Effects Of New Compounds Research Articles

Therapeutically targeting the CALR/CD47 pathway in MPN to reactivate natural immunosurveillance mechanisms within the body to enhance treatment outcomes.

170 Background: MPNs are a group of related myeloid malignancies characterized by alterations in mature blood cell production/bone marrow environment and have a tendency to evolve into acute myeloid leukaemia. We demonstrated that CD47 blockade in combination with ruxolitinib, increased CALR expression enhancing cytotoxicity in vitro, promoting enhanced neoplastic clone clearance. With this study we describe a potential methodology for assessing effect of new compounds or combinations and the impact of modulating the immunoresponse upon myeloid malignant clones. Methods: Utilising HEL 92.1.7 and SET-2 cells (JAK2 mutated), Marimo cells (CALR mutated) and K562 cell line models; we will incubate with routine therapies (hydroxyurea, anagrelide, ruxolitinib) in combination with a range of anti-CD47 compounds (Anti-CD47 monocloncal antibodies, BET-1 inhibitors, SIRa inhibitor) and will determine the impact upon CD47 and CALR cell surface expression via flow cytometry. Monocyte derived macrophage (MDM) will be produced through Phorbol 12-myristate 13-acetate (PMA) differentiation of a monocytic Thp-1 cell line. Expression of macrophage cell surface markers (CD11b, CD14), as well as intracellular markers (CD68), will be detected by flow cytometry. MDM will then be polarized to either a pro-inflammatory M1, or anti-inflammatory M2 phenotype, with lipopolysaccharide/interferon gamma or interleukins 4 and 13, respectively. Co-culture experiments will then be undertaken to determine how different anti-CD47 therapy combination impact macrophage polarization and destruction of MPN cell lines. Results: We predict that CALR/CD47 levels on each cell line subtype will respond differently highlighting heterogeneity within MPNs and demonstrating the clear need for a more personalised immunotherapy approach. Alterations in JAK/STAT pathway and BET inhibition may hinder macrophage polarisation to the anti-tumorigenic M1 macrophage phenotype. We theorise that indirect co-culture of M1 macrophage with MPN suspension cells under different treatment modalities will enhance MPN cell death and decrease CD47 expression to a greater level than that which we expect to see in M2 polarised macrophage. We also anticipate that the M2 polarised macrophage, which dominate in the tumour microenvironment as MPN progresses, will fail to phagocytose MPN cells and may not be rescued by novel immunotherapeutics. Conclusions: Our group demonstrated the role of CD47 and CALR expression as a key mechanism and a potential target to enhance presentation of the cancer cell to the immune system, and we believe that understanding the interaction of CD47/CALR – macrophages, will drive new therapeutical approaches able to modulate the immune response and improve patients outcomes, potentially leading to complete MPN clone eradiation and cure.

Assessing lethal and sublethal effects of pesticides on honey bees in a multifactorial context

The registration of novel pesticides that are subsequently banned because of their unexpected negative effects on non-target species can have a huge environmental impact. Therefore, the pre-emptive evaluation of the potential effects of new compounds is essential. To this aim both lethal and sublethal effects should be assessed in a realistic scenario including the other stressors that can interact with pesticides. However, laboratory studies addressing such interactive effects are rare, while standardized laboratory-based protocols focus on lethal effects and not on sub-lethal effects.We propose to assess both lethal and sublethal effects in a multifactorial context including the other stressors affecting the non-target species. We tested this approach by studying the impact on honey bees of the insecticide sulfoxaflor in combination with a common parasite, a sub-optimal temperature and food deprivation. We studied the survival and the transcriptome of honey bees, to assess both the lethal and the potential sublethal effects of the insecticide, respectively. With this method we show that a field realistic concentration of sulfoxaflor in food does not affect the survival of honey bees; however, the significant impact on some key genes indicates that sublethal effects are possible in a realistically complex scenario.Moreover, our results demonstrate the feasibility and reliability of a novel approach to hazard assessment considering the interactive effects of pesticides. We anticipate our approach to be a starting point for a paradigm shift in toxicology: from an unifactorial, mortality-centered assessment to a multifactorial, comprehensive approach. This is something of the utmost importance to preserve pollination, thus contributing to the sustainability of our food production system.

