Structural Moieties Research Articles

Cladosporitides A–C, three polyketides from an endophytic fungi Cladosporium tenuissimum

Three new polyketides, named cladosporitides A–C (1–3), were isolated from an endophytic fungi Cladosporium tenuissimum derived from the stem of Berberis heteropoda. Their structures were determined by extensive spectroscopic analysis including HRMS, 1D and 2D NMR data. Compound 1 possesses an unusual octahydro-2H-2,5-epoxychromene tricyclic structure moiety. An anti-inflammatory assay indicated that compounds 1–3 showed moderate inhibitory activities against LPS-induced NO production in RAW 264.7 cells with IC50 values ranging from 22.32 to 33.97 μM.

Structural Modification of Sylibin to Derivatives of Sylibin/Hydnocarpin D/Silandrin, and Evaluation of their Cytotoxicity against Cancer Cells.

Flavonolignans like silybin, hydnocarpin, and siliandrin are a group of natural compounds combining the structural moieties of flavonoid and phenylpropanoid (lignan). Hydnocarpin and silandrin have been less explored because of their trace occurrence in nature. The present study aimed at chemical conversion of silybin to hydnocarpin and siliandrin. Another objective was to synthesize a series of amide derivatives and biologically evaluate them with regard to their anti-cancer effects. In order to selectively convert silybin to 23-iodo silybin, 23-iodo hydnocarpin D and 23- iodo isosilandrin, the ratio of Ph3P, imidazole and molecular iodine was meticulously adjusted. These three iodide compounds were converted into amide compounds by chemical transformation. MTT method was applied to evaluate their anti-cancer potency. The binding affinity to related proteins was calculated by molecular docking. A total of 45 new amido-derivatives were synthesized and structurally characterized by NMR and HRMS. Some of them showed moderate to good antiproliferative potency against cancer cells. The activity of compound 10j was further testified by colony formation assay and molecular docking. The synthesis of 23-iodo silybin, 23-iodo hydnocarpin D and 23-iodo isosilandrin from silybin was successfully accomplished by one simple iodination reaction. Some of the amide derivatives of sylibin/hydnocarpin D /silandrin exhibited a remarkable inhibitory effect of proliferation on cancer cells compared to silybin. These results would pave the way for further investigation on the derivatives of flavonolignans for the treatment of cancer.

Theoretical Design of Novel Boron-Based Nanowires via Inverse Sandwich Clusters.

Borophene has important application value, boron nanomaterials doped with transition metal have wondrous structures and chemical bonding. However, little attention was paid to the boron nanowires (NWs). Inspired by the novel metal boron clusters Ln2Bn − (Ln = La, Pr, Tb, n = 7–9) adopting inverse sandwich configuration, we examined Sc2B8 and Y2B8 clusters in such novel structure and found that they are the global minima and show good stability. Thus, based on the novel structural moiety and first-principles calculations, we connected the inverse sandwich clusters into one-dimensional (1D) nanowires by sharing B−B bridges between adjacent clusters, and the 1D-Sc4B24 and 1D-Y2B12 were reached after structural relaxation. The two nanowires were identified to be stable in thermodynamical, dynamical and thermal aspects. Both nanowires are nonmagnetic, the 1D-Sc4B24 NW is a direct-bandgap semiconductor, while the 1D-Y2B12 NW shows metallic feature. Our theoretical results revealed that the inverse sandwich structure is the most energy-favored configuration for transition metal borides Sc2B8 and Y2B8, and the inverse sandwich motif can be extended to 1D nanowires, providing useful guidance for designing novel boron-based nanowires with diverse electronic properties.

