Multifunctional Inhibitors Research Articles

Structural, CSD, and computational studies of 6b, 11b-Dihydroxy-6b, 11-b-dihydro-7H-indeno[1,2-b]naptho[2,1-d]furan-7-one, a therapeutic potential small molecule

Biochemical and pharmacological investigations carried out on the small molecule 6b, 11b-Dihydroxy-6b, 11-b-dihydro-7H-indeno[1,2-b]naptho[2,1-d]furan-7-one (DHFO) has shown that it is an analgesic, anti-inflammatory agent, and a dual 5-LOX/COX-2 inhibitor. DHFO is also a free-radical scavenger, a potent antioxidant, and an inhibitor of lipid peroxidation. We studied the structural properties of DHFO using single-crystal X-ray crystallography, Hirshfeld surfaces, and energy frameworks studies. Additionally, we also examined the conformational behavior of 29 molecular analogues of DHFO retrieved from the Cambridge Structural Database (CSD), which were similar to DHFO in flexibility, the effect of the substitution, and electrostatic interaction forces. Besides, we carried out the molecular docking studies to analyze the binding efficiency of DHFO with COX-1, COX-2, 5-LOX, and Cdc25B-cd (the catalytic domain of human Cdc25B phosphatase, which is identified as an arsenic reductase) proteins co-crystallized with standard drugs such as meloxicam. DHFO showed a better affinity with COX-2 than COX-1 and can potentially bind with CdC25B-cd protein. The drug-likeness of DHFO was also evaluated using Lipinski's rule, the SwissADME database, and DHFO possessed potential drug-likeness properties. In summary, the DHFO may potentially act as a multifunctional inhibitor by binding cyclooxygenase and arsenic binding proteins.

Triazoles as class of multifunctional corrosion inhibitors. Review IV. Magnesium alloys

Triazoles as class of multifunctional corrosion inhibitors. Review IV. Magnesium alloys

The synthetic varespladib molecule is a multi-functional inhibitor for PLA2 and PLA2-like ophidic toxins

BackgroundThe treatment for snakebites is early administration of antivenom, which can be highly effective in inhibiting the systemic effects of snake venoms, but is less effective in the treatment of extra-circulatory and local effects. To complement standard-of-care treatments such as antibody-based antivenoms, natural and synthetic small molecules have been proposed for the inhibition of key venom components such as phospholipase A2 (PLA2) and PLA2-like toxins. Varespladib (compound LY315920) is a synthetic molecule developed and clinically tested aiming to block inflammatory cascades of several diseases associated with high PLA2s. Recent studies have demonstrated this molecule is able to potently inhibit snake venom catalytic PLA2 and PLA2-like toxins. MethodsIn vivo and in vitro techniques were used to evaluate the inhibitory effect of varespladib against MjTX-I. X-ray crystallography was used to reveal details of the interaction between these molecules. A new methodology that combines crystallography, mass spectroscopy and phylogenetic data was used to review its primary sequence. ResultsVarespladib was able to inhibit the myotoxic and cytotoxic effects of MjTX-I. Structural analysis revealed a particular inhibitory mechanism of MjTX-I when compared to other PLA2-like myotoxin, presenting an oligomeric-independent function. ConclusionResults suggest the effectiveness of varespladib for the inhibition of MjTX-I, in similarity with other PLA2 and PLA2-like toxins. General significanceVarespladib appears to be a promissory molecule in the treatment of local effects led by PLA2 and PLA2-like toxins (oligomeric dependent and independent), indicating that this is a multifunctional or broadly specific inhibitor for different toxins within this superfamily.

Design, synthesis and evaluation of novel dimethylamino chalcone-O-alkylamines derivatives as potential multifunctional agents against Alzheimer's disease.

A novel series of dimethylamino chalcone-O-alkylamines derivatives was designed and synthesized as multifunctional agents for the treatment of AD. All the target compounds exhibited significant abilities to inhibit and disaggregate Aβ aggregation, and acted as potential selective AChE inhibitors, biometal chelators and selective MAO-B inhibitors. Among these compounds, compound TM-6 showed the greatest inhibitory activity against self-induced Aβ aggregation (IC50=0.88μM) and well disaggregation ability toward self-induced Aβ aggregation (95.1%, 25μM), the TEM images, molecular docking study and molecular dynamics simulations provided reasonable explanation for its high efficiency, and it was also found to be a remarkable antioxidant (ORAC-FL values of 2.1eq.), the best AChE inhibitor (IC50=0.13μM) and MAO-B inhibitor (IC50=1.0μM), as well as a good neuroprotectant. UV-visual spectrometry and ThT fluorescence assay revealed that compound TM-6 was not only a good biometal chelator by inhibiting Cu2+-induced Aβ aggregation (95.3%, 25μM) but also could disassemble the well-structured Aβ fibrils (88.1%, 25μM). Further, TM-6 could cross the blood-brain barrier (BBB) invitro. More importantly, compound TM-6 did not show any acute toxicity in mice at doses of up to 1000mg/kg and improved scopolamine-induced memory impairment. Taken together, these data indicated that TM-6, an excellent balanced multifunctional inhibitor, was a potential lead compound for the treatment of AD.