Design, Synthesis, and Biological Evaluation of the Quorum-Sensing Inhibitors of Pseudomonas aeruginosa PAO1.

Due to the resistance of Gram-negative bacteria Pseudomonas aeruginosa PAO1 to most clinically relevant antimicrobials, the use of traditional antibiotic treatments in hospitals is challenging. The formation of biofilms, which is regulated by the quorum-sensing (QS) system of Pseudomonas aeruginosa (PA), is an important cause of drug resistance. There are three main QS systems in P. aeruginosa: the las system, the rhl system, and the pqs system. The inhibitors of the las system are the most studied. Previously, the compound AOZ-1 was found to have a certain inhibitory effect on the las system when screened. In this study, twenty-four compounds were designed and synthesized by modifying the Linker and Rings of AOZ-1. Using C. violaceum CV026 as a reporter strain, this study first assessed the inhibitory effects of new compounds against QS, and their SAR was investigated. Then, based on the SAR analysis of compound AOZ-1 derivatives, the parent core of AOZ-1 was replaced to explore the structural diversity. Then, nine new compounds were designed and synthesized with a new nucleus core component of 3-amino-tetrahydro-l,3-oxazin-2-one. The compound Y-31 (IC50 = 91.55 ± 3.35 µM) was found to inhibit the QS of C. violaceum CV026. Its inhibitory effect on C. violaceum CV026 was better than that of compound AOZ-1 (IC50 > 200 µM). Furthermore, biofilm formation is one of the important causes of Pseudomonas aeruginosa PAO1 resistance. In this study, it was found that compound Y-31, with a new nucleus core component of 3-amino-tetrahydro-l,3-oxazin-2-one, had the highest biofilm inhibition rate (40.44%). The compound Y-31 has a certain inhibitory effect on the production of PAO1 virulence factors (pyocyanin, rhamnolipid, and elastase) and swarming. When the concentration of compound Y-31 was 162.5 µM, the inhibition rates of pyocyanin, rhamnolipid, and elastase were 22.48%, 6.13%, and 22.67%, respectively. In vivo, the lifetime of wildtype Caenorhabditis elegans N2 infected with P. aeruginosa PAO1 was markedly extended by the new parent nucleus Y-31. This study also performed cytotoxicity experiments and in vivo pharmacokinetics experiments on the compound Y-31. In conclusion, this study identified a compound, Y-31, with a new nucleus core component of 3-amino-tetrahydro-l,3-oxazin-2-one, which is a potential agent for treating P. aeruginosa PAO1 that is resistant to antibiotics and offers a way to discover novel antibacterial medications.

Novel cinnamic acid-based PET derivatives as quorum sensing modulators

Poly(ethylene terephthalate) (PET) is widely used material in the healthcare due to its mechanical properties including resistance to chemicals and abrasion. However, it is susceptible to bacterial attachment and contamination. This study addresses some newly designed model compounds of PET with antimicrobial properties that could potentially be incorporated into PET materials. All compounds were synthesized for the first time by labeling an integral part of PET with chromophores in the form of esters of cinnamic and ferulic acids. After complete structural characterization, the effect of new compounds on microbial growth and communication (quorum sensing, QS) was analyzed and further investigated using molecular docking. The obtained results indicate that the introduction of chromophores that have one part of cinnamic acid enriched with a methoxy functional group in them acts as QS modulators. Moreover, compounds exhibited dose-dependent selectivity toward QS signaling pathways and the highest tested concentration of compounds showed Pseudomonas Quinolone Signal (PQS) inhibitory activity suggesting that these compounds have a potential effect on pyocyanin production. Docking studies demonstrated that compounds hold binding power to all four QS protein targets (LuxP, periplasmatic protein that binds AI-2 inducer and forms a complex able to transduce the autoinducer signal, RhIR protein that is a key QS transcriptional regulator that activates the genes involved in the synthesis of rhamnolipids and pyocyanin, AbaI protein that has a role in QS signal transduction, and LasR protein which is a key QS transcriptional regulator that activates transcription of genes coding for some virulence-associated traits) while the highest binding strength is observed with compounds 2 and 6 containing single cinnamic acid fragment, suggesting their further biomedical application.