Novel monomers with N‐methyl‐D‐glucamine segments and their application in structured porous materials for arsenic capture

AbstractThe N‐methyl‐D‐glucamine moieties exhibit high ability and selectivity toward arsenate ions in water by a complexation mechanism that involves their hydroxyl groups. In this work, the syntheses of two monomers containing N‐methyl‐D‐glucamine, namely 4‐vinylbenzyl‐N‐methyl‐D‐glucamine (VbNMDG), and N‐methyl‐D‐glucamine methacrylamide (MNMDG) were studied. Different synthetic routes were considered in order to obtain liquid monomers able to polymerize and selectively capture arsenic. Furthermore, the incorporation of protective groups like trimethylsilyl moieties in the molecular structure was assessed to prevent transfer reactions during further polymerization. After polymerization, hydroxyl groups were deprotected using hydrofluoric acid. Following this methodology, structured microporous polymeric films based on colloidal crystal templates were prepared. NMR and FTIR techniques were used to follow the reactions and to determine the chemical structure of the obtained products. The morphology of materials was characterized by SEM. The performances of the developed polymeric films to selectively capture arsenic were determined. Films showed an improved and reproducible sensitivity to arsenic detection exhibiting high values of arsenic capturing capability (around 90%).

Radical Cyclization of 1,n-Enynes and 1,n-Dienes for the Synthesis of 2-Pyrrolidone.

2-Pyrrolidones have aroused enormous interest as a useful structural moiety in drug discovery; however, not only does their syntheses suffer from low selectivity and yield, but also it requires high catalyst loadings. The radical cyclization of 1,n-enynes and 1,n-dienes has demonstrated to be an attractive method for the synthesis of 2-pyrrolidones due to its mild reaction conditions, fewer steps, higher atom economy, excellent functional group compatibility, and high regioselectivity. Furthermore, radical receptors with unsaturated bonds (i. e. 1,n-enynes and 1,n-dienes) play a crucial role in realizing radical cyclization because of the ability to selectively introduce one or more radical sources. In this review, we discuss representative examples of methods involving the radical cyclization of 1,n-enynes and 1,n-dienes published in the last five years and discuss each prominent reaction design and mechanism, providing favorable tools for the synthesis of valuable 2-pyrrolidone for a variety of applications.

Hydrogen-Bonded Supramolecular Liquid Crystal Polymers: Smart Materials with Stimuli-Responsive, Self-Healing, and Recyclable Properties.

Hydrogen-bonded liquid crystalline polymers have emerged as promising “smart” supramolecular functional materials with stimuli-responsive, self-healing, and recyclable properties. The hydrogen bonds can either be used as chemically responsive (i.e., pH-responsive) or as dynamic structural (i.e., temperature-responsive) moieties. Responsiveness can be manifested as changes in shape, color, or porosity and as selective binding. The liquid crystalline self-organization gives the materials their unique responsive nanostructures. Typically, the materials used for actuators or optical materials are constructed using linear calamitic (rod-shaped) hydrogen-bonded complexes, while nanoporous materials are constructed from either calamitic or discotic (disk-shaped) complexes. The dynamic structural character of the hydrogen bond moieties can be used to construct self-healing and recyclable supramolecular materials. In this review, recent findings are summarized, and potential future applications are discussed.

Presence of 2-hydroxymyristate on endotoxins is associated with death in neonates with Enterobacter cloacae complex septic shock

SummaryEnterobacter cloacae complex species are involved in infections among critically ill patients. After a recent E.cloacae outbreak of fulminant neonatal septic shock, we conducted a study to determine whether septic shock severity and its lethal consequence are related to structural features of the endotoxin (lipopolysaccharide [LPS]) of the strains isolated from hospitalized infants and more specifically its lipid A region. It appeared that the LPSs are very heterogeneous, carrying fifteen different molecular species of lipid A. The virulence was correlated with a structural feature identified by matrix-assisted laser desorption ionization–time of flight mass spectrometry and gas chromatography coupled with mass spectrometry: the presence of 2-hydroxymyristic acid as a secondary substituent in lipid A. This is the first published evidence linking LPS structural moiety to neonatal sepsis outcome and opens the possibility of using this fatty acid marker as a detection tool for high-risk patients, which could help reduce their mortality.

