Initial Compound Research Articles

Solid Polymer Electrolyte Membranes on the Basis of Fluorosiloxane Matrix

Hydrosilylation reactions of 2,4,6,8-tetrahydro-2,4,6,8-tetramethylcyclotetrasiloxane (D4H) with 2,2,3,3,4,4,5,5-octafluoropentyl acrylate at 1:4.2 ratio of initial compounds catalysed by platinum catalysts have been studied and corresponding adduct D4R' has been obtained. Ring opening polymerization of D4R in the presence of dry potassium hydroxide has been carried out and comb-type polymers with 2,2,3,3,4,4,5,5-octafluoropentyl propionate side groups have been obtained. The synthesized product D4R and polymers were analyzed by FTIR, 1H, 13C, and 29Si NMR spectroscopy. The solid polymer electrolyte membranes have been obtained via sol-gel reactions of polymers with tetraethoxysilane doped with lithium trifluoromethylsulfonate (triflat) and lithium bis(trifluorosulfonyl)imide. It has been found that the electric conductivity of the polymer electrolyte membranes at room temperature changes in the range of (1.9•10-6) – (5.9•10-10) S•cm-1.

Synthesis of β2-Agonist Metabolites of 2-(4-Amino-3,5-Dichlorophenyl)-2-(Alkylamino)Ethanols and their Excretion with Urine in Comparison to the Initial Compounds

Synthesis of β2-Agonist Metabolites of 2-(4-Amino-3,5-Dichlorophenyl)-2-(Alkylamino)Ethanols and their Excretion with Urine in Comparison to the Initial Compounds

Tamoxifen as a Zika Virus Therapeutic

Zika virus (ZIKV) is an arbovirus belonging to the flaviviridae family with a risk assessment that has increased in recent years and was labeled a global health emergency by the WHO in 2016. There are currently no FDA approved treatment options available for ZIKV, so expeditious development of treatment options is urgent. An on-market drug, tamoxifen (Tam), was selected as a promising candidate for repurposing due to its wide range of biological activities and because it has already been shown to possess activity against hepatitus C (HCV), a related flavivirus. Anti-ZIKV activity of Tam was assessed by compound screens using infectious virus and mechanistic details were gleaned from time of addition and virucidal studies. Tam and the active form, 4-hydroxytamoxifen, showed promising antiviral activity in initial compound screening and up to 8 hours post infection, though the virucidal assay indicated that they do not possess any direct virucidal activity. Additionally, Tam was assessed for its activity against ZIKV in the human male germ cell line, SEM-1, and virus titers show diminished replication of ZIKV over a seven day period compared to controls. These data indicate that Tam has potential to be repurposed as an anti-ZIKV therapeutic and warrants further investigation.

High-throughput screening of the ReFRAME, Pandemic Box, and COVID Box drug repurposing libraries against SARS-CoV-2 nsp15 endoribonuclease to identify small-molecule inhibitors of viral activity.

SARS-CoV-2 has caused a global pandemic, and has taken over 1.7 million lives as of mid-December, 2020. Although great progress has been made in the development of effective countermeasures, with several pharmaceutical companies approved or poised to deliver vaccines to market, there is still an unmet need of essential antiviral drugs with therapeutic impact for the treatment of moderate-to-severe COVID-19. Towards this goal, a high-throughput assay was used to screen SARS-CoV-2 nsp15 uracil-dependent endonuclease (endoU) function against 13 thousand compounds from drug and lead repurposing compound libraries. While over 80% of initial hit compounds were pan-assay inhibitory compounds, three hits were confirmed as nsp15 endoU inhibitors in the 1–20 μM range in vitro. Furthermore, Exebryl-1, a ß-amyloid anti-aggregation molecule for Alzheimer’s therapy, was shown to have antiviral activity between 10 to 66 μM, in Vero 76, Caco-2, and Calu-3 cells. Although the inhibitory concentrations determined for Exebryl-1 exceed those recommended for therapeutic intervention, our findings show great promise for further optimization of Exebryl-1 as an nsp15 endoU inhibitor and as a SARS-CoV-2 antiviral.

