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At the Institute of Cytology and Genetics (Novosibirsk, Russia) for over 85 generations, gray rats have been selected for high aggression toward humans (aggressive rats) or its complete absence (tame rats). Aggressive rats are an interesting model for studying fear-induced aggression. Benzopentathiepin TC-2153 exerts an antiaggressive effect on aggressive rats and affects the serotonergic system: an important regulator of aggression. The aim of this study was to investigate effects of TC-2153 on key serotonergic-system enzymes - tryptophan hydroxylase 2 (TPH2) and monoamine oxidase A (MAOA) - in the brain of aggressive and tame rats. Either TC-2153 (10 or 20 mg/kg) or vehicle was administered once intraperitoneally to aggressive and tame male rats. TPH2 and MAOA enzymatic activities and mRNA and protein levels were assessed. The selection for high aggression resulted in upregulation of Tph2 mRNA in the midbrain, of the TPH2 protein in the hippocampus, and of proteins TPH2 and MAOA in the hypothalamus, as compared to tame rats. MAO enzymatic activity was higher in the midbrain and hippocampus of aggressive rats while TPH2 activity did not differ between the strains. The single TC-2153 administration decreased TPH2 and MAO activity in the hypothalamus and midbrain, respectively. The drug affected MAOA protein levels in the hypothalamus: upregulated them in aggressive rats and downregulated them in tame ones. Thus, this study shows profound differences in the expression and activity of key serotonergic system enzymes in the brain of rats selectively bred for either highly aggressive behavior toward humans or its absence, and the effects of benzopentathiepin TC-2153 on these enzymes may point to mechanisms of its antiaggressive action.

Topotecan administered intraperitoneally at single doses of 0.25, 0.5, and 1 mg/kg induced chromosomal aberrations in bone marrow cells of F 1 (CBA×C57BL/6) hybrid mice in a dose-dependent manner. A tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitor, an usnic acid derivative OL9-116 was inactive in a dose range of 20-240 mg/kg, but enhanced the cytogenetic effect of topotecan (0.25 mg/kg) at a dose of 40 mg/kg (per os). The TDP1 inhibitor, a coumarin derivative TX-2552 (at doses of 20, 40, 80, and 160 mg/kg per os), increased the level of aberrant metaphases induced by topotecan (0.25 mg/kg) by 2.1-2.6 times, but was inactive at a dose of 10 mg/kg. The results indicate that TDP1 inhibitors enhance the clastogenic activity of topotecan in mouse bone marrow cells in vivo and are characterized by different dose profiles of the co-mutagenic effects., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

Respiratory syncytial virus (RSV) is known to cause annual epidemics of respiratory infections; however, the lack of specific treatment options for this disease poses a challenge. In light of this, there has been a concerted effort to identify small molecules that can effectively combat RSV. This article focuses on the mechanism of action of compound K142, which was identified as a primary screening leader in the earlier stages of the project. The research conducted demonstrates that K142 significantly reduces the intensity of virus penetration into the cells, as well as the formation of syncytia from infected cells. These findings show that the compound's interaction with the surface proteins of RSV is a key factor in its antiviral activity. Furthermore, pharmacological modeling supports that K142 effectively interacts with the F-protein. However, in vivo studies have shown only weak antiviral activity against RSV infection, with a slight decrease in viral load observed in lung tissues. As a result, there is a need to enhance the bioavailability or antiviral properties of this compound. Based on these findings, we hypothesize that further modifications of the compound under study could potentially increase its antiviral activity.

Tyrosyl-DNA-phosphodiesterase 1 (TDP1) is an important enzyme in the DNA repair system. The ability of the enzyme to repair DNA damage induced by a topoisomerase 1 poison such as the anticancer drug topotecan makes TDP1 a promising target for complex antitumor therapy. In this work, a set of new 5-hydroxycoumarin derivatives containing monoterpene moieties was synthesized. It was shown that most of the conjugates synthesized demonstrated high inhibitory properties against TDP1 with an IC 50 in low micromolar or nanomolar ranges. Geraniol derivative 33a was the most potent inhibitor with IC 50 130 nM. Docking the ligands to TDP1 predicted a good fit with the catalytic pocket blocking access to it. The conjugates used in non-toxic concentration increased cytotoxicity of topotecan against HeLa cancer cell line but not against conditionally normal HEK 293A cells. Thus, a new structural series of TDP1 inhibitors, which are able to sensitize cancer cells to the topotecan cytotoxic effect has been discovered.