Identification of side effects of COVID-19 drug candidates on embryogenesis using an integrated zebrafish screening platform

Drug repurposing is an important strategy in COVID-19 treatment, but many clinically approved compounds have not been extensively studied in the context of embryogenesis, thus limiting their administration during pregnancy. Here we used the zebrafish embryo model organism to test the effects of 162 marketed drugs on cardiovascular development. Among the compounds used in the clinic for COVD-19 treatment, we found that Remdesivir led to reduced body size and heart functionality at clinically relevant doses. Ritonavir and Baricitinib showed reduced heart functionality and Molnupiravir and Baricitinib showed effects on embryo activity. Sabizabulin was highly toxic at concentrations only 5 times higher than Cmax and led to a mean mortality of 20% at Cmax. Furthermore, we tested if zebrafish could be used as a model to study inflammatory response in response to spike protein treatment and found that Remdesivir, Ritonavir, Molnupiravir, Baricitinib as well as Sabizabulin counteracted the inflammatory response related gene expression upon SARS-CoV-2 spike protein treatment. Our results show that the zebrafish allows to study immune-modulating properties of COVID-19 compounds and highlights the need to rule out secondary defects of compound treatment on embryogenesis. All results are available on a user friendly web-interface https://share.streamlit.io/alernst/covasc_dataapp/main/CoVasc_DataApp.py that provides a comprehensive overview of all observed phenotypic effects and allows personalized search on specific compounds or group of compounds. Furthermore, the presented platform can be expanded for rapid detection of developmental side effects of new compounds for treatment of COVID-19 and further viral infectious diseases.

Development and In Vivo Assessment of 4-Phenyltellanyl-7-chloroquinoline-loaded Polymeric Nanocapsules in Alzheimer's Disease Models.

Alzheimer's disease (AD) is the most common form of dementia in older people, and available treatments are palliative and produce undesirable side effects. The 4-phenyltellanyl-7-chloroquinoline (TQ) is an organochalcogen compound studied due to its pharmacological properties, particularly its antioxidant potential. However, TQ possesses some drawbacks such as low aqueous solubility and high toxicity, thus warranting the search for tools that improve the safety and effectiveness of new compounds. Here, we developed and investigated the biological effects of TQ-loaded polymeric nanocapsules (NCTQ) in an AD model in transgenic Caenorhabditis elegans expressing human Aβ1-42 in their body-wall muscles and Swiss mice injected with Aβ25-35. The NCTQ displayed good physicochemical properties, including nanometer size and maximum encapsulation capacity. The treatment showed low toxicity, reduced Aβ peptide-induced paralysis, and activated an endoplasmic reticulum chaperone in the C. elegans model. The Aβ injection in mice caused memory impairment, which NCTQ mitigated by improving working, long-term, and aversive memory. Additionally, no changes in biochemical markers were evidenced in mice, demonstrating that there was no hepatotoxicity in the tested doses. Altogether, these findings provide insights into the neuroprotective effects of TQ and indicate that NCTQ is a promising candidate for AD treatment.