Design, synthesis and biological evaluation of novel FXIa inhibitors with 2-phenyl-1H-imidazole-5-carboxamide moiety as P1 fragment.

Factor XIa, as a blood coagulation enzyme, amplifies the generation of the last enzyme thrombin in the blood coagulation cascade. It was proved that direct inhibition of factor XIa could reduce pathologic thrombus formation without an enhanced risk of bleeding. WSJ-557, a nonpurine imidazole-based xanthine oxidase inhibitor in our previous reports, could delay blood coagulation during its animal experiments, which prompted us to investigate its action mechanism. Subsequently, during the exploration of the action mechanism, it was found that WSJ-557 exhibited weak invitro factor XIa binding affinity. Under the guide of molecular modeling, we adopted molecular hybridization strategy to develop novel factor XIa inhibitors with WSJ-557 as an initial compound. This led to the identification of the most potent compound 44g with a Ki value of 0.009μM, which was close to that of BMS-724296 (Ki=0.0015μM). Additionally, serine protease selectivity study indicated that compound 44g display a desired selectivity, more 400-fold than those of thrombin, factor VIIa and factor Xa in coagulation cascade. Moreover, enzyme kinetics studies suggested that the representative compound 44g acted as a competitive-type inhibitor for FXIa, and molecular modeling revealed that it could tightly bind to the S1, S1' and S2' pockets of factor XIa. Furthermore, invivo efficacy in the rabbit arteriovenous shunt model suggested that compound 44g demonstrated dose-dependent antithrombotic efficacy. Therefore, these results supported that compound 44g could be a potential and efficacious agent for the treatment of thrombotic diseases.

Initial defensive secretory compounds emitted from the live millipede and the induction of apoptotic cell death

The initial defensive secretory compounds emitted from a live millipede have not yet been clarified. This study focused on elucidating the initial secretory compounds emitted from a live millipede. Pre-concentration of the defensive secretory volatile organic compounds (VOC) from the live Polidesmida millipedes, Chamberlinius hualienensis and Oxidus gracilis, was performed using a three-stage VOC concentration technique by an on-line GC/MS system. As a result, the monoterpenes derived from the plant metabolite; i.e., α-pinene, α-thujene, β-pinene, 3-carene, β-myrcene, β-phellandrene, γ-terpinene, o,m,p-cymenes, limonene and camphene were first detected as the initial secretory substances. It was elucidated that some plant monoterpenes have a repellent effect and antifungal and antibacterial actions which are used as defensive substances. In addition, this study also confirmed that these monoterpenes induced apoptotic cell death involved in the induction of the caspase 3/7 activity. The millipede feeds on fallen or withered leaves containing the monoterpenes. Thus, the millipede accumulates the plant defensive secretions in the exocrine defense glands of the body somites, which would be used as against predators.

Influence of the type of salt-forming acids on the antiradiation activity of T1023 analogs – salts of N-isobutanoyl-S-isopropylisothiourea

According to leading experts, the vast arsenal of radioprotective agents available in the world today does not fully meet modern practical needs, both in the field of radiation protection, and in the prevention and treatment of complications of radiotherapy. The purpose of the study was to evaluate the effect of the salt-forming acids type on the radioprotective activity of NOS inhibitor T1023. The chemical part of this study included methods of chemical synthesis, physicochemical and elemental analysis. Pharmacological part – assessment of acute toxicity using V.B. Prozorovsky express method and the study of radioprotective activity using Till and McCulloch method based on the ability of mice hematopoietic cells to form spleen colonies after irradiation. The number of endogenous hematopoietic spleen colonies were assessed on the 8th day after total exposure to gamma-irradiation at a dose of 6 Gy in six independent experiments. As a result of directed chemical synthesis, six new derivatives of T1023 – salts of N-isobutanoyl-S-isopropylisothiourea have been developed, identified and characterized. The results of studying the safety and radioprotective activity of the synthesized compounds showed that changes in the salt-forming acid don’t significantly influence the toxicity: all studied compounds are in the 3rd class of toxicity and hazard. At the same time, it was found that the replacement of the salt-forming acid significantly influenced the severity of the radioprotective effect. For some of these compounds radioprotective efficacy is comparable to or exceeds the efficacy of the initial compound T1023. It is important to note that these new compounds were used in lower, more save doses than T1023. The results suggest promising further development of NOS inhibitors – isothiourea derivatives as radioprotective agents.

