This study reports the design, synthesis, and comprehensive biological evaluation of a new class of orthopoxvirus inhibitors utilizing natural bicyclic monoterpenoid scaffolds as strategic replacements for synthetic polycyclic cores. A focused library of amides based on camphor, apo-/isocamphane, and nopol-derived amines was synthesized and screened for activity against vaccinia (VACV), cowpox (CPXV), ectromelia (ECTV) and variola (VARV) viruses. Structure-activity relationship (SAR) analysis identified the importance of a para-substituted electron-withdrawing group on the benzamide moiety, with the apocamphanyl amine series yielding the most potent candidate, compound 13d. Compound 13d exhibited potent in vitro antiviral activity with IC50 values of 0.32 μM (VACV), 4.43 μM (CPXV), 3.28 μM (ECTV), and 1.6 μM (VARV) coupled with high selectivity indices (up to 1226). Further profiling revealed metabolic stability of 13d in mouse blood and favorable pharmacokinetics in mice following a single intragastric dose (100 mg kg-1), characterized by rapid absorption and a long elimination half-life (T 1/2 ∼ 6.7 h), supportive of once-daily dosing. Computational studies involving pharmacophore analysis, molecular docking, and MD simulations elucidated the binding mode to the p37 phospholipase domain and rationalized the observed SAR, highlighting the critical role of hydrophobic interactions and stereochemistry. These findings validate the bicyclic monoterpenoid platform as a promising strategy for discovering potent, metabolically stable anti-orthopoxvirus agents and establish 13d as a compelling lead candidate for further preclinical development.

The antiviral activity of 12 nitrogenand oxygen-containing heterocyclic compounds was studied by screening against the vaccinia virus in Vero cell culture and the data obtained were compared with the results of ab initio quantum chemical calculations using the DFT (density functional theory) method. The index of selectivity was found to be contingent upon the toxicity of the compounds under study. Compounds containing a 2,3-dichlorobenzyl group were found to be more toxic and unpromising as antiviral compounds. In addition, biological testing showed that (E)-azomethines containing a fragment of 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole showed no antiviral activity. Compounds derived from vanillin and vanillal have proved to be the most promising in relation to the smallpox vaccine virus. The method of preliminary quantum chemical modeling can make it possible to identify unpromising, low-activity structures even at the planning stage of work on the synthesis and bioscreening of new chemical compounds.

In 2022, the number of mpox cases spiked worldwide, leading to a surge in scientific research on members of the Orthopoxvirus genus and the discovery of new compounds exhibiting anti-orthopoxvirus activity. This work is devoted to the synthesis of compounds containing an adamantane fragment and the evaluation of their activity against the vaccinia virus, offering a possible mechanism of the antiviral action of the synthesized agents. Among all the studied adamantane derivatives, three compounds (2, 4, and 12) were found to demonstrate the highest antiviral activity, with the most promising compound 2 (N-(adamantan-1-yl)isonicotinamide) having the lowest toxicity level with a selectivity index (SI) of 115. The pharmacophoric profiles of these compounds are similar to the pharmacophoric profile of tecovirimat, an inhibitor of the membrane viral protein p37. Analysis of the results of molecular modeling suggests that the investigated compounds can inhibit the vaccinia virus by suppressing the phospholipase activity of membrane viral protein p37.

The study presents the discovery of a novel class of N-arylated 1,2,4-oxadiazol-5(4H)-ones as potent inhibitors of orthopoxviruses, including the variola virus (VARV). Through systematic structural modifications, two lead compounds, 4 (4-CF3/4-NO2) and 10 (4-I/4-NO2), demonstrated in submicromolar concentration antiviral activity against Vaccinia virus (VACV), cowpox virus (CPXV), ectromelia virus (ECTV), and VARV, with selectivity indices (SI) up to 13738. Studies of mechanisms of action, including time-of-addition experiments and molecular modeling, have shown that these compounds can target the conserved protein p37, which plays a key role in the envelope of the virus. Furthermore, bioinformatic analysis revealed potential interactions with late-stage replication proteins encoded by the A39R and C8L genes. The synthesized derivatives showed activity higher than that of Cidofovir, although they were less effective than that of Tecovirimate. This work highlights the potential of oxadiazolone-based scaffolds as broad-spectrum antipoxviral agents that meet the unmet need for therapy against emerging and re-emerging orthopoxviral threats.