Structural Diversity in the Reactions of Dimetallic Alkyl Titanium Oxides with Isonitriles and Nitriles

A detailed study of the reaction of the dinuclear [{Ti(η5-C5Me5)R2}2(μ-O)] (R = Me 1, CH2Ph 2) compounds with a series of organic isonitriles (R′NC, R′ = tBu, iPr, CH2SiMe3, Xyl) (Xyl = 2,6-Me2C6H3) and nitriles (R′CN, R′ = tBu, iPr, SiMe3) has been carried out. Single-crystal X-ray structural studies revealed a variety of reactivity and structural moieties. Theoretical calculations (density functional theory, DFT) were used to understand the mechanism of some uncommon reactions observed experimentally. Reactions of 1 and 2 with isocyanides tBuNC, iPrNC, and Me3SiCH2NC led to the formation of dimetallic η2-iminoacyl species [{Ti(η5-C5Me5)(R′NCR)R}2(μ-O)] (R = Me, R′ = tBu 3, iPr 4, CH2SiMe3 5; R = CH2Ph, R′ = CH2SiMe3 6). Complex 4 underwent net rearrangements at room temperature to give the imido-vinylamido derivative [Ti2(η5-C5Me5)2(μ-O)(μ-NiPr) {N(iPr)CMe═CMe2}Me] (7), whereas the reaction of complex 2 with XylNC rendered the N─C bond cleavage product [{Ti(η5-C5Me5)(CH═CHPh)}(μ-O)(μ-κ2-N,C─N(MeC6H3)CH2){Ti(η5-C5Me5)}] (8). The reactions of 1 with nitriles tBuCN and iPrCN gave the ketimido products [{Ti(η5-C5Me5)Me(CN(Me)R′)}2(μ-O)] (R′ = tBu 9, iPr 10), whereas the analogous processes with 2 gave the alkenyl-imido complexes [{Ti(η5-C5Me5)(CH2Ph)2}(μ-O){Ti(η5-C5Me5)(═NC(R′)═C(H)Ph)(NCR′)}] (R′ = tBu 11, iPr 12) with the concomitant coordination of a nitrile molecule. Complex 1 reacts with Me3SiCN to afford the nitrile–isonitrile isomerization product [{Ti(η5-C5Me5)Me2}(μ-O){Ti(η5-C5Me5)(κ2-C,N-Me2CNSiMe3)(CNSiMe3)] (13).

Synthesis and Antifungal Activity Evaluation of Phloeodictine Analogues.

The phloeodictine-based 6-hydroxy-2,3,4,6-tetrahydropyrrolo[1,2-a]pyrimidinium structural moiety with an n-tetradecyl side chain at C-6 has been demonstrated to be a new antifungal template. Thirty-four new synthetic analogues with modifications of the bicyclic tetrahydropyrrolopyrimidinium skeleton and the N-1 side chain have been prepared and evaluated for in vitro antifungal activities against the clinically important fungal pathogens including Cryptococcus neoformans ATCC 90113, Candida albicans ATCC 90028, Candida glabrata ATCC 90030, Candida krusei ATCC 6258, and Aspergillus fumigatus ATCC 90906. Nineteen compounds (5, 21-31, 34-38, 44, and 48) showed antifungal activities against the aforementioned five fungal pathogens with minimum inhibitory concentrations (MICs) in the range 0.88-10 μM, and all were fungicidal with minimum fungicidal concentrations (MFCs) similar to the respective MIC values. Compounds 24, 36, and 48 were especially active against C. neoformans ATCC 90113 with MIC/MFC values of 1.0/1.0, 1.6/1.6, and 1.3/2.0 μM but exhibited low cytotoxicity with an IC50 > 40 μM against the mammalian Vero cells. The structure and antifungal activity relationship indicates that synthetic modifications of the phloeodictines can afford analogues with potent antifungal activity and reduced cytotoxicity, necessitating further preclinical studies of this new class of antifungal compounds.