Anti-inflammatory efficacy and relevant SAR investigations of novel chiral pyrazolo isoquinoline derivatives: Design, synthesis, in-vitro, in-vivo, and computational studies targeting iNOS

Isoquinoline alkaloids are a rich source of multimodal agents with distinctive structural specificity and various pharmacological activities. In the present report, we propose a combination of design, synthesis, computational study, primary in-vitro screening using the lipopolysaccharide (LPS)-induced RAW 264.7 cell line, and in-vivo evaluation in mice models as a novel approach to speed up anti-inflammatory drugs discovery. The nitric oxide (NO) inhibitory effect of new compounds revealed that all of them displayed the potent NO inhibitory ability in a dose-dependent manner with no obvious cytotoxicity. A series of the model compounds 7a, 7b, 7d, 7f, and 7g have been identified as the most promising, with IC50 values of 47.76 μM, 33.8 μM, 20.76 μM, 26.74 μM, and 47.8 μM respectively in LPS-induced RAW 264.7 cell line. Structure-activity relationship (SAR) studies on a range of derivatives aided in identifying key pharmacophores in the lead compound. Western blotting data of 7d identified that our synthesized compounds can down-regulate and suppress the expression of the key inflammatory enzyme, inducible nitric oxide synthase (iNOS). These results suggested that synthesized compounds may be potent anti-inflammatory agents, inhibiting the NO-release, in turn, iNOS inflammatory pathways. Furthermore, in-vivo anti-inflammatory detection via xylene-induced ear edema in mice revealed that these compounds could also inhibit swelling in mice, with model compound 7h showing an inhibition activity (64.4%) at a concentration of 10 mg/kg comparable to the reference drug celecoxib. Molecular docking results showed that shortlisted compounds (7b, 7c, 7d, 7e, and 7h) had a potential binding affinity for iNOS with low energies, with S-Score to be −7.57, −8.22, −7.35, −8.95, −9.94 kcal/mol, respectively. All results demonstrated that the newly synthesized chiral pyrazolo isoquinoline derivatives are highly potential anti-inflammatory agents.

Artificial Intelligence in Drug Toxicity Prediction: Recent Advances, Challenges, and Future Perspectives.

Toxicity prediction is a critical step in the drug discovery process that helps identify and prioritize compounds with the greatest potential for safe and effective use in humans, while also reducing the risk of costly late-stage failures. It is estimated that over 30% of drug candidates are discarded owing to toxicity. Recently, artificial intelligence (AI) has been used to improve drug toxicity prediction as it provides more accurate and efficient methods for identifying the potentially toxic effects of new compounds before they are tested in human clinical trials, thus saving time and money. In this review, we present an overview of recent advances in AI-based drug toxicity prediction, including the use of various machine learning algorithms and deep learning architectures, of six major toxicity properties and Tox21 assay end points. Additionally, we provide a list of public data sources and useful toxicity prediction tools for the research community and highlight the challenges that must be addressed to enhance model performance. Finally, we discuss future perspectives for AI-based drug toxicity prediction. This review can aid researchers in understanding toxicity prediction and pave the way for new methods of drug discovery.

Behavioral Pharmacology as the Main Approach to Study the Efficiency of Potential Psychotropic Drugs: Analysis of Modern Methods (Review)

Introduction. Behavioral methods on laboratory animals are recognized as the main approach in studying the activity of potential psychotropic drugs and allow us to evaluate the main effects of new compounds, increase the possibility of predicting a successful outcome of future clinical trials.Text. This review article analyzes the main modern behavioral models in rodents that are widely used for screening and studying the pharmacological activity of potential psychotropic drugs. The advantages and disadvantages of each test are highlighted and complexes of behavioral methods are demonstrated that most conclusively confirm the reproducibility of the results obtained in clinical trials. The description and evaluation of behavioral methods that characterize the state of anxiety, which are used to screen for new compounds with anxiolytic activity (tests «Open field», «Dark-light chamber», «Elevated plus maze», «Sequence of rays»). The range of tests used to study cognitive functions and memory processes is widely presented (various mazes – T-shaped, U-shaped, radial maze, Barnes maze, E-maze; water mazes – Morris, T-maze) with a description of a comparative analysis and necessary conditions that ensure the reliability of information. An important direction in the field of behavioral pharmacology is the modeling of violations of social behavior and the study of approaches for its correction – the main methods necessary for the study of social behavior are presented in the review by the tests «Three-chamber social test», «Open field» extended test, etc.Conclusion. Behavioral pharmacology dictates the need for close interaction between preclinical and clinical stages of research in the framework of the development of translational medicine and the development of approaches that provide evidence for the reproducibility of the results obtained in clinical trials. It is also necessary to improve existing and develop new behavioral models of mental disorders and to search for new ways to study the mechanisms of formation of behavioral disorders.