The continuing worldwide mpox outbreak (2022-present) provokes interest in the search for new small organic molecules possessing anti-viral activity against orthopoxviruses. In the course of this search a series of new 2-(2-arylethenyl)imidazoles were synthesized. Structural features of these derivatives were studied by means of NMR spectroscopy and single-crystal X-ray diffraction analysis. It was not surprising that all the title compounds were trans-isomers. Prevailing tautomers for 2-(2-arylethenyl)-1-hydroxyimidazoles were determined. If a carbonyl-containing substituent was present at position 5 of the imidazole, then the compound existed predominantly in a N-hydroxy-tautomeric form both in the gaseous phase and in solution in polar aprotic solvents. In crystal form, either a single N-hydroxy-tautomer or a mixture of both tautomers (N-hydroxyimidazole and imidazole N-oxide) were observed. For 2-(2-arylethenyl)-1-hydroxy-4,5-dimethylimidazoles in solution in polar aprotic solvents an equilibrium mixture of both tautomers in rapid interconversion was registered. Predominant conformers were determined for the 1-hydroxyimidazoles, 1-methoxyimidazoles, and 1-methylimidazole 3-oxides under consideration. Cytotoxicity and virus-inhibiting activity against Vaccinia virus were evaluated in vitro for all the imidazole derivatives under study. 2-(2-Arylethenyl)-1-methoxyimidazoles were determined to be the most promising. They also exhibited activities against zoonotic orthopoxviruses such as Cowpox virus and Mousepox (Ectromelia) virus. The lead compound 1-(1-methoxy-4-methyl-2-((E)-2-(4-nitrophenyl)ethenyl)-1H-imidazol-5-yl)ethanone 4b demonstrated the highest selectivity index against Vaccinia virus (SI = 305).

Fruits of many Rosa species are extensively used as a vitamin source. Meanwhile, information about metabolites and biological activities of Rosa underground parts is still rare. The aim of this investigation was to evaluate extracts of the roots and rhizomes of Rosa majalis, Rosa canina, and Rosa glauca as sources of antioxidant and anti-influenza compounds and to determine the tissue distribution of the metabolites. The latter were quantified by spectrophotometry and HPLC. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay was used for antioxidant-activity assessment. The antiviral activities were evaluated as 50% inhibitory concentrations (IC50). Histochemical analysis was performed to determine tissue localization of metabolites in the roots and rhizomes. The EtOH extract of R. majalis showed the highest concentrations of phenolic compounds (84.51 mg per gram of dry mass of the roots) and saponins (166.23 mg & sdot;g-1). Total gallic and ellagic acids were the main phenolic compounds in the majority of the extracts. The H2O extract of R. glauca manifested the highest free-radical-scavenging activity (7.01 trolox equivalents) and anti-influenza effects (IC50 15.6 and 76.7 mu g & sdot;mL-1) against strains A/Aichi/2/68 (H3N2) and A/chicken/Kurgan/05/2005 (H5N1), respectively. The examination of tissue localization of the metabolites showed that phenolic compounds are distributed throughout the root and rhizomes, in particular, in the phloem and cortex. Our findings prove the good value of the underground parts of the tested Rosa species as sources of compounds for efficient inhibition of free-radical damage and of influenza virus. Processing of these plant materials can contribute to the sustainability of rose professional planting.

A series of 7-(het)aryl-6-benzyloxycarbonyl-substituted dihydro(azolo)pyrimidines were synthesized by exploiting the multicomponent Biginelli reaction between benzyl acetoacetate, various aldehydes, aminoazoles (3-aminopyrazole, 5-aminotetrazole, and 3-amino-1,2,4-triazole) or urea. The compounds obtained were assessed for their cytotoxicity and the antiviral activity in MDCK cell culture against the influenza virus strain A/California/04/2009 (H1N1)v (subtype A/H1N1pdm09) in comparison with the known anti-influenza drugs rimantadine, oseltamivir, and triazide. In addition, using molecular docking, the free energies for binding of the polymerase proteins PA (polymerase acidic) and PB2 (polymerase basic) of the internal ribonucleoprotein (RNP) of influenza virus (IV) A/California/04/2009 (H1N1)v with dihydro(azolo)pyrimidines. Compounds 1a and 11 were found to be the most active against this strain of influenza virus, but the value of binding free energies of the PB2 protein for compound 11 was higher (12.55 mu g/mL).