Role of apoptosis repressor with caspase recruitment domain (ARC) in cell death and cardiovascular disease.

Apoptosis repressor with caspase recruitment domain (ARC) is a highly effective and multifunctional inhibitor of apoptosis that is mainly expressed in postmitotic cells such as cardiomyocytes and skeletal muscle cells. ARC contains a C-terminal region rich in proline and glutamic acid residues and an N-terminal caspase recruitment domain (CARD). The CARD is originally described as a protein-binding motif that interacts with caspase through a CARD-CARD interaction. Initially, the inhibitory effect of ARC was only found in apoptosis, however, it was later found that ARC also played a regulatory role in other types of cell death. As a powerful cardioprotective factor, ARC can protect the heart by inhibiting the death of cardiomyocytes in various ways. ARC can reduce the cardiomyocyte apoptotic response to various stresses and injuries, including extrinsic apoptosis induced by death receptor ligands, cellular Ca2+ homeostasis and the dysregulation of endoplasmic reticulum (ER) stress, oxidative stress and hypoxia. In addition, changes in ARC transcription and translation levels in the heart can cause a series of physiological and pathological changes, and ARC can also perform corresponding functions through interactions with other molecules. Although there has been much research on ARC, the functional redundancy among proteins shows that ARC still has much research value. This review summarizes the molecular characteristics of ARC, its roles in the various death modes in cardiomyocytes and the roles of ARC in cardiac pathophysiology. This article also describes the potential therapeutic effect and research prospects of ARC.

Impurity D of Anticancer Drug Fulvestrant as a Potential Multifunctional Inhibitor for the Marburg Virus

A commonality between viruses and cancer is their ability to seize cellular machinery to rapidly proliferate while suppressing the host’s innate immune response. Using probe molecules, specific sites within the virion protein 35 (VP35) of the Marburg virus that have a high affinity to dsRNA (also known as the interferon inhibitory domain, IID), RNA-dependent RNA polymerase (RdRp), and nucleoside triphosphates (NTPs) were identified in silico. Using the dsRNA- binding site as the target, three po

Identification of Putative “Multifunctional Drug” Against Anthrax Toxins via Integrative Computational Approach

Background: The intentional dissemination of the “anthrax letter” led the researchers to increase their efforts towards the development of medical countermeasures against anthrax bioterrorism. A virulent strain of Bacillus anthracis secretes deadly three protein exotoxin (protective antigen, lethal factor and edema factor) that is the causative agent of anthrax and considered as serious biological weapons. Objective: Due to limited existing therapeutics options, there is still an insecure situation to combat anthrax. This prompted us to design a multifunctional inhibitor instead of a traditional one that competes simultaneously with the Protective Antigen (PA), Lethal Factor (LF) and Edema Factor (EF) for their binding sites. Methods: We integrated a pharmacophore modeling approach with the virtual screening and molecular docking analysis in the context of unique structural characteristics of deadly anthrax toxins. Results: Initially, we screened 56,000 natural compounds against designed pharmacophore consensus that returned 351 hits. Out of these initial screening hits, only 100 compounds passed out through Lipinski filter that comprised of 12 chemically relevant clusters. By exclusion of duplicate and based on their fit score in each cluster, 15 unique compounds were selected for detailed study. Putative multifunctional compounds subjected to deep structural analysis in the milieu of anthrax toxins binding pockets to gauge critical structural crunch. Conclusion: Our integrative approach provides a novel therapeutic window to develop a small molecular inhibitor that simultaneously targets three components of anthrax deadly toxin at the molecular level to elicit the desired biological process.