Discovery of uncompetitive inhibitors of SapM that compromise intracellular survival of Mycobacterium tuberculosis

SapM is a secreted virulence factor from Mycobacterium tuberculosis critical for pathogen survival and persistence inside the host. Its full potential as a target for tuberculosis treatment has not yet been exploited because of the lack of potent inhibitors available. By screening over 1500 small molecules, we have identified new potent and selective inhibitors of SapM with an uncompetitive mechanism of inhibition. The best inhibitors share a trihydroxy-benzene moiety essential for activity. Importantly, the inhibitors significantly reduce mycobacterial burden in infected human macrophages at 1 µM, and they are selective with respect to other mycobacterial and human phosphatases. The best inhibitor also reduces intracellular burden of Francisella tularensis, which secretes the virulence factor AcpA, a homologue of SapM, with the same mechanism of catalysis and inhibition. Our findings demonstrate that inhibition of SapM with small molecule inhibitors is efficient in reducing intracellular mycobacterial survival in host macrophages and confirm SapM as a potential therapeutic target. These initial compounds have favourable physico-chemical properties and provide a basis for exploration towards the development of new tuberculosis treatments. The efficacy of a SapM inhibitor in reducing Francisella tularensis intracellular burden suggests the potential for developing broad-spectrum antivirulence agents to treat microbial infections.

Study of (In2S3)х·(AgIn5S8)1–х solid solutions

Herein, single crystals of compounds In2S3, AgIn5S8 and solid solutions (In2S3)x·(AgIn5S8)1–x were grown by directional crystallization. The composition of the obtained single crystals was determined by microprobe X-ray spectral analysis. It is found that the content of the components in the grown single crystals is in satisfactory agreement with the specified composition in the initial charge. The structure of the obtained materials was determined by the X-ray method. It is shown that both the initial compounds and the solid solutions based on them were crystallized in the cubic structure of the spinel. The unit cell parameters of the In2S3, AgIn5S8 compounds and the solid solutions based on them, which vary linearly with the composition x, were calculated by the least squares method. The density was determined by the pycnometric method, and the microhardness of the In2S3 and AgIn5S8 compounds and the (In2S3)x·(AgIn5S8)1–x solid solutions was determined by the Knoop method. It is shown that the density, like the unit cell parameter, changes linearly with the composition x, but the dependence of microhardness on the x parameter has a maximum for x = 0.4. Using differential thermal analysis (DTA), the temperatures of phase transformations were determined and the phase diagram of the In2S3–AgIn5S8 system was constructed, which is characterized by a small crystallization interval and belongs to type III according to the Rosebom classification. The curves of liquidus and solidus are concave to the abscissa axis and have a common point.

Bioreporters for direct mode of action-informed screening of antibiotic producer strains

A big challenge in natural product research of today is rapid dereplication of already known substances, to free capacities for the exploration of new agents. Prompt information on bioactivities and mode of action (MOA) speeds up the lead discovery process and is required for rational compound optimization. Here, we present a bioreporter approach as a versatile strategy for combined bioactivity- and MOA-informed primary screening for antimicrobials. The approach is suitable for directly probing producer strains grown on agar, without need for initial compound enrichment or purification, and works along the entire purification pipeline with culture supernatants, extracts, fractions, and pure substances. The technology allows for MOA-informed purification to selectively prioritize activities of interest. In combination with high-resolution mass spectrometry, the biosensor panel is an efficient and sensitive tool for compound deconvolution. Concomitant information on the affected metabolic pathway enables the selection of appropriate follow-up assays to elucidate the molecular target.