A new method is proposed for the synthesis of pyrido[3,4-c]cinnolines and pyrido[3,2-c]cinnolines. Pyridine-3-diazonium tetrafluoroborates, containing donor methoxy groups in one of the aryl substituents, form pyridocinnolines at 0 degrees C by intramolecular azo coupling reaction. The 2 '-methoxy group in the aryl substituent of the pyridine-3-diazonium salt participates in the aromatic nucleophilic substitution reaction, which results in the elimination of the diazo group to form benzofuro[2,3-c]pyridine and benzofuro[3,2-b]pyridine. The intermediate and target reaction products were isolated in high yields.

As known, the lipid peroxidation processes play an important role in regulation of the metabolism in the biological system of varying complexity. Besides, it is shown that the state of the physicochemical regulatory system of the lipid peroxidation is a base for the ecological monitoring, and the disruptions in the redox-state of the natural water is due to a development of its toxic properties. However, the status of lipid peroxidation process after the public utilityaccident is poorly studied. The aim of this work was to study dynamics of the lipid composition and its physicochemical proper-ties in samples of the Dubna River water after the accident with sewer in Verbilki (June 2020) to assess their role in toxigenization of the nature water. The low content of hydrophobic compounds and no phospholipids identified in the natural water before the accident. Five days after the accident, the content of the hydrophobic compound was 8.4 times higher than the initial value. Within 9 days after the accident, the phospholipids in water samples are predominantly in the easily oxidizable fractions. These data are confirmed by UV-spectrophotometry and TLC methods. The data obtained and the literature analysis allow us to conclude that a significant increase in the content of hydrophobic compounds (including ketodienes and fat acids) with pronounced toxic properties and lytic effect on biological membranes causes toxigenization of natural water

The interrelation between the composition of components of five samples of natural water and state indices for the lipid peroxidation regulatory system in a model system based on the natural phospholipids was explored and involvement of natural phospholipids in the formation of the toxicity of the natural water was also studied. It is shown that the presence of N- and P-containing compounds in natural water samples leads to inhibition of the processes relevant to lecithin autooxidation and luminescence intensity of luminous bacteria, has a significant effect on the spontaneous aggregation of lecithin, while an increase in the content of hydrophobic compounds results in a higher negative value of the ξ potential of its particles. High sensitivity of the lipid peroxidation regulatory system to the presence of components even at low concentrations in the natural water makes it a promising tool to test the effect of natural water on biological objects. Mathematical processing of UV spectra of the natural water samples with the Gauss method can be used as an express test for the analysis of its hydrochemical composition. The effects of natural water components on the state of membranes of biological objects and intracellular processes are confirmed by means of biotesting methods.

The role of minor fractions of the liver phospholipids in the mechanism of adaptation of four species of wild rodents trapped in different years in the Chernobyl accident zone in areas with a dose rate of the external gamma radiation in 1987 from 0.02 to 200 mR/h to an increased radiation background is studied, depending on the radioresistance of the species. In the first year after the accident, an increase in the share of PL lysoforms and sphingomyelin involved in apoptosis and an increase in cardiolipin taking part in the interaction of DNA with the membrane were revealed. Within 5 years after the accident, there is an increase in the sum share of phosphatidylinositol and phosphatidylserine taking part in the transport of calcium ions and in the regulation of intracellular processes. Data obtained and the analysis of the literature allow us to conclude that changes in the proportion of minor fractions of PL in the liver of wild rodents living on territories with the increased radiation levels, causing adaptive rearrangements of cellular metabolism, were the basis for the formation of new subpopulations of rodents in these territories with a different from norm system of regulation of lipid peroxidation.