Триазолы — класс многофункциональных ингибиторов коррозии. Обзор. Ч. III. 1,2,3-бензотриазол, его производные. Алюминиевые сплавы

Триазолы — класс многофункциональных ингибиторов коррозии. Обзор. Ч. III. 1,2,3-бензотриазол, его производные. Алюминиевые сплавы

Триазолы — класс многофункциональных ингибиторов коррозии. Обзор. Ч. II. 1,2,3-бензотриазол, его производные. Железо и стали

Триазолы — класс многофункциональных ингибиторов коррозии. Обзор. Ч. II. 1,2,3-бензотриазол, его производные. Железо и стали

New hybrids of tacrine and indomethacin as multifunctional acetylcholinesterase inhibitors

A new series of hybrid compounds were designed, consisting of anti-AChE and BuChE activity components with an anti-inflammatory component. A series of 9-amino-1,2,3,4-tetrahydroacridine and indomethacin derivatives were synthesized. All compounds were created using alkyldiamine with different chain lengths as a linker. Various biological activities were evaluated, including inhibitory activity against AChE and BuChE. The tested compounds showed high inhibitory activities against cholinesterases. The IC50 values for all compounds ranging from 10 nM to 7 µM. The potency of inhibition was much higher than well-known AChE and BuChE inhibitors (tacrine and donepezil). Compound 3h had the strongest inhibitory activity; kinetic studies showed it to have a mixed-type of acetylcholinesterase inhibition properties. The cytotoxicity of the newly-synthesized compounds against HepG2 (hepatocarcinoma cells) and EA.hy96 (human vein endothelial cells) cell lines was determined using the MTT and MTS tests. All investigated compounds presented similar cytotoxic activity against HepG2 and EA.hy926 cell line, ranged in micromolar values. Compounds with longer linkers showed higher antioxidant activity. The most active compound was 3h. Docking studies confirmed interactions with important regions of AChE and BuChE. Its multifunctional properties, i.e. high activity against AChE and BuChE, antioxidant activity and low cytotoxicity, highlight 3h as a promising agent for the treatment of AD.

The multifunctional dopamine D2/D3 receptor agonists also possess inhibitory activity against the full-length tau441 protein aggregation

Neurodegeneration leads to variety of diseases which are linked to aberrant protein or peptide aggregation, as a one possible mechanism. Hence, small drug molecules targeting aggregation are of interest. Tau protein aggregation is one of the biomarkers of neurodegenerative diseases and is a viable drug target. Toward multifunctional inhibitors, we aim to incorporate structural elements in a potential drug in order to preserve dopamine agonist activity, which elevates disease symptoms associated with motor skills, and promote inhibitory activity against aggregation of the full-length tau (2N4R, tau441) protein. In our design, we introduced various moieties (catechol, non-catechol, biphenyl, piperazine, and thiazole) to determine which functional group leads to the greatest aggregation inhibition of tau. In vitro, tau aggregation was induced by heparin and monitored by using fluorescence aggregation assay, transmission electron microscopy and 4,4′-Dianilino-1,1′-binaphthyl-5,5′-disulfonic acid dipotassium salt (Bis-ANS) fluorescence spectroscopy. The catechol containing compounds, D-519 and D-520, prevented aggregation of tau. By contrast, non-catechol and thiazole containing compounds (D-264 and D-636) were poor inhibitors. The Bis-ANS studies revealed that the potent inhibitors bound solvent-exposed hydrophobic sites. Based on the density functional theory calculations on inhibitors tested, the compounds characterized with the high polarity and polarizability were more effective aggregation inhibitors. These findings could lead to the development of small multifunctional drug inhibitors for the treatment of tau-associated neurodegeneration.

Research universal combined inhibitor for the oil and gas industry

Using the gravimetric method, the inhibitory efficiency of the combined inhibitor with respect to hydrogen sulfide and carbon dioxide corrosion of St3 steel in model produced water MI was studied. Corrosion tests were carried out in 0,5 liter sealed vessels on St3 samples of size 30х20х1. Gossypol resin + MARZA was used as a multifunctional combined inhibitor. Diesel fuel and kerosene were used as solvent. It has been established that the protective effect of using a multi-functional combined inhibitor in formation water with oil containing hydrogen sulfide and carbon dioxide using kerosene as a solvent ranges from 75 to 96 and for diesel as 80 to 100. The combined inhibitor allows to achieve in the MI medium containing hydrogen sulfide and carbon dioxide in the process of daily testing the corrosion rate of steel is about 0,04 g/m2·h. only in a concentration of not less than 70 mg/l. However, with an increase in the duration of the test by an order of magnitude, a similar corrosion rate is observed already at an inhibitor concentration of 50 mg/l. The same is characteristic of carbon dioxide and hydrogen sulfide - carbon dioxide solutions.