New polycarbonate siloxanes based on siloxane-<i>N</i>-phthalimidines

Objectives. Polymeric carbonate siloxanes containing a siloxane-N-phthalimidine group in the chain frame are new synthetic comb-like macromolecule systems. This work aims to study the possibility of applying them in the form of film materials for heat-resistant, high-performance gas-permeable membranes.Methods. Comb-like polycarbonate siloxanes of the siloxane-containing polyether class were obtained using various polycondensation methods. i.e., by the polymer-analogous transformation of polycarbonate-allyl-N-phthalimidines, using their reaction in an alkyl hydride siloxane solution; polycondensation of N-(3-(pentamethyldisiloxane)-propyl)-3,3-bis-(4'-hydroxyphenyl)phthalimidine with diphenylolpropane bis-chloroformate in a solution using triethylamine as an acceptor of hydrochloric acid; interphase polycondensation of the above reagents in a dichloromethane aqueous alkali system. The structures of the obtained initial and polymeric compounds were confirmed by proton nuclear magnetic resonance spectroscopy and elemental analysis. All of the synthesized comb-like copolymers had good solubility in several available solvents and film formations.Results. The new comb-like polycarbonate siloxanes had high thermal stability. According to thermogravimetric analysis, the introduction of up to 20 wt % siloxane units makes it possible to increase the heat resistance of polycarbonate siloxanes by 25 °C. Concurrently, their glasstransition temperature reaches 160 °C. Copolymers of polycarbonate siloxanes in the form of films have a high tensile strength above 50 MPa and an elastic modulus of up to 2000 MPa. The permeability coefficients of gases through a copolymer of polycarbonate siloxanes in the form of a film for several gases surpass the permeability of industrial polycarbonate from diphenylolpropane and fluorine-containing siloxane polycarbonate.Conclusions. The results achieved indicate the possibility of creating new polymeric combshaped siloxane systems with a variable structure that can contribute to obtaining the properties desired from them. Combined with high selectivity gas separation, this makes it possible to use such comb-shaped polycarbonate siloxanes as film membrane materials with an increased operating temperature range.

Anaerobic digestion of hydrothermal liquefaction wastewater from spent coffee grounds

Spent coffee grounds (SCG) are high water content lignocellulosic residues generated in large amounts by the instant coffee production industry. Recent interest in the use of SCG as biomass for biocrude oil production via hydrothermal liquefaction (HTL) pointed to the generation of an aqueous effluent rich in organic matter of high aromaticity, denominated post hydrothermal wastewater (PHWW). The anaerobic digestion of PHWW was investigated as a treatment option and was evaluated for its energy recovery potential through methane production. Sequencing batch reactors were subjected to increasing initial chemical oxygen demand (COD) levels from 1000 mg COD L−1 to 8000 mg COD L−1, to allow for gradual biomass adaptation to the substrate recalcitrance and toxicity. The highest COD removal rate was observed for an initial COD level of 4000 mg COD L−1. Under this condition, the average methane yield was 187 ± 13 mLCH4 g−1 CODadded, with average COD and total phenols removal efficiencies of 60 ± 1% and 48 ± 4%, respectively. A kinetic evaluation revealed that the methane yield decreased sharply for initial phenolic compounds concentrations above 900 mg GAE L−1. Methane production represented a 22.8% increase in the energy recovered from SCG.

ПОЛУЧЕНИЕ СУЛЬФИРОВАННОГО ПРОИЗВОДНОГО ЖИРНЫХ КИСЛОТ МАСЛА СПИРУЛИНЫ

A new sulfonated derivative of Spirulina oil fatty acids was obtained in the work.This derivative is obtained from dry biomass of microalgae in several stages: extraction of lipids from dry biomass, lipid methylation, amination of the formed methyl esters of Spirulina fatty acids, modification of amide with maleic anhydrideand subsequent reaction of the synthesized monoester with sodium bisulfate. The conditions for all stages of the synthesis of the sulfonated derivative were optimized.The initial compounds and reaction products were identified by IR spectroscopy.

Phenotypic Discovery of SB1501, an Anti-obesity Agent, through Modulating Mitochondrial Activity.