Introduction. Since early May 2022, more than 90,000 cases of monkeypox virus infection have been reported in more than 70 countries around the World. This is the largest outbreak of monkeypox ever recorded outside of Africa. The aim of the study is to confirm the first case of monkeypox in Russia, to isolate and sequence a new strain of monkeypox virus (MPXV), and to assess its sensitivity to the 7-[N-(4-trifluoromethylbenzoyl)-hydrazinocarbonyl]-tricyclo-[3.2.2.0^2,4]non-8-en-6-carboxylic acid (NIOCH-14) antipox drug. Materials and methods. The biological materials obtained from the affected area of the skin (contents of vesicles), a nasopharyngeal smear, sputum and venous blood from a patient with suspected monkeypox were used. The disease was confirmed by PCR followed by determination of the nucleotide sequence of viral DNA by sequencing. Isolation of the new MPXV strain from clinical samples was carried out in Vero E6 cells. The antiviral effectiveness of NIOCH-14 against the new MPXV strain was assessed using an adapted spectrophotometric method. Results. A diagnostic study of the biological samples of a patient who returned from a tourist trip to European countries with complaints of skin rashes all over the body revealed MPXV DNA. A new strain of MPXV was isolated from vesicles in Vero E6 cells, and the genomic sequence MPXV-pustule S45 was assembled using high-throughput parallel sequencing (NGS). Discussion. The effectiveness of the finished dosage form of NIOCH-14 against the new strain of MPXV based on the results of determining the 50% virus inhibitory concentration (IC50) was 0.02 μg/mL, and the selectivity index (SI) was 15,000. Conclusion. In this study, the pathogen of monkeypox was detected and identified using real-time PCR, NGS and electron microscopy, and the first imported case of this disease in Russia was confirmed. It has been proven that the drug NIOCH-14 exhibits high antiviral activity in vitro against the new MPXV strain.

Scientific interest in orthopoxvirus infections and search for new highly effective compounds possessing antiviral activity against orthopoxviruses have significantly increased as a result of worldwide mpox outbreak in 2022. The present work deals with the synthesis of new 2-arylimidazoles exhibiting in vitro activity not only against the vaccinia virus, cowpox virus and ectromelia (mousepox) virus but also against the variola virus. Among the imidazole derivatives under consideration (1-hydroxyimidazoles, 1-methoxyimidazoles, 1-benzyloxyimidazoles, and imidazole N-oxides), the most promising antiviral activity is demonstrated by 1-hydroxyimidazoles, which may exist as two prototropic tautomers. Both of these tautomers may be manifested in different crystal structures of these compounds, according to single-crystal X-ray diffraction analysis, while predominantly one of them (N-hydroxy-tautomeric form) is present in DMSO-d 6 solutions and in the gaseous state, as shown by NMR spectroscopy and quantum-chemical calculations. The leader compound 1-hydroxy-2-(4-nitrophenyl)imidazole 4a demonstrated the highest selectivity indices against the vaccinia virus (SI = 1072) and the variola virus (SI = 373).

The dynamics of water physicochemical properties and hydrochemical characteristics in the Dubna River was studied from April 18, 2021 to July 4, 2021. The study showed an increase in pH with increasing water temperature and considerable variation in the concentrations of ammonium, nitrite, and phosphate ions in it. Promising approaches were shown to be the use of mathematical processing of UV-spectra of water samples by Gauss method and model biological systems based on natural lipids (low-temperature oxidation of lecithin, and its ability to spontaneously aggregate in a polar environment) for assessing the quality of natural water and its effect on the regulation of oxidation processes in biological objects. Thus, analysis of UV-spectra revealed the presence in water of hydrophobic organic compounds throughout the observation period, compounds with conjugated double bonds and N-containing compounds in late April, free fatty acids, organic compounds with a carbonyl group and P-containing compounds at the end of May and an increase in the diversity of components in water samples in late June. Water samples taken in summer, increased the rate of lecithin oxidation by a factor of more than 1.8, and, throughout the observation period, they caused staged changes in the size of aggregates formed by it and produced a considerable effect on their dzeta-potential.

Selective synthesis of polycarbonyl conjugates of (+)‐fenchone and (+)‐camphor was carried out (44–90% yields) via the ring‐opening transformation of 5‐acyl‐4‐pyrones with hydrazones of the corresponding monoterpenoids. A strong influence of the hydrazone fragment on the observed tautomeric equilibrium of the tricarbonyl system was shown. Although the major tautomer of the conjugates is the acyclic polycarbonyl form, the camphor‐based conjugates undergo new type of ring‐chain tautomerism, diketoenaminone‐dihydropyridone equilibrium, and predominantly exist in the cyclic dihydropyridone form in DMSO‐d6. The polyketones can undergo intramolecular cyclization to form N‐amino‐4‐pyridones in high selectivity. In vitro screening for activity against the influenza virus H1N1 and vaccinia virus was estimated for the obtained conjugates. The (+)‐fenchone derivatives demonstrated the higher activity against vaccinia virus than camphor derivatives. The conjugate, which was prepared from diethyl isochelidonate and hydrazone (+)‐fenchone, showed the highest activity against vaccinia virus (SI = 17).

