Action Of Alcohols Research Articles

SYNTHESIS AND STUDY OF ANTINOCICEPTIVE ACTIVITY OF SUBSTITUTED 2-(3-CYANO-4,5,6,7-TETRAHYDROBENZO[B]THIOPHEN-2-YLAMINO)-4-OXOBUT-2-ENOATES

In the current work, we present results the study of synthetic transformations of substituted 3-thienylimino-3H-furan-2-one derivatives containing a nitrile substituent in the third position of the thiophene ring under the action of nucleophilic reagents. This class of compounds is of great for study due to the presence of several reaction centers in its structure, which makes it possible to obtain products of various structures, while retaining important pharmacophore groups - fragments of 2-aminothiophene and a fragment of 2,4-dioxobutanoic acid. We have synthesized and studied for biological activity substituted 2-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylamino)-4-oxobut-2-enoates, which were obtained by a multistep synthesis method. The proposed method provides high yields of target compounds and includes the reaction of 4-aryl-2-hydroxy-4-oxobutanoic acids with 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile, followed by intramolecular cyclization of the resulting products under the action of propionic anhydride, as well as decyclization of the resulting substituted 3-thienylimino-3H-furan-2-ones under the action of primary alcohols. The structure of the finally isolated compounds was confirmed by 1H and 13C NMR spectroscopy and the elemental analysis. The resulting compounds were screened in vivo to detect and evaluate their biological activity and acute toxicity. Antinociceptive activity was studied in white outbred mice of both sexes by the hot plate test with intraperitoneal injection. Acute toxicity was studied according to the Pershin method, based on monitoring the condition of mice for 10 days after intraperitoneal injection of the test compounds. According to the results obtained, the tested compounds have a pronounced antinociceptive activity, and the assessment of acute toxicity indicates that they belong to the V class of practically non-toxic drugs. The high values of antinociceptive activity in combination with low toxicity make the considered substituted 2-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylamino)-4-oxobut-2-enoates a highly promising class for further study in order to search for and develop new biologically active compounds with analgesic effect. For citation: Sharavyeva Yu.O., Makhmudov R.R., Shipilovskikh D.A., Silaichev P.S., Gorbunova I.A. Synthesis and study of antinociceptive activity of substituted 2-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylamino)-4-oxobut-2-enoates. ChemChemTech [Izv. Vyssh. Uchebn. Zaved. Khim. Khim. Tekhnol.]. 2024. V. 67. N 7. P. 19-27. DOI: 10.6060/ivkkt.20246707.7029.

Decyclization of substituted 3-(4-nitrobenzoyl)hydrasono3<i>H</i>-furan-2-ones under the action of primary alcohols and investigation of analgesic activity and acute toxicity of reaction products

The decyclization of substituted 3-(4-nitrobenzoyl)hydrazono-3 H -furan-2-ones under the action of primary alcohols, which proceeds with the formation of the corresponding substituted 2-[2-(4-nitrobenzoyl)hydrazono]-4-oxobutanoates, has been studied. The analgesic activity and acute toxicity of the obtained compounds were studied, it was found that the obtained compounds exhibit a pronounced analgesic effect, and also have low toxicity. According to the drug toxicity classification, the obtained primary substituted 2-[2-(4-nitrobenzoyl)hydrazono]-4-oxobutanoates belong to class V of practically non-toxic drugs.

Decyclization of substituted 2-[2-oxofuran-3(2<i>h</i>)-ylidene)furan-2-carbohydrazides by the action of alcohols and analgesic activity of the obtained compounds

A new series of substituted 4-oxo-2-[2-(furan-2-ylcarbonyl)hydrazinylidene]butanoic acids and 2-[2-oxofuran3(2 H )-ylidene]furan-2-carbohydrazides was synthesized. A methodology was developed for their decyclization under the action of primary and secondary alcohols with the formation of substituted alkyl 4-oxo-2-[2-(furan-2ylcarbonyl)hydrazinylidene]butanoates, which exist in the form of three isomeric forms. Among the synthesized compounds, substances with pronounced analgesic activity were found.

Decyclization of Substituted 2-[2-Oxofuran-3(2H)-ylidene)furan-2-carbohydrazides by the Action of Alcohols and Analgesic Activity of the Obtained Compounds

Decyclization of Substituted 2-[2-Oxofuran-3(2H)-ylidene)furan-2-carbohydrazides by the Action of Alcohols and Analgesic Activity of the Obtained Compounds

Effects of Volatile Organic Compounds on Biofilms and Swimming Motility of Agrobacterium tumefaciens.