Respiratory syncytial virus (RSV) causes annual epidemics of respiratory infection. Usually harmless to adults, the RSV infection can be dangerous to children under 3 years of age and elderly people over 65 years of age, often causing serious problems, even death. At present, there are no vaccines and specific chemotherapeutic agents for the treatment of this disease, so the search for low-molecular weight compounds to combat RSV is a challenge. In this work, we have shown, for the first time, that monoterpene-substituted arylcoumarins are efficient RSV replication inhibitors at low micromolar concentrations. The most active compound has a selectivity index of about 200 and acts most effectively at the early stages of infection. The F protein of RSV is a potential target for these compounds, which is also confirmed by molecular docking and molecular dynamics simulation data.

The Bdnf (brain-derived neurotrophic factor) gene contains eight regulatory exons (I-VIII) alternatively spliced to the protein-coding exon IX. Only exons I, II, IV, and VI are relatively well studied. The BDNF system and brain serotonergic system are tightly interconnected and associated with aggression. The benzopentathiepine TC-2153 affects both systems and exerts antiaggressive action. Our aim was to evaluate the effects of TC-2153 on the Bdnf exons I-IX's expressions and serotonin receptors' mRNA levels in the brain of rats featuring high aggression toward humans (aggressive) or its absence (tame). Aggressive and tame adult male rats were treated once with vehicle or 10 or 20 mg/kg of TC-2153. mRNA was quantified in the cortex, hippocampus, hypothalamus, and midbrain with real-time PCR. Selective breeding for high aggression or its absence affected the serotonin receptors' and Bdnf exons' transcripts differentially, depending on the genotype (strain) and brain region. TC-2153 had comprehensive effects on the Bdnf exons' expressions. The main trend was downregulation in the hypothalamus and midbrain. TC-2153 increased 5-HT 1B receptor hypothalamusc mRNA expression. For the first time, an influence of TC-2153 on the expressions of Bdnf regulatory exons and the 5-HT 1B receptor was shown, as was an association between Bdnf regulatory exons and fear-induced aggression involving genetic predisposition.

The stability of a new coumarin derivative, agent K-142, bearing α-pinene residue and possessing antiviral activity against respiratory syncytial virus (RSV) was studied in whole mice blood in vitro, and a method for its quantification in this matrix was developed and validated. The sample preparation method was precipitation of whole blood with a mixture of 0.2 M ZnSO 4 with MeOH (2:8 v / v ) containing 2-adamantylamine hydrochloride as an internal standard (IS). Analysis was carried out by HPLC-MS/MS using reversed phase chromatography and a triple quadrupole mass spectrometer 6500 QTRAP (SCIEX) in multiple reaction monitoring (MRM) mode. The transitions 351.2 → 217.1 Da and 152.2 → 93.1/107.2 Da were monitored for K-142 and the IS, respectively. The method was validated in terms of selectivity, calibration curve, LLOQ, accuracy and precision, stability, recovery and carry over. The developed method was used for a pharmacokinetics study of the compound after its oral administration to mice at a dose of 20 mg/kg.

Striatal-enriched protein tyrosine phosphatase (STEP) is a signal transduction protein involved in the pathogenesis of neuropathologies. A STEP inhibitor (TC-2153) has antipsychotic and antidepressant effects. Here, we evaluated the role of STEP in fear-induced aggression using Norway rats selectively bred for 90 generations for either high aggression toward humans (aggressive rats) or its absence (tame rats). We studied the effects of acute administration of TC-2153 on behavior and STEP expression in the brain of these animals and the influence of chronic treatment with TC-2153 on the behavior and STEP expression in aggressive rats in comparison with classic antidepressant fluoxetine, which is known to exert antiaggressive action. Acute TC-2153 administration decreased the aggressive reaction to humans in aggressive rats, while having no impact on the friendly behavior of tame rats. Moreover, in the elevated plus-maze test, the drug had an anxiolytic effect on both aggressive and tame rats. Aggressive rats demonstrated elevated levels of a STEP isoform (STEP46) as compared to tame animals, whereas acute TC-2153 administration significantly reduced STEP46 protein concentration in the brain of aggressive rats. Chronic treatment of aggressive rats with either TC-2153 or fluoxetine attenuated fear-induced aggression. Chronic administration of fluoxetine enhanced the exploratory activity in the elevated plus-maze test and decreased the STEP46 protein level in aggressive rats' hippocampus, whereas chronic TC-2153 administration did not affect these parameters. Thus, STEP46 can play an important role in the mechanisms of aggression and may mediate antiaggressive effects of TC-2153 and fluoxetine., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Respiratory syncytial virus (RSV) is a critical cause of infant mortality. However, there are no vaccines and adequate drugs for its treatment. We showed, for the first time, that O-linked coumarin-monoterpene conjugates are effective RSV inhibitors. The most potent compounds are active against both RSV serotypes, A and B. According to the results of the time-of-addition experiment, the conjugates act at the early stages of virus cycle. Based on molecular modelling data, RSV F protein may be considered as a possible target.