Carbon dioxide capture from flue gas in biochar produced from spent coffee grounds: Effect of surface chemistry and porous structure

Coffee is a relevant agricultural product and one of the most consumed hot beverages globally. To assess the impact of pyrolysis temperatures (400–600 ℃) and heating rates from 5 to 20 ℃/min on the biochar production yields and textural characteristics, spent coffee grounds was subjected to slow-pyrolysis in a pilot-scale reactor. Further, complementary spectroscopic and textural analyses were executed to evaluate the impacts of pyrolysis temperatures on the corresponding biochar surface properties including textural characteristics, reactivity, and surface functionalities. The correlation of pyrolysis temperature with change in biochar’s surface properties along with CO2 mitigation efficiency is examined. The ultimate analysis, FTIR spectroscopy, 13C NMR spectroscopy and Raman scattering measurements confirmed an increment in the degree of aromaticity or decomposition of organic complexes in biochar. The development of basic surface functionalities after the thermal treatment was ascertained by XPS and NEXAFS analyses. Based on the surface composition and textural properties, the CO2 adsorption capacity of SCG-600 was assessed under varying adsorption temperatures at ambient pressure employing a fixed-bed reactor. In this investigation, SCG-600 showed a large CO2 uptake of 2.8 mmol/g under a typical post-combustion scenario. CO2 adsorption mechanism followed the pseudo-first-order kinetics and lower activation energy over varying investigated temperatures reveals the binding process is physical in nature. SCG-600 could be proposed as promising biochar that possesses a combination of higher surface area, well-developed microporous structure, heterogeneous and basic surface functional moieties to meet the specific requirements in dynamic CO2 adsorption.

Antibiotic resistant bacteria and genes in shrimp aquaculture water: Identification and removal by ferrate(VI)

Enclosed shrimp culturing ponds are breeding environments for the spread of antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARGs) in the aquatic environment. This paper surveyed the presence of antibiotics, ARB, and ARGs in aquaculture waters and demonstrated their removal by ferrate (Fe(VI), FeO42-). Tetracyclines were the most prevalent antibiotics, followed by quinolones and β-lactam. The bacterial resistance rates to three antibiotics were ordered as follows: amoxicillin (AMX) > oxytetracycline (OTC) > enrofloxacin (ENR). Proteobacteria, Verrucomicrobia, and Bacteroidetes were the predominant phyla, while sul1 and sul2 were the predominant ARGs. sul2 was positively correlated with Proteobacteria. Water quality parameters significantly influenced the dissemination of tetracycline resistance genes in aquacultures due to high organic waste accumulation. The removal efficiency of antibiotics by Fe(VI) depended on the structural moieties of antibiotics, with phenol-containing antibiotics more thoroughly oxidized (i.e., OTC) than amine-containing (ENR and AMX) antibiotics. Greater removal of antibiotics in aquaculture waters suggested that the constituents of farming water enhances the efficacy of antibiotics removal by Fe(VI). An acidic pH environment enhanced Fe(VI) inactivation of ARB over the circumneutral pH. The presented results are intended to improve aquaculture managing practices to minimize the antibiotic proliferation in aquaculture waters and the environment.

Virus Nanoparticles & Different Nanoparticles Affect Lung Cancer- A New Approach

In the past, few decades cancer has become a worldwide problem to mankind. Lung cancer is the most life-threatening among all cancer types. Non-small cell lung cancer (NSCLC) is the main reason for approximately 80% to 90% of deaths. Lack of early detection and incompetent conventional therapies is the leading cause for poor prognosis and overall survival rate of lung cancer patients. Immense progress in the field of nanotechnology and nanomedicine has given inspiration to the development of an alternative strategy in the treatment of lung cancer. The unique physicochemical properties of the nanoparticles likeability to cross the different biological barriers, effectiveness in delivering hydrophobic drugs which are difficult to incorporate in the body, and targeting in the particular disease sites have given rise to enormous advantages for nanoparticulate systems for the early diagnosis and active delivery of drugs for a better treatment for lung cancer. Recently, many formulations of nanocarriers like lipid-based, polymeric and branched polymeric, metal-based, magnetic, and mesoporous silica are being used in this treatment. Innovative strategies have been employed to utilize the multicomponent, three-dimensional structure of nanoparticles and modify it and construct a new structure moiety that has multifunctional capabilities. Developing such designs permits simultaneous drug delivery of chemotherapeutics as well as anticancer gene therapies to site-specific targets. In lung cancer, nanoparticle-based therapeutics is now breaking the ground in the diagnosis, imaging, screening, and treatment of primary and metastatic tumors. This review emphasizes the pathogenesis of lung cancer and its treatment by nanotechnology.