Volatile organic compounds (VOCs) emitted by bacteria play an important role in the interaction between microorganisms and other organisms. They can inhibit the growth of phytopathogenic microorganisms, modulate plant growth, and serve as infochemicals. Here, we investigated the effects of ketones, alcohols, and terpenes on the colony biofilms of plant pathogenic Agrobacterium tumefaciens strains and swimming motility, which can play an important role in the formation of biofilms. It was shown that 2-octanone had the greatest inhibitory effect on biofilm formation, acting in a small amount (38.7 g/m3). Ketone 2-butanone and unsaturated ketone β-ionone reduced the formation of biofilms at higher doses (145.2–580.6 and 387.1–1548.3 g/m3, respectively, up to 2.5–5 times). Isoamyl alcohol and 2-phenylethanol decreased the formation of biofilms at doses of 88.7 and 122.9 g/m3 by 1.7 and 5 times, respectively, with an increased effect at 177.4 and 245.9 g/m3, respectively. The agrobacteria cells in mature biofilms were more resistant to the action of ketones and alcohols. These VOCs also suppressed the swimming motility of agrobacteria; the radius of swimming zones decreased ~from 2 to 5 times. Terpenes (−)-limonene and (+)-α-pinene had no significant influence on the colony biofilms and swimming motility at the doses used. The results obtained represent new information about the effect of VOCs on biofilms and the motility of bacteria.

Opening of the 1,3,5-triazine ring in 3-methyl-5-(trinitromethyl)tetrazolo[1,5-a][1,3,5]triazin-7-one by the action of alcohols

Opening of the 1,3,5-triazine ring in 3-methyl-5-(trinitromethyl)tetrazolo[1,5-a][1,3,5]triazin-7-one by the action of alcohols

Glycogen Phosphorylase: A Drug Target of Amino Alcohols in Echinococcus granulosus, Predicted by a Computer-Aided Method.

Echinococcosis is an important parasitic disease that threats human health and animal husbandry worldwide. However, the low cure rate of clinical drugs for this disease is a challenge. Hence, novel compounds and specific drug targets are urgently needed. In this study, we identified drug targets of amino alcohols with effects on Echinococcus species. The drug targets were predicted with the idTarget web server. Corresponding three-dimensional structures of the drug targets were built after sequence BLAST analysis and homology modeling. After further screening by molecular docking, the activities of the candidate targets were validated in vitro. We ultimately identified glycogen phosphorylase as a potential drug target for amino alcohols. There are two genes coding glycogen phosphorylase in Echinococcus granulosus (EgGp1 and EgGp2). EgGp1 was abundant in E. granulosus PSCs, while EgGp2 was abundant in the cysts. These proteins were located at suckers and somas of E. granulosus PSCs and near the rostellum of cysts developed from PSCs. The effective compounds docked into a pocket consisting of E124, K543 and K654 and affected (either inhibited or enhanced) the activity of E. granulosus glycogen phosphorylase. In this study, we designed a method to predict drug targets for echinococcosis treatment based on inverse docking. The candidate targets found by this method can contribute not only to understanding of the modes of action of amino alcohols but also to modeling-aided drug design based on targets.

The influence of xylate on the volumo- and osmoregulatory function of the kidneys in diabetes complicated by the syndrome of endogenous intoxication of purulent-septic origin.

The combination of insulin-independent diabetes mellitus with endogenous purulent-septic genesis syndrome is a fairly common nosology. The search for ways to optimize the results of its treatment, after screening observations, led to the expediency to consider the pharmacodynamic aspects of the action of polyhydric alcohols through the prism of homeostatic support functions. Detailing this direction was focused on the consideration of the action of xylate mediated through the volumetric and osmoregulatory function of the kidneys. The effect of xylate on the volumo-and osmoregulatory function of the kidneys in insulin-independent diabetes mellitus complicated by the syndrome of endogenous intoxication of purulent-septic origin was investigated. The study group consisted of 53 patients with insulin-independent diabetes mellitus complicated by the syndrome of endogenous intoxication of purulent-septic origin (IDCSEI). Under the condition of infusion loading (3 ml/kg/h for three hours) with Ringer's solution or xylate within the fragments of planned intensive care, indicators characterizing the state of the volumo- and osmoregulatory function of the kidneys were investigated. The loading with Ringer's solution in patients with IDCSEI increases sodium clearance by 260±47.8% (Δ, p=0.020), without changing the concentration of sodium ions in the blood plasma and filtration fraction and purifying the blood plasma from osmotically active substances 147±46.9% ( Δ, p=0.011). Extension of the extracellular space by infusion solutions by 3 ml/kg/h for three hours in patients with insulin-dependent diabetes mellitus, complicated by the syndrome of endogenous intoxication by purulent-septic genesis, activates volumetric and osmoregulatory function. Extension of extracellular space with infusion solu­tion by 3 ml/kg/h for three hours in patients with insulin-independent diabetes mellitus activates volumo- and osmo­regulatory function. Activation of volumetric function occurs by reducing the reabsorption of sodium and water in the proximal nephron, without increase of glomerular filtration rate, increasing the distal transport of sodium and water.