We synthesized a series of amides with a benzo[d][1,3]dithiol core. The chemical library of compounds was tested for their cytotoxicity and inhibiting activity against influenza virus A/California/07/09 (H1N1)pdm09 in MDCK cells. For each compound, values of CC 50 , IC 50 and selectivity index (SI) were determined. Compounds of this structure type were for the first time found to exhibit anti-influenza activity. The structure of an amide substituent in the tested compounds was demonstrated to have a significant effect on their activity against the H1N1 influenza virus and cytotoxicity. Compound 4d has a high selectivity index of about 30. 4d was shown to be most potent at early stages of viral cycle. In direct fusogenic assay it demonstrated dose-dependent activity against fusogenic activity of hemagglutinin of influenza virus. Based on molecular docking and regression analysis data, viral hemagglutinin was suggested as possible target for these new antiviral agents., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Tyrosine phosphatase STEP (striatal-enriched tyrosine protein phosphatase) is a brain-specific protein phosphatase and is involved in the pathogenesis of many neurodegenerative diseases. Here, we examined the impact of STEP on the development of age-related macular degeneration (AMD)-like pathology in senescence-accelerated OXYS rats. Using OXYS and Wistar rats (control), we for the first time demonstrated age-dependent changes in Ptpn5 mRNA expression, STEP46 and STEP61 protein levels, and their phosphatase activity in the retina. The increases in STEP protein levels and the decrease of total and STEP phosphatase activities in the retina (as compared with Wistar rats) preceded the manifestation of clinical signs of AMD in OXYS rats (age 20 days). There were no differences in these retinal parameters between 13-month-old Wistar rats and OXYS rats with pronounced signs of AMD. Inhibition of STEP with TC-2153 during progressive AMD-like retinopathy (from 9 to 13 months of age) reduced the thickness of the retinal inner nuclear layer, as evidenced by a decreased amount of parvalbumin-positive amacrine neurons. Prolonged treatment with TC-2153 had no effect on Ptpn5 mRNA expression, STEP46 and STEP61 protein levels, and their phosphatase activity in the OXYS retina. Thus, TC-2153 may negatively affect the retina through mechanisms unrelated to STEP.

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an important DNA repair enzyme in humans, and a current and promising inhibition target for the development of new chemosensitizing agents due to its ability to remove DNA damage caused by topoisomerase 1 (Top1) poisons such as topotecan and irinotecan. Herein, we report our work on the synthesis and characterization of new Tdp1 inhibitors that combine the arylcoumarin (neoflavonoid) and monoterpenoid moieties. Our results showed that they are potent Tdp1 inhibitors with IC 50 values in the submicromolar range. In vivo experiments with mice revealed that compound 3ba (IC 50 0.62 µM) induced a significant increase in the antitumor effect of topotecan on the Krebs-2 ascites tumor model. Our results further strengthen the argument that Tdp1 is a druggable target with the potential to be developed into a clinically-potent adjunct therapy in conjunction with Top1 poisons., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

A number of substituted benzopentathiepin-6-amines and their analogues without a polysulfur ring were synthesized and evaluated in vitro for antimicrobial activity against a panel of reference bacterial and fungal strains. Trifluoroacetamide 14 demonstrated high antibacterial activity against Staphylococcus aureus (MRSA strain) with a MIC of 4 μg/mL, which was four-fold higher than the activity of a reference drug amoxicillin. This compound was also most active against the Candida albicans fungus (MIC of 1 μg ml -1 ), whereas amide 17 containing a morpholine substituent was most active against the Cryptococcus neoformans fungus (MIC of 2 μg ml -1 ). These compounds have no hemolytic activity and are low cytotoxic. Replacement of the pentathiepine ring with 1,3-dithiolan-2-one or 1,3-dithiolane moieties leads to loss of antimicrobial activity. Based on the QSAR analysis and molecular docking data, bacterial DNA ligase might be one of the targets for the antibacterial activity of substituted benzopentathiepin-6-amines against S. aureus.

The serotoninergic 5-HT 2A receptor is involved in the mechanism of depression and antidepressant drugs action. Earlier we showed that striatal-enriched protein tyrosine phosphatase (STEP) inhibitor - 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (TC-2153) affects both the brain serotoninergic system and the brain-derived neurotropic factor that are known to be involved in the psychopathology of depression. In the present study we investigated the effects of chronic TC-2153 administration on behavior in the standard battery of tests as well as the effects of acute and chronic TC-2153 treatment on the brain 5-HT 2A receptors in mice. We obtained a prominent antidepressant-like effect of chronic TC-2153 treatment in the forced swim test without any adverse side effects on locomotor activity, anxiety, exploration, motor skill and obsessive-compulsive-like behavior. Moreover, both acute and chronic TC-2153 administration inhibited the functional activity of 5-HT 2A receptors estimated by the number of 2,5-dimethoxy-4-iodoamphetamine (DOI, agonist of 5-HT 2A receptors)-induced head-twitches. TC-2153 treatment also attenuated the DOI-induced c-fos expression in cortical and hippocampal neurons and reduced the 5-HT 2A receptor protein level in the hippocampus and frontal cortex, but not in the striatum. Taken together, our combined data demonstrate that the antidepressant effect of STEP inhibitor TC-2153 could be mediated by its inhibitory properties towards the 5-HT 2A receptor-mediated signaling., (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)