A comprehensive stability assessment of insulin degludec using New customized validated RP-HPLC and SEC-HPLC methods in an orthogonal testing protocol

Stress testing of biopharmaceuticals plays an important role in preparation of their stability profiles through investigation of possible degradation pathways and identification of degradation products, so in this study Insulin Degludec which is a new generation ultra-long-acting basal insulin is subjected to stress conditions as different temperatures, different pH, oxidation, mechanical agitation, and repeated freeze and thaw cycles to generate possible degradation products and aggregation that are investigated by two new validated RP-HPLC and SEC-HPLC methods in addition to dynamic light scattering (DLS) and native polyacrylamide gel electrophoresis (Nu-PAGE). SEC-HPLC was used to investigate formation of aggregates whose results were correlated with those obtained from DLS and Nu-PAGE, while RP-HPLC was used to investigate any possible chemical modifications. The Proposed RP-method had limit of detection (LOD) and limit of quantitation (LOQ) of 0.012 mg/mL and 0.045 mg/mL respectively and accuracy of 99.22 ± 1.07 %, while the SEC methods had limit of detection (LOD) and limit of quantitation (LOQ) of 0.012 mg/mL and 0.031 mg/mL, respectively. The degradation pattern due to high temperature effect and oxidation is investigated by LC- tandem mass spectrometry. Results showed that Insulin degludec is highly stable under low temperature, mechanical agitation and repeated freeze and thaw stress conditions but elevated temperature and high acidic condition lead to formation of aggregates and also chemical modifications including deamidation, isomerization and oxidation. Such different chemical degradation pathways are due to presence of variable reactive moieties in Insulin degludec structure. Insulin degludec is highly vulnerable to oxidation at the sulfur containing cysteine residue in B chain in position B7 forming trioxidation derivative when exposed to hydrogen peroxide. Formation of A21-Asp and A18-Asp deamidated variants as well as B3-Asp and B3-isoAsp deamidated variants are prominent degradation pathways at neutral pH but at elevated temperature.

Biochemical Characterization and Synthetic Application of α‐1,3‐Glucosyltransferase from Pneumococcus Serotype 18C

AbstractThe enzymatic activity and function of a new α‐1,3‐glucosyltransferase, Cps18CU, derived from Streptococcus pneumoniae serotype 18C was identified for the first time using the enzymatically synthetic disaccharide Rhaβ1,4‐Glcα‐PP‐O(CH2)11‐OPh as the acceptor substrate. Further investigation on substrate specificity revealed that Cps18CU exhibited broad toleration toward various NDP‐Glc donors and also accepted such disaccharide acceptor containing Rhaβ1,4‐Glc moiety in structure. Finally, Cps18CU was employed into a one‐pot two‐enzyme reaction system, furnishing trisaccharide Glcα1,3‐Rhaβ1,4‐Glcα‐PP‐O(CH2)11‐OPh in an 81 % yield.