Experimental results on the effect of phospholipids ( l -α-phosphatidylcholine, dipal-mitoylphosphatidylcholine, egg yolk lecithin; soybean lecithin) on the inhibitory efficiency of 20 antioxidants (AOs) are summarized depending on the structure and kinetic parameters of AOs in reactions with free peroxyl radicals and the composition of phos-pholipids. The reactivity of AOs and their mixtures with phospholipids was evaluated using three model systems: the initiated oxidation of ethylbenzene and methyl oleate (kinetic oxidation region) and the autooxidation of neat methyl oleate in a free-air exposure system (diffusive oxidation region). For the most part, the addition of phospholipids leads to a change in the antiradical and antioxidant activity of AOs and in the initial oxidation rate due to the complexation between AOs and phospholipids (confirmed by UV and IR spectroscopy) and the effect of AOs on the ability of phospholipids to self-aggregate (demonstrated by dynamic light scattering). This effect depends on the structure of AOs, their ability to be involved in side reactions, the phospholipid composition, the polarity of the medium, and the intensity of oxidation processes. The obtained data and the literature analysis demonstrate that it is necessary to investigate in detail the mechanism of interrelations between AOs and phospholipids, which are the main components of biological membranes, in order to obtain an adequate preliminary evaluation of the most promising newly synthesized compounds for practical use.

The participant of the minor fractions of the liver phospholipids in the mechanism of adaptation for four species of wild rodents caught in the different years in the Chernobyl accident zone at the areas with level of the dose rate of the external γ-irradiation from 0.02 to 200 mR/h in 1987 is studied in dependence on the radioresistance of species. At first year after accident the growth of the lysoforms of phospholipids share and sphingomyelin involved in the apoptosis process and the increase of cardiolipin taking part in the interaction of DNA with membrane is revealed, During 5 years after the accident there is the increase of the sum share of phosphatidylinositol and phosphatidylserine taking part in the calcium ion transport and in regulation of the inner cell processes. Data obtained and analysis of literature allow us to conclude that the change of proportion of the minor fractions of phospholipids in liver of the wild rodents living at areas with the increased radiation level causing the adaptive reorganizations in the cell metabolism are the base for formation of the new subpopulations in these territories having the lipid peroxidation regulatory system different from norm.

The influence of the composition and physicochemical properties of lecithin lipids, the duration of exposure to ultrasound, and centrifugation on the composition and physicochemical properties of liposomes formed from lecithin has been studied. It has been revealed that the intensity of lipid peroxidation has an inverse correlation with the phospholipid level in the total lipid composition of lecithin and a direct correlation with the relative content of cardiolipin in the composition of lecithin phospholipids. It has been shown that the duration of ultrasound exposure and centrifugation causes changes in the composition and properties of the liposome lipids. Decreases in the pH of the medium and the intensity of lipid peroxidation of liposomes were observed under centrifugation. It was revealed that the changes in the ability of the liposome lipids to oxidation depending on the duration of ultrasound exposure and centrifugation are due to the relative changes in the sum percentage of the acidic minor fractions in the composition of their phospholipids.

The parameters of the UV spectra of quercetin, dihydroquercetin, genistein, preparations of natural phospholipids (PLs), and mixtures of flavonoids with PLs in chloroform are determined by mathematical processing of these spectra using the Gauss method. It is shown that the position of the maximum of band II in the UV spectra of the studied flavonoids does not depend on the nature of the solvent, and the dependence of the optical density of bands II and I in solutions of these flavonoids on their concentration obeys the Bouguer–Lambert–Beer law. It is found that the parameters of the UV spectra of natural lipids significantly depend on the polarity of the solvent and the composition of PLs. Using genistein as an example, it is shown that the flavonoid interacts with the conjugated double bonds of fatty acids of PLs and nitrogen- and phosphorus-containing groups of PLs also participate in the formation of complexes.