Experimental investigation of new compound adsorption on carbon steel in 1M HCl

The effect of new compounds named, 6,6'-(((2,2-dimethylpropane-1,3-diyl)bis(azanediyl))bis(methylene))bis(2- methoxyphenol) (RSH) on the corrosion inhibiting of ST- 37 low carbon steel in 1.0 M HCl has been studied. The inhibitor effects on the corrosion behaviour of the samples have been determined at three different concentrations, 0.5, 1.0, 1.5 and 2.0 mg/L. Weight loss, polarization curves, AC impedance measurements and Atomic Force Microscopy (AFM) have been utilized to study the corrosion behaviour of carbon steel in corrosive environment in the presence and absence of new ligand. Results show that the inhibition occurs through adsorption of the inhibitors molecules on the metal surface. The inhibition efficiency was found to increase with increasing inhibitor’s concentration. Polarization data indicated that this compounds act as mixed-type inhibitors. The corrosion efficiency of RSH at an optimal concentration of 2mg/L is 86. The adsorption of inhibitors follows the Langmuir isotherm. The values of free energy of adsorption in the presence of the corrosion inhibitor are around -32 KJmol-1, which indicate chemiosorption of the molecules. Powerful Atomic Force microscopy is used for the surface morphology studies.

Integration of LC/MS-based molecular networking and molecular docking allows in-depth annotation and prediction of the metabolome: A study of Salvia miltiorrhiza Bunge

Plant secondary metabolites play essential roles in plant-environment interactions and biological communication. Although untargeted metabolomics is widely used in plant research, it suffers from limited annotated metabolites and relatively poor reliability. Herein, we report a technical route of untargeted metabolomics that involves using MS-DAIL to preprocess the data, using Cytoscape to construct a molecular network and quickly expand secondary metabolites annotation, using SIRIUS4 to construct a mass spectrum tree and summarize the fragmentation rules, and using bioinformatics analysis and molecular docking to predict the latent effect of new compounds. The new method annotates metabolites and finds new substances according to mass spectrometry similarity, and predicts its potential application value before separating new substances. 34 tanshinones and 31 phenolic acids were rapidly annotated by the technical route, and the structures of two new salvianolic acids with large molecular weights were deduced by the summarized mass spectrometry fragmentation rules. The results of molecular docking indicated that the two new substances may act on aldose reductase and plasminogen . The new technical route established in this study is helpful for the identification of plant secondary metabolites and the prediction of potential application value of new compounds. The method established in this study is helpful to promote plant metabolomics studies. • A new technical route for rapid compound annotation is proposed. • The method identified two new phenolic acid compounds in Salvia miltiorrhiza. • Molecular docking methods are used to predict the potential activity of novel compounds.

The effect of novel synthetic semicarbazone- and thiosemicarbazone-linked 1,2,3-triazoles on the apoptotic markers, VEGFR-2, and cell cycle of myeloid leukemia