Amperometric determination of ecotoxic N-methyl-p-aminophenol sulfate in photographic solution and river water samples based on graphene oxide/CeNbO4 nanocomposite catalyst

The electronic conductivity of the metal oxides is generally increased by hybridization of highly conductive carbon supportive materials. In this present work, we have demonstrated a novel one-pot preparation of cerium niobate (CeNbO4) nanoparticles embedded with graphene oxide (GO/CeNbO4) composite, for ultrasensitive detection of the photographic developing agent, metol (MTL). The as-prepared GO/CeNbO4 was analyzed by various characterization techniques. The intensive characterization techniques were used to affirm the detailed structural moiety, size, morphology, and surface area of GO/CeNbO4. The GO/CeNbO4 modified glassy carbon electrode (GCE) affords a superior electrocatalytic activity toward MTL. The obtained amperometric response on the GO/CeNbO4/GCE holding an extremely low level detection of 10 nM and superior sensitivity of 10.97 µA µM–1 cm–2 toward MTL detection. Besides, the GO/CeNbO4/GCE also gives excellent selectivity, stability, repeatability, and reproducibility. We achieved excellent recovery results in real photographic solution and river water samples analysis with great accuracy. This work offers a novel insight into the growth of the carbon-based niobate family with electrochemical sensor applications.

Pyrido[3,4‐d]pyrimidine as an Acceptor of Thermally Activated Delayed Fluorescent Emitters: Time‐dependent Density Functional Theory Study

Pyrido[3,4‐d]pyrimidine (PyPm) was designed as a new acceptor of thermally activated delayed fluorescent (TADF) emitters and the potential of the new acceptor moiety for TADF properties was investigated. Time‐dependent density functional theory calculation was performed to estimate TADF characteristics by comparing five isomers of PyPm‐based TADF emitters. Geometries of the emitters were affected by the presence of hydrogen bonding depending on the substitution position of the phenyl linker in the donor‐phenyl linker‐acceptor type backbone structure, which also influenced the molecular orbital distributions. The nature of the triplet excited state was also dependent on the substitution position of the phenyl linker and donor moiety in the molecular structure, and the substitution at 5 position of the PyPm provided small singlet‐triplet energy gap and hybridized local and charge transfer triplet excited state for efficient reverse intersystem crossing. From the computational calculation results, it can be expected that PyPm would effectively work as an acceptor of TADF emitters.

Electrochemical Energy Storage: Porosity Engineering of MOF‐Based Materials for Electrochemical Energy Storage (Adv. Energy Mater. 20/2021)

In article number 2100154, Zhengxiao Guo and co-workers assess the state-of-the-art of design and synthesis strategies for tuning the pore structure and chemistry of metal-organic frameworks (MOFs) in order to enhance the performance of electrochemical energy storage devices. The importance of “porosity engineering” by careful selection of linkers and metal-centres to tune the rich and regular structural and chemical moieties is emphasized.

Characterizing the Specificity of Osmolyte Effects on Protein Thermal Stability

Osmolytes are small organic molecules that demonstrate the ability to shift protein unfolding equilibria when present as solution components, and provide proteins with protection from denaturation against thermal stress. While many subclasses of osmolytes are known, it is unclear whether there is an intrinsic stabilization hierarchy among the molecules that applies to all proteins. Additionally, it is uncertain what physicochemical properties of osmolytes confer their ability to act as stabilizers or destabilizers in solution. Our investigation utilizes differential scanning fluorimetry (DSF) to measure protein stability in two structure-based surveys: 1) determining whether there is a stabilization hierarchy among the three main chemical classes of osmolytes with respect to the model proteins, human C-reactive protein (CRP) and tumor necrosis factor alpha (TNFα), and 2) investigating the structural moiety requirements for amino acid osmolytes in the stabilization of CRP and myoglobin. The former part of our investigation reveals that ectoine is the most effective stabilizer of CRP, yet is a destabilizer when acting on TNFα, suggesting that there is no one osmolyte, or class of osmolytes, that confers the greatest stability across multiple proteins. The latter part of our investigation reveals that myoglobin is stabilized only by zwitterionic amino acids, as removal of either the carboxylate or amino moiety from the amino acid abrogates all thermal stabilizing effects. In contrast, in the case of CRP the carboxylate proved to be the dominant stabilizing group, as compounds lacking the amino group conferred slightly greater thermal stability than the complete amino acid osmolyte. Collectively, our results affirm that osmolyte effects on protein thermal stability are highly protein-specific. In addition, our data suggests that contemporary models to explain the osmolyte effect may not apply to all protein systems. These results may have significant implications for the development of chemistries aiming to stabilize diverse protein targets in biospecimens for diagnostic applications.