Compounds simultaneously carrying the monoterpene and coumarin moieties have been tested for cytotoxicity and inhibition of activity against influenza virus A/California/07/09 (H1N1)pdm09. The structure of substituents in the coumarin framework, as well as the structure and the absolute configuration of the monoterpenoid moiety, are shown to significantly influence the anti-influenza activity and cytotoxicity of the compounds under study. The compounds with a bicyclic pinane framework exhibit the highest selectivity indices (the ratios between the cytotoxicity and the active dose). The derivative of (-)-myrtenol 15c, which is characterized by promising activity, low cytotoxicity, and synthetic accessibility, has the greatest potential among this group of compounds. It exhibited the highest activity when added to the infected cell culture at early stages of viral reproduction., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Behavioral effects of classic antidepressants, fluoxetine and imipramine, and new psychotropic benzopentathiepin TC-2153 (20 mg/kg, per os) were studied on mice differing in the predisposition to catalepsy-noncataleptic AKR strain and cataleptic strains CBA and AKR.CBA-D13Mit76 (D13). Mice of D13 strain was created by transferring the CBA-allele of major locus of catalepsy to AKR genome. In the forced swim test (FST) fluoxetine showed antidepressant effect on mice of all three strains, imipramine was effective only in D13 mice, while TC-2153 produced antidepressant effect on AKR and D13 mice. Unlike to imipramine and fluoxetine, TC-2153 did not produce negative side effects in the open field and elevated plus-maze tests. Thus, TC-2153 produces antidepressant effects similar to imipramine and fluoxetine, without any visible negative side effect on locomotory activity and anxiety. The D13 mice in the FST showed high sensitivity to the studied drugs in comparison to the parent strains and can be used as new genetic model for investigation of the mechanism of antidepressant effects.

Rationale: The creation of effective psychotropic drugs is the key problem of psychopharmacology. Natural compounds and their synthetic analogues attract particular attention., Objectives: The effect of a new synthetic analogue of varacin, 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (TC-2153), on the behavior and the expression of the genes coding BDNF (Brain-Derived Neurotrophic Factor, Bdnf) and CREB (cAMP response element-binding protein, Creb) implicated in the mechanism of psychotropic drug action as well as gp130 (Il6st) implicated in the mechanism of hereditary catalepsy in the brain of mice of ASC (Antidepressant Sensitive Catalepsy) strain was studied., Results: Acute per os administration of 20 or 40 mg/kg, but not 10 mg/kg of TC-2153 significantly decreased catalepsy. At the same time, in the open field test, 10 or 20 mg/kg of TC-2153 did not influence the locomotor activity, grooming or time spent in the center, while the highest dose of the drug (40 mg/kg) significantly reduced time in the center without any effect on locomotion and grooming. Chronic TC-2153 treatment (10 mg/kg for 12-16 days) did not influence the behavior in the open field but significantly attenuated catalepsy, increased Bdnf mRNA and decreased Il6st mRNA levels in the hippocampus., Conclusions: The results suggest: 1) TC-2153 as a new drug with potential psychotropic and anticataleptic activities and 2) the involvement of BDNF and gp130 in the molecular mechanism of TC-2153 action.

Study of molecular mechanisms of psychotropic drug action is the main aim of molecular psychopharmacology. New synthetic analog of variacin 8-(Trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine (TX-2153) was shown to produce anxiolytic and anticonvulsant effects on mice. Here the effect of chronic administration of TX-2153 on expression of some serotonin-related genes in mouse brain was investigated. The drug (10 mg/kg, per os, 16 days) was administered to adult males of ASC (Antidepressant Sensitive Catalepsy) mouse strain characterizing by alterations in behavior and brain serotonin system. The expression of genes encoding 1) the key enzyme of serotonin synthesis, tryptophan hydroxylase 2 (TPH2), 2) main enzyme of serotonin degradation, monoamine oxydase A (MAOA), 3) 5-HT transporter (SERT) and 4) 5-HT(1A) receptor was studied using quantitative RT-PCR. TX-2153 significantly reduced m-RNA level of 5-HT(1A) receptor and MAOA genes in the midbrain without any effect on expression of these genes in the frontal cortex and hippocampus. The drug failed to affect expression of TPH2 and SERT genes in the midbrain. The result indicates involvement of the brain 5-HT system in the molecular mechanism underlying the effect of TX-2153.