Antioxidant Berberine-Derivative Inhibits Multifaceted Amyloid Toxicity.

SummaryMultiple lines of evidence indicate that amyloid beta (Aβ) peptide is responsible for the pathological devastation caused in Alzheimer's disease (AD). Aβ aggregation species predominantly contribute to multifaceted toxicity observed in neuronal cells including generation of reactive oxygen species (ROS), mitochondrial dysfunction, interfering with synaptic signaling, and activation of premature apoptosis. Herein, we report a natural product berberine-derived (Ber-D) multifunctional inhibitor to ameliorate in cellulo multifaceted toxicity of AD. The structural attributes of polyphenolic Ber-D have contributed to its efficient Cu chelation and arresting the redox cycle to prevent the generation of ROS and rescue biomacromolecules from oxidative damage. Ber-D inhibits metal-dependent and -independent Aβ aggregation, which is supported by in silico studies. Ber-D treatment averts mitochondrial dysfunction and corresponding neuronal toxicity contributing to premature apoptosis. These key multifunctional attributes make Ber-D a potential therapeutic candidate to ameliorate multifaceted Aβ toxicity in AD.

Discovery and Biological Evaluation of New Selective Acetylcholinesterase Inhibitors with Anti-Aβ Aggregation Activity through Molecular Docking-Based Virtual Screening.

Discovery of novel multifunctional inhibitors targeting acetylcholinesterase (AChE) has becoming a hot spot in anti-Alzheimer's disease (AD) drug development. In the present study, four potent small molecule inhibitors (A01, A02, A03 and A04) of AChE with new chemical scaffold were identified. Inhibitor A03 displayed the most potent inhibition activity on AChE at enzymatic level with IC50 value of 180 nM, and high selectivity towards AChE over butyrylcholinesterase (BChE) by more than 100-fold. The binding modes of compounds A01-A04 were carefully analyzed by molecular docking and molecular dynamics (MD) simulation to provide informative clues for further structure modification. Finally, the anti-amyloid beta (Aβ) aggregation and neuroprotective activity were also well investigated. Our findings highlighted the therapeutic promise of AChE inhibitors A01-A04 for AD treatment.

Multifunctional Inhibitor Mixtures for Abating Corrosion on HY80 Steel under Marine Environments

The commercially available high strength steel, HY80, has been commonly used as part of naval hull construction since the 1950s. Corrosion of HY80 is associated with high costs due to material replacement, labour and lengthy down times of assets. The use of corrosion inhibitors as part of the steel paint system is a cost-effective method of stifling corrosion attack. Incorporation of an antimicrobial component into the inhibitor is also beneficial in combatting microbiologically influenced corrosion (MIC). This work examines the efficacy and mechanisms of corrosion inhibition from mixing lanthanum trans−4-hydroxy cinnamate (La(4OHCin)3) with the candidate antimicrobial compounds, imidazolinium trans−4-hydroxy cinnamate (IMI-4OHCin) or cetrimonium nalidixate (CetNal) in artificial seawater. The most effective inhibitor combination was the mixture of La(4OHCin)3 and IMI-4OHCin at their respective solubility limits (La+IMI). Examination of steel surfaces with optical profilometry after a 5 day immersion period concluded that the presence of La+IMI in solution resulted in significant minimisation of material corroded from the steel relative to the uninhibited sample. The inhibition mechanism for this mixture was determined to be predominantly anodic. On the other hand, all solutions containing the CetNal compound appeared to accelerate corrosion attack.

CCI52 sensitizes tumors to 6-mercaptopurine and inhibits MYCN-amplified tumor growth

The antimetabolite 6-mercaptopurine (6-MP) is an important component in the treatment of specific cancer subtypes, however, the development of drug resistance and dose-limiting toxicities can limit its effectiveness. The therapeutic activity of 6-MP requires cellular uptake, enzymatic conversion to thio-GMP and incorporation of thio-GTP into RNA and DNA, as well as inhibition of de novo purine synthesis by methyl-thio-IMP. Mechanisms that prevent 6-MP entry into the cell, prevent 6-MP metabolism or deplete thiopurine intermediates, can all lead to 6-MP resistance. We previously conducted a high-throughput screen for inhibitors of the multidrug transporter MRP4 using 6-MP sensitivity as the readout. In addition to MRP4-specific inhibitors, we identified a compound, CCI52, that sensitized cell lines to 6-MP independent of this transporter. CCI52 and its more stable analogue CCI52-14 also function as effective chemosensitizers in vivo, substantially extending survival in a transgenic mouse cancer model treated with 6-MP. Chemosensitization was associated with an increase in thio-IMP, suggesting that CCI52 functions directly on 6-MP uptake or metabolism. In addition to its chemosensitizing effects, CCI52 and CCI52-14 inhibited the growth of MYCN-amplified high-risk neuroblastoma cell lines and delayed tumor progression in a MYCN-driven, transgenic mouse model of neuroblastoma. These multifunctional inhibitors may be useful for the further development of anticancer agents and as tools to better understand 6-MP metabolism.

