pressure. Materials and methods: Based on the previously made forecast and on the similarity with the selected compounds, the synthesis of new compounds was carried out – melatonin isosters having a 2,3-dihydro-1,4-benzodioxin cycle connected by a linker of various chemical structure with a nitrogen-containing heterocyclic core. The structure of the synthesized compounds was proved by 1H- and 13C- NMR spectroscopy, purity and individuality – by chromatographic methods. Intraocular pressure in laboratory animals was measured using a contact veterinary tonometer Tonovet (Finland). Cytotoxicity was assessed using MTT test on normal rat skin fibroblasts. Results: Derivatives (benzodioxane-2-yl)methanol reduced the level of IOP in varying degrees of severity. The VMA-22-37 compound showed the greatest activity. With topical application of a 0.4% solution, the compound reduced the intraocular pressure of intact rats by 26.6%, while not affecting the control eye. This compound also has low cytotoxicity. Conclusion: Derivatives (benzodioxane-2-yl)methanol is promising for the search for compounds capable of reducing increased intraocular pressure.

Glaucoma is one of the major causes of irreversible blindness worldwide. Increased intraocular pressure (IOP) is a key factor in the onset and progression of this disease. The drugs used to treat glaucoma influence a variety of biological targets. Azolopyrimidine derivatives have attracted significant attention as potential agents for the treatment of glaucoma because they presumed to be analogs of adenosine receptor (AR) agonists and antagonists. In this study, a series of novel 3(4)-alkyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-amines were synthesized to develop promising ophthalmic hypotensive drugs. The synthesized compounds demonstrated significant hypotensive activity against IOP, which opens new possibilities for glaucoma therapy.

This study is dedicated to the development of multimodal anticancer agents. We have obtained ruthenium complexes conjugated with the steroid-type antitumor drug abiraterone acetate in order to take advantage of the dual antitumor properties of both ruthenium and abiraterone. The compounds exhibit good antiproliferative activity against cancer cells, with selectivity over primary fibroblasts. Real-time cell analysis revealed that compound dichlorido(η6-p-cymene)(abiraterone acetate)ruthenium(II) had pronounced antiproliferation activity compared to abiraterone acetate. Flow cytometric studies on the mechanism of cell death have revealed that the most active compound induces apoptosis more effectively than abiraterone acetate. Our findings demonstrate the potential of this novel dual-action compound as promising candidates for further development as anticancer agents.

Aim.Glaucoma is a whole group of diseases caused by increased intraocular pressure (IOP), leading to atrophy of the optic nerve and irreversible blindness. Melatonin has a wide range of biological activity, including antioxidant and antiglaucoma, but its use is limited by insufficient stability and duration of action. To search for new, more effective antiglaucoma agents among derivatives of 3-arylidene-2-oxindole, melatonin analogues, a search for quinonoxidoreductase 2 (NQO2) inhibitors was performed, antioxidant activity was determined and the effect of active compounds on intraocular pressure was studied.Materials and methods.The study of inhibitory activity against NQO2 was evaluated kinetically using menadione and N-benzyl-dihydronicotinamide assubstrate and co-substrate, respectively. Antiradical activity was studied for reducing superoxide-dependentluminescence in a reaction medium containing hemoglobin, luminol and hydrogen peroxide using the Infinite M200 PRO microplate reader (Tecan, Austria), as well as for free radical binding tests OH•-, ABTS and DPPH. Cytotoxicity assessment was carried out using a standard MTT test on MCF-7 and HepG2 line cells. Intraocular pressure in laboratory animals was measured using a contactveterinary tonometer Tonovet (Finland).Results.Derivatives of 3-arylidene-2-oxindole have demonstrated significant antioxidant activity. A number of NQO2 inhibitors have also been identified. The most active compound inhibits human NQO2 with an IC50of 0,4 μM. The compound also showed anti-radical activity, binding the superoxide anion to IC50of 6,1 μM, superior to melatonin on both counts, and low cytotoxicity. With topical application of a 0,4% solution, the compound reduced the intraocular pressure of intact rats by (40,9 ± 6,4) %, while not having a systemic hypotensive effect.Conclusion.Derivatives of 3-arylidene-2-oxindole are promising for drug discovery for the treatment of eye diseases associatedwith increased intraocular pressure or oxidative stress, such as glaucoma, uveitis and diabetic retinopathy.