Obesity has become a pandemic that threatens the quality of life and discovering novel therapeutic agents that can reverse obesity and obesity-related metabolic disorders are necessary. Here, we aimed to identify new anti-obesity agents using a phenotype-based approach. We performed image-based high-content screening with a fluorogenic bioprobe (SF44), which visualizes cellular lipid droplets (LDs), to identify initial hit compounds. A structure-activity relationship study led us to yield a bioactive compound SB1501, which reduces cellular LDs in 3T3-L1 adipocytes without cytotoxicity. SB1501 induced the expression of gene products that regulate mitochondrial biogenesis and fatty acid oxidation in 3T3-L1 adipocytes. Daily treatment with SB1501 improved the metabolic states of db/db mice by reducing body fat mass, adipose tissue mass, food intake, and increasing glucose tolerance. The anti-obesity effect of SB1501 may result from perturbation of the PGC-1α-UCP1 regulatory axis in inguinal white adipose tissue and brown adipose tissue. These data suggest the therapeutic potential of SB1501 as an anti-obesity agent via modulating mitochondrial activities.

Electrochemically-stabilized carbon materials for supercapacitor prototypes

A study is presented on supercapacitor prototypes using chimney soot as the active electrode material. Despite its highly developed surface and the existence of capacitive properties, some compounds present in chimney soot make it unstable during the charge process. The irreversible electrochemical process leads to anodic oxidation and cathodic reduction of the soot. In this work, chimney soot was treated electrochemically with different electrochemical potentials, thus altering the initial organic compounds in the material; different parts of organic compounds were affected, so that more stable compounds remained, without all functional groups being removed. The altered material was investigated by IR and TEM spectroscopy. Supercapacitor prototypes were subjected to charge-discharge cycles and their capacitances were determined and compared.

MCH-R1 Antagonist GPS18169, a Pseudopeptide, Is a Peripheral Anti-Obesity Agent in Mice

Melanin-concentrating hormone (MCH) is a 19 amino acid long peptide found in the brain of animals, including fishes, batrachians, and mammals. MCH is implicated in appetite and/or energy homeostasis. Antagonists at its receptor (MCH-R1) could be major tools (or ultimately drugs) to understand the mechanism of MCH action and to fight the obesity syndrome that is a worldwide societal health problem. Ever since the deorphanisation of the MCH receptor, we cloned, expressed, and characterized the receptor MCH-R1 and started a vast medicinal chemistry program aiming at the discovery of such usable compounds. In the present final work, we describe GPS18169, a pseudopeptide antagonist at the MCH-R1 receptor with an affinity in the nanomolar range and a Ki for its antagonistic effect in the 20 picomolar range. Its metabolic stability is rather ameliorated compared to its initial parent compound, the antagonist S38151. We tested it in an in vivo experiment using high diet mice. GPS18169 was found to be active in limiting the accumulation of adipose tissues and, correlatively, we observed a normalization of the insulin level in the treated animals, while no change in food or water consumption was observed.

Micropatterned Coculture With 3T3-J2 Fibroblasts Enhances Hepatic Functions and Drug Screening Utility of HepaRG Cells.

Human liver models are useful for assessing compound metabolism/toxicity; however, primary human hepatocyte (PHH) lots are limited and highly variable in quality/viability. In contrast, cell lines, such as HepaRG, are cheaper and more reproducible surrogates for initial compound screening; however, hepatic functions and sensitivity for drug outcomes need improvement. Here, we show that HepaRGs cocultured with murine embryonic 3T3-J2 fibroblasts, previously shown to induce PHH functions, could address such limitations. We either micropatterned HepaRGs or seeded them "randomly" onto collagen-coated plates before 3T3-J2 coculture. Micropatterned cocultures (HepaRG-MPCCs) secreted 2- to 4-fold more albumin and displayed more stable cytochrome P450 activities than HepaRG conventional confluent monocultures (HepaRG-CCs) and HepaRG micropatterned hepatocytes (HepaRG-MPHs) for 4 weeks, even when excluding dimethyl sulfoxide from the medium. Furthermore, HepaRG-MPCCs had the most albumin-only positive cells (hepatic), lowest cytokeratin 19 (CK19)-only positive cells (cholangiocytic), and highest mean albumin intensity per cell than HepaRG random cocultures and monocultures; however, 80%-84% of HepaRGs remained bipotential (albumin+/CK19+) across all models. The 3T3-J2s also induced higher albumin in HepaRG spheroids than HepaRG-only spheroids. Additionally, although rifampin induced CYP3A4 in HepaRG-MPCCs and HepaRG-CCs, only HepaRG-MPCCs showed the dual omeprazole-mediated CYP1A2/3A4 induction as with PHHs. Lastly, when treated for 6 days with 47 drugs and evaluated for albumin and ATP to make binary hepatotoxicity calls, HepaRG-MPCCs displayed a sensitivity of 54% and specificity of 100% (70%/100% in PHH-MPCCs), whereas HepaRG-CCs misclassified several hepatotoxins. Ultimately, HepaRG-MPCCs could be a more cost-effective and reproducible model than PHHs for executing a tier 1 compound screen.