Roles of transforming growth factor-\u03b2 and phosphatidylinositol 3-kinase isoforms in integrin \u03b21-mediated bio-behaviors of mouse lung telocytes

BackgroundTelocytes (TCs) have the capacity of cell–cell communication with adjacent cells within the tissue, contributing to tissue repair and recovery from injury. The present study aims at investigating the molecular mechanisms by which the TGFβ1-ITGB1-PI3K signal pathways regulate TC cycle and proliferation.MethodsGene expression of integrin (ITG) family were measured in mouse primary TCs to compare with other cells. TC proliferation, movement, cell cycle, and PI3K isoform protein genes were assayed in ITGB1-negative or positive mouse lung TCs treated with the inhibition of PI3Kp110α, PI3Kα/δ, PKCβ, or GSK3, followed by TGFβ1 treatment.ResultsWe found the characters and interactions of ITG or PKC family member networks in primary mouse lung TCs, different from other cells in the lung tissue. The deletion of ITGB1 changed TCs sensitivity to treatment with multifunctional cytokines or signal pathway inhibitors. The compensatory mechanisms occur among TGFβ1-induced PI3Kp110α, PI3Kα/δ, PKCβ, or GSK3 when ITGB1 gene was deleted, leading to alterations of TC cell cycle and proliferation. Of those PI3K isoform protein genes, mRNA expression of PIK3CG altered with ITGB1-negative TC cycle and proliferation.ConclusionTCs have strong capacity of proliferation through the compensatory signaling mechanisms and contribute to the development of drug resistance due to alterations of TC sensitivity.

Development of a New Multifunctional Inhibitor for Protecting Oil Industry Equipment From Corrosion

In order to protect oil industry borehole equipment and the product transport system from corrosion, and also to improve oil recovery in highly viscous oil deposits a new reagent is developed based on acidol, technical-grade isopropyl alcohol, and technical-grade phosphatide. Laboratory studies show that the reagent reduces the oil dynamic viscosity by a factor of 2.9, and is also effective as an inhibitor (the degree of overall corrosion protection is 94–96 %), while the protective effect of general corrosion is 94–96 %. Industrial testing shows that as a results of action of the reagent in the bottom-hole formation zone oil production increases on average by 22 %, and the degree of protection from overall corrosion is 90 %. Measurements also show a reduction in flow pressure in product transport pipelines 20 % from 0.12 to 0.096 MPa.

DEVELOPMENT OF NEW RESOURCE- SAVING TECHNOLOGIES FOR INCREASING THE EFFICIENCY OF THE OIL PRODUCT TRANSPORTATION SYSTEM

Background Chemicals with inhibitory properties are widely used to protect pipelines from internal corrosion. This method characterized by easy implementation, is the most promising. But, unfortunately, the reagents used do not always provide a sufficiently high protective effect. This may be due to the solubility (dispersibility) of the inhibitor; this problem is usually solved in practice by increasing the reagent dosage, which also does not always have the desired effect. Aims and Objectives The article presents a new multifunctional inhibitor, which has the properties of surfactants, designed to reduce hydraulic resistance, reduce the dynamic viscosity of oil, and also to protect equipment from corrosion. Results A new high-performance multifunctional inhibitory composition based on technical lecithin-phosphatide and monoethanolamine was developed to protect the pipelines of the field transport system from corrosion. Laboratory tests showed that the reagent not only effectively inhibits corrosion processes, but also reduces hydraulic losses, reducing the dynamic viscosity of oil by 3 times. At an optimum concentration of 500 mg/l, the protective effect of corrosion is 94-95 %. Field tests showed that the protective effect of reagent from general corrosion was 89 %. In infield pipelines, the flow pressure decreased by 23 %.

Triazoles as class of multifunctional corrosion inhibitors. Review. Part I–2. 1,2,3-benzotriazole and its derivatives. Copper, zinc and alloys of them

Triazoles as class of multifunctional corrosion inhibitors. Review. Part I–2. 1,2,3-benzotriazole and its derivatives. Copper, zinc and alloys of them