Halides of 2-aminobenzimidazolium and derivatives of 9-substituted 2-(4-fluorophenyl)imidazo[1,2-a]benzimidazoles have been studied for ten types of biological activity in vitro. Among the aminobenzimidazolium derivatives, a compound with NHE-1 inhibitory activity has been identified. It has been demonstrated that imidazobenzimidazole derivatives affect the duration of the refractory period of rat atria, platelet aggregation, and hemorheological activity and inhibit the formation of end products of glycation. No DPP-4 inhibitory, antioxidant, kappa-opioid, and 5-HT2A and 5-HT3 antagonistic activities have been found among the studied compounds.

Six compounds of the 5(7)-alkylamino-6-nitroazolopyrimidine and 8-alkylazolo[5,1- b ]purine series were selected based on the structural analysis of A 1 adenosine receptor inhibitors and the role of this biological target in the modulation of intraocular pressure, an important factor in the pathogenesis of glaucoma. These heterocycles were shown to exhibit a weak affinity towards the A 1 adenosine receptor on an in vitro model of the adenosine-dependent change of the chronotropic effect on isolated atria of white mice. On the other hand, thiadiazolo[3,2- a ]pyrimidines and triazolo[5,1- b ]purine displayed an in vivo hypotensive effect in rats . The leading compound, 5-methyl-8-(hydroxyethyl)triazolo[5,1- b ]purine) (0.2% solution), caused a 34% reduction of ophthalmotonus in 3 h without an adverse resorptive effect. In addition, using the MTT-test it was shown on the human HepG2 cell line that the heterocycles affecting the intraocular pressure were by one to two orders of magnitude less cytotoxic than the reference doxorubicin.

A novel polydentate chelating antioxidant ligand and series of organotin complexes on its base were synthesized and characterized by NMR 1H, 13C, 119Sn, IR spectroscopy, X-ray, and elemental analysis. Their antioxidant activity was evaluated in DPPH and NBT-tests, and as lipoxygenase inhibitory activity. It was shown that ligand alone is a radical scavenger, while introducing tin in the structure of the compound significantly decreases its activity. For the ligand alone the ability to strongly suppress the formation of advanced glycation end products (AGEs) was shown, which may be associated with the established antiradical activity. All synthesized compounds appeared to be moderate lipoxygenase inhibitors. The stability of compounds to hydrolysis under different pH was estimated. The ligand undergoes decomposition after about an hour, while organotin complexes on its base demonstrate vast stability, showing signs of decomposition only after 5 h of experimentation. Cytotoxicity of compounds was studied by standard MTT-test, which showed unorthodox results: the ligand itself demonstrated noticeable cytotoxicity while the introduction of organotin moiety either did not affect the toxicity levels or reduced them instead of increasing. Organotin complexes possess luminescence both as powders and DMSO solutions, its quantum yields reaching 67% in DMSO. The combination of luminescence with unique cytotoxic properties allows us to propose the synthesized compounds as perspective theranostic agents.

A series of purine ribonucleosides bearing chiral amino acid amides at the C6 position of 2-chloropurine was synthesized. Molecular docking of the synthesized analogs of 2-chloroadenosine by their affinity for A1 adenosine receptors (A1ARs) was conducted. The investigation of A1AR stimulating activity of synthesized nucleosides was carried out in a model of an isolated mouse atrium. We have shown that derivatives with tyrosine, valine, and serine residues exhibit the properties of A1AR partial agonists. Animal experiments in the open field test have shown that these compounds have different profiles of psychoactive action. These nucleosides have an ophthalmic hypotensive effect and reduce intraocular pressure in a manner slightly inferior to that of timolol and brimonidine. The synthesized nucleosides can be the basis for further design and synthesis of new A1AR agonists.