A Unified Method for the Recovery of Metals from Chalcogenides

Metal chalcogenides are ubiquitous starting materials for the extraction of metals from both primary and secondary sources. In this study, it is shown that chalcogenide compounds are electrochemically active and can be solubilized from solid powders by electrochemical oxidation in a deep eutectic solvent. Importantly, the metal ions released into solution were unaffected by the type of chalcogenide present in the initial compound, maintaining the same speciation as would be obtained from dissolution of a chloride salt. Therefore, metals can be recovered by the same process from mixtures of chalcogenides. The chalcogenides form a mixture of oxyanions in the + IV and + VI oxidation states, which are separable via standard processes.

Features and consistent patterns of changes in properties of the system AIIIBV - ZnTe solid solutions

By the methods developed for the InSb-ZnTe, GaSb-ZnTe systems, in the regions of mutual solubility of the initial binary compounds (InSb and ZnTe, GaSb and ZnTe), solid solutions (InSb)x(ZnTe)1-x, (GaSb)x(ZnTe)1-x have been obtained.X-ray, IR and Raman spectroscopic, electrophysical studies of the obtained solid solutions (in comparison with the initial binary compounds and among themselves) have been carried out, following the results of which the obtained solid solutions have been certified as substitutional solid solutions with a cubic sphalerite structure. The information on multicomponent diamond-like semiconductors has been expanded.The acid-base properties of the InSb-ZnTe, GaSb-ZnTe systems components surfaces, varying in composition from weak acid to weakly basic, have been studied.General and distinctive features in the “behavior” of the InSb-ZnTe, GaSb-ZnTe systems solid solutions have been revealed. The relative influence of binary components on the type of dependences “property – composition” has been demonstrated and explained.Practical recommendations have been given for the use of solid solutions with the lowest pHiso values as materials for the manufacture of sensors for main gases trace contamination.

Angular momentum effects in fission

Background: The role of angular momentum in fission has long been discussed but the observable effects are difficult to quantify. Purpose: We discuss a variety of effects associated with angular momentum in fission and present quantitative illustrations. Methods: We employ the fission simulation model $\mathtt{FREYA}$ which is well suited for this purpose because it obeys all conservation laws, including linear and angular momentum conservation at each step of the process. We first discuss the implementation of angular momentum in $\mathtt{FREYA}$ and then assess particular observables, including various correlated observables. We also study potential effects of neutron-induced fission of the low-lying isomeric state of $^{235}$U relative to the ground state. Results: The fluctuations inherent in the fission process ensure that the spin of the initial compound nucleus has only a small influence on the fragment spins which are therefore nearly uncorrelated. There is a marked correlation between the spin magnitude of the fission fragments and the photon multiplicity. We also consider the dynamical anisotropy caused by the rotation of an evaporating fragment and study especially the distribution of the projected neutron-neutron opening angles, showing that while it is dominated by the effect of the evaporation recoils, it is possible to extract the signal of the dynamical anisotropy by means of a Fourier decomposition. Finally, we note that the use of an isomeric target, $^{235 {\rm m}}$U($n_{\rm th}$,f), may enhance the symmetric yields and can thus result in higher neutron multiplicities for low total fragment kinetic energy.