Vascular Endothelial Growth Factor II (VEGFR-2) has been proved as a rational target in cancer therapy. Although currently prescribed VEGFR-2 inhibitors are showing potent antitumor activity, they are often causing serious unwanted effects, restricting their extensive use as chemotherapeutics. Herein, after analyzing the structures of the effective VEGFR-2 inhibitor molecules, we report the synthesis of a new set of semicarbazone- and thiosemicarbazone-linked 1,2,3-triazoles with expected potency of inhibiting the VEGFR-2 signaling. The design of new compounds considered maintaining the essential pharmacophoric features of sorafenib for effective binding with the receptor target. All compounds have been evaluated for their growth inhibition effect against a panel of sixty cancer cells at the National Cancer Institute. Leukemia cancer cells, especially HL-60 and SR, were shown to be the most sensitive to the cytotoxic effect of new compounds. Thiosemicarbazones 21, 26, and 30 exhibited the best activity against almost all tested cancer cells. Therefore, a set of subsequent in vitro biological evaluations has been performed to understand the mechanistic effect of these compounds further. They inhibited the VEGFR-2 with IC50 values of 0.128, 0.413, and 0.067 µM respectively compared with 0.048 µM of Sorafenib. The probable mechanistic effect of 30 has been further evaluated on a number of apoptotic and antiapoptotic markers including BAX, BCL2, caspase-3, and caspase-9. Results revealed the potential of the thiosemicarbazone-linked triazole 30 to induce both the early and the late apoptosis, elevate BAX/BCL2 ratio, induce caspase-3 & caspase-9, and arrest the HL-60 cell cycle at the G2/M and G0-G1 phases. Molecular docking of new semicarbazones and thiosemicarbazones into the proposed biological target receptor has also been performed. Results of docking studies proved the potential of new semicarbazone- and thiosemicarbazone-linked 1,2,3-triazoles to effectively bind with crucial residues of the VEGFR-2 binding pocket.

Effects of New Compounds into Substrates on Seedling Qualities for Efficient Transplanting

Automating vegetable seedling transplanting has led to labor-saving opportunities and improved productivity. Some changes in seedling agronomy are necessary for efficient transplanting. In this study, the local nursery substrates were added with the herbaceous peat, the sphagnum peat, and the coir peat, respectively. Effects of the new compound substrates were investigated on the seedling growth qualities and the root substrate strength. In the results, we found that the addition of three compound mediums significantly affected the physiochemical properties of the original substrates. Under the same conditions of cultivating seedlings, appropriate additions of new compounds promoted the seedling growth. Moreover, deficient or excessive additions inhibited the growing development of seedlings and their roots. The corresponding additions also improved the structural characteristics of the root lumps. Compared with the two other compounds, the nursery substrates added with the sphagnum peat were optimized in contribution to the seedling qualities and the root substrate strengths. As the local substrate and the sphagnum peat were mixed at a volume ratio of 2:1, the dry matter accumulation of seedlings was 2.18 times more than the original. Their root lumps had the best consolidation strength. This new compound of substrates may be an effective application for the necessary qualities of seedlings for automatic transplanting.

Experimental and computational investigation of 3,5-di-tert-butyl-2-(((3-((2-morpholinoethyl)(pyridin-2-ylmethyl) amino)propyl)imino) methyl)phenol and related reduced form as an inhibitor for C-steel

The effect of new compounds containing morpholine moiety including: 3,5-di-tert-butyl-2-(((3-((2-morpholinoethyl)(pyridine-2-ylmethyl)amino)propyl)imino)methyl)phenol (L1) and its reduced form, 3,5-di-tert-butyl-2-(((3-((2-morpholinoethyl)(pyridine-2-ylmethyl)amino)propyl)amino) methyl)phenol (L2) on the corrosion inhibiting of C-steel in 1.0 M HCl and 3.5 wt% NaCl was tested by experimental and computational techniques. The concentration of inhibitor varied in the range of 0.2–2.0 mM. The corrosion behavior of C-steel was investigated using electrochemical techniques, including open circuit potential (OCP), potentiodynamic polarization (Tafel), electrochemical impedance spectroscopy (EIS) and scanning electron microscopy (SEM) inhibitor-free and inhibitor-containing solutions. From the Tafel diagram, the icorr of the C-steel electrode in the 1.0 M hydrochloric acid solution represents the highest value among the other inhibitor-containing solutions. The icorr for C-steel in L1 containing solution decreases gradually from 1.43 × 10−4 to 0.91 × 10−4 A/cm2, with the concentration of L1 increasing from 0.2 to 2.0 mM. Along with the increase of the L2 concentration from 0.2 to 2.0 mM, the icorr is reduced by about 41%. EIS studies demonstrated that the capacitance of the double layer increased by the addition of inhibitors and increasing the resistance of charge transfer, suggesting an improvement of the corrosion protection in inhibitor-containing acidic solution. SEM images confirmed the corrosion results in which inhibitor-containing solution protects the C-steel surface against the attack of species. The results showed that in all solutions containing equivalent concentrations of inhibitors, the reduced form of L1 had a better inhibition efficiency than the L1 inhibitor. Inhibitors, L1 and its reduced form exhibit Langmuir adsorption isotherm, in which monolayer adsorption of inhibitors is carried out on the C-steel electrode. The properties of the studied molecules to be corrosion inhibitors were examined with the Gaussian software program. The calculations of the molecules were made in different methods and basis sets.