Introduction: Ligands of adenosine A1Rs are potential candidates for the development of drugs for the treatment of paroxysmal supraventricular tachycardia, angina pectoris, hypertriglyceridemia, type 2 diabetes mellitus, neuropathic pain, and heart failure. At the same time, there is a deficiency of drugs that can regulate the functions of A1 receptors. A number of A1-antagonists are at the various stages of clinical trials; other drugs are not very selective or are characterized by an insufficient breadth of their therapeutic action. Therefore, the search for new medicinal compounds for the prevention and treatment of A1-depended diseases among nitro derivatives of tetrazolo[1,5-a]pyrimidine and 1,2,4-triazolo[1,5-a]pyrimidine is of scientific interest. Materials and methods: The search for active compounds was carried out by in silico and in vitro methods. At the first stage, a computer forecast of A1-antagonistic activity was carried out using the Microcosm BioS software. At the second stage, the prediction results were verified in vitro in a model of isolated mouse atria. Results and discussion: Based on the results of the prediction by the method of maximum similarity to standards, the most active compounds III, VIII, and XVII were selected. After testing the prediction results by the isolated atria method, the compound VIII was characterized by A1-blocking effect in vitro at a concentration of 10 μmol/L. Conclusion: The most promising compound with A1-blocking effect in vitro was identified; it is a derivative of tetrazolo[1,5-a]pyrimidine under the code of VIII. It is of interest for us for further in-depth study of its pharmacological properties.

A quantitative determination method for drug substance RU-31, a derivative of a methoxyphenylimidazo - [1,2-α]benzimidazole possessing antimigraine activity, in biological samples was developed. This method has selectivity and high sensitivity sufficient to allow its use for pharmacokinetic studies of RU-31. The sensitivity of the method (detection limit) for RU-31 is 100 ng/mL; limit of quantitation, 500 ng/mL. The average measurement error is ≤15%.

Migraine and its comorbid conditions are pathogenetically associated with many factors, including hemorheological disorders. A class of drugs with a 5-HT2A antagonistic mechanism of action, is promising for the prevention and treatment of migraine attacks and concomitant pathologies.The aim of the research is to study and compare a hemorheological activity of anti-migraine drugs, antagonists of 5-HT2A receptors of cyproheptadine, and a new drug that completed preclinical studies of the 1-(2-diethylaminoethyl)-2-(4-methoxyphenyl)-imidazo[1,2-a]benzimidazole derivative of the RU- 31 compound.Materials and methods. The study of the hemorheological activity of the RU-31 compound and cyproheptadine, was carried out using an experimental model of rabbit blood hyperthermia in vitro. Pentoxifylline was used as a reference drug. In the course of the work, the parameters of blood viscosity, aggregation and deformability of erythrocytes were recorded.Results. It has been established that in the concentration of 1 μM, the RU-31 compounds reduce blood viscosity by 17% at high shear rates, which is comparable with pentoxifylline in the concentration of 100 μM on the activity level. In the concentration of 1 μM, cyproheptadine also causes a general tendency to reduce blood viscosity at high shear rates, being inferior in activity to the RU-31 compound and pentoxifylline. In the concentration of 1 μM, the RU-31 compound has a pronounced effect on the aggregation ability of erythrocytes in autologous plasma, reducing the aggregation rate by 70%, while the level of activity is not inferior to the drug compared to pentoxifylline in the concentration of 100 μM, and surpasses the drug cyproheptadine. For the RU-31 compound and cyproheptadine, no significant effect on the deformability of erythrocytes has been shown.Conclusion. The capacity of cyproheptadine and the RU-31 compound to influence the rheological properties of blood by reducing blood viscosity and aggregation of erythrocytes has been revealed.