Characterization of a D1 Dopamine Receptor Positive Allosteric Modulator with a Novel Binding Site

The D1 dopamine receptor (D1R) is a crucial regulator of dopaminergic signaling and is involved in neurological processes and diseases. It is an attractive target for treating neuropsychiatric disorders, however, the liabilities of orthosteric agonists have curtailed this treatment modality. Positive allosteric modulators (PAMs) of D1R are therefore an alternative drug development strategy. We discovered two structurally distinct D1R PAMs via a high-throughput screen: MLS1082 and MLS6585. Both PAMs potentiate agonist-stimulated G protein- and β-arrestin-mediated signaling and increase dopamine's affinity for the D1R, though with different maximum efficacy and estimated Kb values. Combination experiments and receptor mutagenesis studies indicated that MLS1082 acts via the previously described intracellular loop-2 (ICL2) allosteric site targeted by two known D1R PAMs, Compound B and DETQ. MLS6585, however, does not act via this ICL2 site. To identify the MLS6585 binding site, chimeras of the D1R and D2R were used. MLS6585 has no PAM activity at the D2R, so loss of potentiation from the introduction of D2R sequences was used to detect potential regions of interest. This chimeric approach identified transmembrane region 7 (TM7) of D1R as a potential site for mediating MLS6585 activity. Further, specific point mutations identified residues near the extracellular region of TM7 that are required for MLS6585 PAM activity. These mutations had no effect on the activities of other PAMs binding to the ICL2 site. We used analog sets of MLS6585 to begin to understand the structure–activity relationships underlying D1R allosteric modulation. In addition to validating the MLS6585 scaffold as a D1R PAM, the analogs implicate structural moieties that are crucial for PAM activity and receptor selectivity. A small number of seemingly inactive analogs appear to act as silent allosteric modulators (SAMs) or neutral allosteric ligands (NALs), in that they blocked the activity of the parent PAM compound, presumably by competing for the same binding site. Together, these efforts increase our understanding of D1R allosteric modulation as a means for developing novel therapeutic interventions.

Adamantane derivatives as potential inhibitors of p37 major envelope protein and poxvirus reproduction. Design, synthesis and antiviral activity.

Currently, smallpox, caused by the variola virus belonging to the poxvirus family, has been completely eradicated according to the WHO. However, other representatives of poxviruses, such as vaccinia virus, cowpox virus, ectromelia virus, monkeypox virus, mousepox virus and others, remain in the natural environment and can infect both animals and humans. The pathogens of animal diseases, belonging to the category with a high epidemic risk, have already caused several outbreaks among humans, and can, in an unfavorable combination of circumstances, cause not only an epidemic, but also a pandemic. Despite the fact that there are protocols for the treatment of poxvirus infections, the targeted design of new drugs will increase their availability and expand the arsenal of antiviral chemotherapeutic agents. One of the potential targets of poxviruses is the p37 protein, which is a tecovirimat target. This protein is relatively small, has no homologs among proteins of humans and other mammals and is necessary for the replication of viral particles, which makes it attractive target for virtual screening. Using the I-TASSER modelling and molecular dynamics refinement the p37 orthopox virus protein model was obtained and its was confirmed by ramachandran plot analysis and superimposition of the model with the template protein with similar function. A virtual library of adamantane containing compounds was generated and a number of potential inhibitors were chosen from virtual library using molecular docking. Several compounds bearing adamantane moiety were synthesized and their biological activity was tested in vitro on vaccinia, cowpox and mousepox viruses. The new compounds inhibiting vaccinia virus replication with IC50 concentrations between 0.133 and 0.515 μM were found as a result of the research. The applied approach can be useful in the search of new inhibitors of orthopox reproduction. The proposed approach may be suitable for the design of new poxvirus inhibitors containing cage structural moiety.