The Discovery of Potent SHP2 Inhibitors with Anti-Proliferative Activity in Breast Cancer Cell Lines.

Despite available treatments, breast cancer is the leading cause of cancer-related death. Knowing that the tyrosine phosphatase SHP2 is a regulator in tumorigenesis, developing inhibitors of SHP2 in breast cells is crucial. Our study investigated the effects of new compounds, purchased from NSC, on the phosphatase activity of SHP2 and the modulation of breast cancer cell lines’ proliferation and viability. A combined ligand-based and structure-based virtual screening protocol was validated, then performed, against SHP2 active site. Top ranked compounds were tested via SHP2 enzymatic assay, followed by measuring IC50 values. Subsequently, hits were tested for their anti-breast cancer viability and proliferative activity. Our experiments identified three compounds 13030, 24198, and 57774 as SHP2 inhibitors, with IC50 values in micromolar levels and considerable selectivity over the analogous enzyme SHP1. Long MD simulations of 500 ns showed a very promising binding mode in the SHP2 catalytic pocket. Furthermore, these compounds significantly reduced MCF-7 breast cancer cells’ proliferation and viability. Interestingly, two of our hits can have acridine or phenoxazine cyclic system known to intercalate in ds DNA. Therefore, our novel approach led to the discovery of SHP2 inhibitors, which could act as a starting point in the future for clinically useful anticancer agents.

Применение метода фармакоэнцефалографии для оценки нейропротекторной активности лекарственных средств

The search and study of new neuroprotective agents is an urgent task of biomedical research. Due to the low translational potential of the results of experimental and preclinical studies, new approaches are needed to evaluate the effectiveness of new compounds that have a positive effect on vascular or traumatic brain lesions. The method of pharmacoencephalography (pharmaco-EEG) is one of the neurophysiological research methods that allows you to assess the functional state of the brain in terms of its bioelectrical activity. Despite the need for surgical intervention, pharmaco-EEG in experimental neuroscience has several advantages over traditionally used behavioral tests, as well as biochemical or molecular genetic methods. This review considers examples of the use of this method to assess the neuroprotective activity of drugs in models of traumatic brain injury and stroke in rodents. However, based on the results of published studies, it can be concluded that pharmaco-EEG is a sensitive method for assessing the effects of drugs on the course of pathological processes in brain damage in rats and can be considered as a useful addition to traditional experimental approaches.

Corrosion behaviour of new oxo-pyrimidine derivatives on mild steel in acidic media: Experimental, surface characterization, theoretical, and Monte Carlo studies