A study on the anxiolytic activity of the new derivatives of 11-dialkylaminoethyl-2,3,4,5-tetrahydrodiazepino[1,2-a]benzimidazole, containing privileged scaffolds of benzodiazepine and benzimidazole in their structure, was conducted. The cytotoxic properties of low levels of six compounds were preliminary determined in vitro using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide test. The screening of these substances for anxiolytic activity was conducted using elevated plus maze (EPM) test in vivo, and DAB-21 was found to be the most active compound. The acute toxicity of DAB-21 was determined as less toxic than that of diazepam. The dose-dependent effect of the most active compound revealed a minimum dose of 1.26 mg/kg, which resulted in the maximum counterphobic effect. The effect of DAB-21 was superior in a number of tests compared with that of diazepam, which indicated a high level of tranquilizing activity for DAB-21. The results of in silico docking analysis suggest that DAB-21 should have a slightly lower anxiolytic activity than diazepam, but should exhibit greater specific affinity for the benzodiazepine site of the GABAA receptor, in comparison with its GABA-binding site. The interaction between DAB-21 and flumazenil in terms of EPM verifies the GABAergic mechanism of action of DAB-21. Our results highlight the potential of 11-dialkylaminomethyl-2,3,4,5-tetrahydrodiazepino[1,2-a]benzimidazoles as promising compounds in the search for new highly effective anxiolytics.

Introduction: Searching for new compounds with anti-anxiety activity resulting from the combination of privileged scaffolds is a promising direction in medicinal chemistry and in the development of new drugs. Anxiolytic potential and cytotoxic properties of previously synthesized molecules, containing fragments of 2,3-benzodiazepine and 1,2,4-triazole – 6-(4-methoxyphenyl)-7H-[1,2,4]triazolo[3,4-A][2,3]benzodiazepines under the generic code RD were studied. Materials and methods: Screening for anxiolytic activity was performed on elevated plus maze (EPM) and open field (OF) test models. Structural and functional analysis of the anti-anxiety activity of the studied substances was carried out. A degree of muscle relaxant effect of the substances was assessed in the tests Grid, Wire, and Rotarod. A cytotoxicity study of RD compounds was carried out using an MTT assay on human hepatocellular carcinoma cells HepG2. Results and discussion: For a number of novel triazolo[3,4-a][2,3]benzodiazepine derivatives, a prominent anxiolytic activity was manifested in terms of EPM test. The results of OF test were consistent with the obtained data and confirmed the presence of the sought activity in the leading compounds. There was no significant effect on muscle tone for the compounds under study. It was observed that RD compounds possessed no cytotoxic properties and were safe for further studies in vivo. Conclusion: Among the new derivatives of 6-(4-methoxyphenyl)-7H-[1,2,4]triazolo[3,4-a][2,3]benzodiazepine under the code RD, substances (RD-4, 12, 13) with a high anxiolytic activity comparable to diazepam and tofisopam were found. The most promising compound is RD-4 due to its pronounced anxiolytic and low cytotoxic properties.

The bioequivalence of the tablet dosage form of RU-31 substance was studied. The main pharmacokinetic parameters were determined. The actual relative bioequivalence index was calculated and turned out to be ~100%. RU-31 from tablets did not accumulate upon triple administration at a dose of 10 mg/kg.

A study of the natural stone in the masonry of secular buildings ? two palaces of Novgorodian archbishops from the 14th and 15th centuries ? was made as part of the extensive archaeological and restoration work in the Novgorod Kremlin that began in 2006. The two structures are unique among mediaeval Novgorodian architecture of the 12th?15th centuries, other surviving examples of which are exclusively church buildings. The aim of the study was to determine whether the intended function of a building had on the particularities of the selection of types of stone and the choice of quarry sites. The main methods of study were laboratory analyses (thin section microscopy, X-ray fluorescence spectroscopy, electron microscopy and X-ray diffraction analysis). which showed that the durable, but hard to work, limestone used in the walls of the buildings was quarried for the most part from the Il?men Clint, 50 km from Novgorod on the other side of Lake Il?men. For paving floors, however, the builders used trimmed slabs of limestone obtained in a different place, possibly on the River Shelon?, 70 km from Novgorod or further afield. A comparison with other works of Novgorodian architecture from the 12th?15th centuries showed that this sort of differentiation between sources for building stone was established practice, as was the use of those particular quarry sites. In the course of this work, we developed a methodology for the identification of limestone that we recommend for use in further studies of the building stone used in Novgorodian architecture. The results obtained are proving important for the resolution of practical tasks in the restoration of Novgorod?s architectural monuments. ? 2020 Elsevier Masson SAS. All rights reserved.