In this work, the effects of new compounds, namely, 1-amino-5-(4-methylbenzoyl)-4-(4-methylphenyl) pyrimidin-2 (1H)-thione (AMMP), and 1-(5-(4-Methoxybenzoyl)-4-(4-methoxyphenyl) 2-oxopyrimidin-1 (2H)-yl)-3-phenylthiourea (MMOPH) has been successfully investigated as a corrosion inhibitor for mild steel in a 1 M HCl solution. This investigation has been done by electrochemical techniques (potentiodynamic polarization, and electrochemical impedance spectroscopy), surface characterization (scanning electron microscopy with energy dispersive x-ray spectroscopy, and atomic force microscopy), and theoretical calculations (density function theory and Monte Carlo simulation). The electrochemical results showed that both compounds act as mixed-type inhibitors. However, MMOPH is more efficient than AMMP (95.9% compared with 84.1% at 5 × 10−4 M and an immersion time of 1 h). Additionally, the effect of immersion time on inhibitor efficiency was studied. The current density was reduced with the presence of inhibitors from 517.93 to 56.18 and 9.96 μA.cm−2 at 5 × 10−4 M and an immersion time of 1 h for AMMP and MMOPH, respectively. In both substances, the Langmuir isotherm system showed the best fit, with physisorption and chemisorption being the types of adsorption. The results of surface characterization indicated that both compounds can be adsorbed on mild steel surfaces to minimize corrosion. The obtained Monte Carlo simulation results suggest that the inhibitors are adsorbed vertically and the formation of a protective layer on the metal surface. The density function theory calculations for inhibitors found the protonated state is more reactive than the neutral state and agree with experimental results and follow the order MMOPH ˃ AMMP. The results showed that both compounds can be used as new corrosion inhibitors for mild steel in aggressive environments.

Naftalenilmetilen Hidrazin Türevlerinin Antimikrobiyal Aktiviteleri

In clinical microbiology and antibacterial research, the significance of drug-resistant pathogens is growing up. Hydrazine-type compounds constitute the main classes of chemicals for the investigation of multidrug resistant agents which causes microbial infections. In the current study antimicrobial activities of certain Naphthalenylmethylen Hydrazine derivatives were examined to appraise their efficacy. The effectiveness of new compounds were evaluated using 2-fold serial dilutions against Staphylococcus aureus, Methicillin-Resistant-Staphylococcus aureus (MRSA), Enterococcus faecalis, Pseudomonas aeruginosa, Escherichia coli, and Candida albicans. Minimum inhibitory concentration (MIC) was determined for test compounds and for the reference standards Ciprofloxacin, ampicillin, and miconazole. According to the results, although the new compounds demonstrated poor antibacterial effects in general, the 1e and 1h compounds showed off significant antibacterial effects, especially against MRSA strains.

The Role of Supplementation with Natural Compounds in Post-Stroke Patients.

Malnutrition is a serious problem in post-stroke patients. Importantly, it intensifies with hospitalization, and is related to both somatic and psychological reasons, as well as is associated with the insufficient knowledge of people who accompany the patient. Malnutrition is a negative prognostic factor, leading to a reduction in the quality of life. Moreover, this condition significantly extends hospitalization time, increases the frequency of treatment in intensive care units, and negatively affects the effectiveness of rehabilitation. Obtaining growing data on the therapeutic effectiveness of new compounds of natural origin is possible through the use of pharmacodynamic and analytical methods to assess their therapeutic properties. The proper supply of nutrients, as well as compounds of natural origin, is an important element of post-stroke therapy, due to their strong antioxidant, anti-inflammatory, neuroprotective and neuroplasticity enhancing properties. Taking the above into account, in this review we present the current state of knowledge on the benefits of using selected substances of natural origin in patients after cerebral stroke.

Sesquiterpene Lactones with the 12,8-Guaianolide Skeleton from Algerian Centaurea omphalotricha.

In continuing our investigation on the chemical diversity of Algerian plants, we examined Centaurea omphalotricha, whose chemical composition has been poorly studied. The present work was aimed at characterizing the secondary metabolite pattern of the CHCl3 extract of the aerial parts of this plant that displayed antiproliferative properties in a preliminary screening on HeLa cell line. The chemical analysis led us to characterize the bioactive oxygenated terpenoid fraction which includes, within major known metabolites, two new minor sesquiterpene lactones, centaurolide-A (1) and centaurolide-B (2). The structures of two compounds exhibiting the 12,8-guaianolide skeleton were determined by spectroscopic methods as well as by chemical correlation with inuviscolide (3), a well-known bioactive guaianolide isolated from Dittrichia (=Inula) viscosa. Centaurolides A and B represent the first report of 8,12-guaianolide skeleton in Centaurea genus. The effect of new compounds 1 and 2 and inuviscolide (3) on HeLa cell has also been evaluated.