Synthesis and Properties of Alkyl 2-[2-(Diarylmethylidene)hydrazinyl]-5,5-dimethyl-4-oxohex-2-enoates

Ring opening of 3-[(diarylmethylidene)hydrazinylidene]-5-tert-butylfuran-2(3H)-ones by the action of alcohols afforded previously unknown alkyl 2-[2-(diarylmethylidene)hydrazinyl]-5,5-dimethyl-4-oxohex-2-enoates which were found to exist in solution as mixtures of tautomers.

Structural Basis of Alcohol Inhibition of the Pentameric Ligand-Gated Ion Channel ELIC

The structural basis for alcohol modulation of neuronal pentameric ligand-gated ion channels (pLGICs) remains elusive. We determined an inhibitory mechanism of alcohol on the pLGIC Erwinia chrysanthemi (ELIC) through direct binding to the pore. X-ray structures of ELIC co-crystallized with 2-bromoethanol, in both the absence and presence of agonist, reveal 2-bromoethanol binding in the pore near T237(6') and the extracellular domain (ECD) of each subunit at three different locations. Binding to the ECD does not appear to contribute to the inhibitory action of 2-bromoethanol and ethanol as indicated by the same functional responses of wild-type ELIC and mutants. In contrast, the ELIC-α1β3GABAAR chimera, replacing the ELIC transmembrane domain (TMD) with the TMD of α1β3GABAAR, ispotentiated by 2-bromoethanol and ethanol. Theresults suggest a dominant role of the TMD in modulating alcohol effects. The X-ray structures andfunctional measurements support a pore-blocking mechanism for inhibitory action of short-chain alcohols.

Synthesis of novel polycyano-containing organic ligands via double carbanion cleavage of 1',3'-dioxo-1',3'-dihydrospiro[cyclopropane-1,2'-indene] derivatives.

A novel fast, convenient and inexpensive synthesis of 1',3'-dioxo-1',3'-dihydrospiro[cyclopropane-1,2'-indene]-2,2,3,3-tetracarbonitrile and dimethyl 2,3-dicyano-1',3'-dioxo-1',3'-dihydrospiro[cyclopropane-1,2'-indene]-2,3-dicarboxylate is reported. These compounds undergo double carbanion cleavage under the action of alcohols resulting in the formation of stable salts, containing new allylic-type anions with potential application in organic electronics and as ionic liquid components.

Structural Basis for Allosteric Coupling at the Membrane-Protein Interface in Gloeobacter violaceus Ligand-gated Ion Channel (GLIC)

Ligand binding at the extracellular domain of pentameric ligand-gated ion channels initiates a relay of conformational changes that culminates at the gate within the transmembrane domain. The interface between the two domains is a key structural entity that governs gating. Molecular events in signal transduction at the interface are poorly defined because of its intrinsically dynamic nature combined with functional modulation by membrane lipid and water vestibules. Here we used electron paramagnetic resonance spectroscopy to delineate protein motions underlying Gloeobacter violaceus ligand-gated ion channel gating in a membrane environment and report the interface conformation in the closed and the desensitized states. Extensive intrasubunit interactions were observed in the closed state that are weakened upon desensitization and replaced by newer intersubunit contacts. Gating involves major rearrangements of the interfacial loops, accompanied by reorganization of the protein-lipid-water interface. These structural changes may serve as targets for modulation of gating by lipids, alcohols, and amphipathic drug molecules.

GABAA receptor modulation by terpenoids from Sideritis extracts

ScopeGABAA receptors are modulated by Sideritis extracts. The aim of this study was to identify single substances from Sideritis extracts responsible for GABAA receptor modulation.Methods and resultsSingle volatile substances identified by GC have been tested in two expression systems, Xenopus oocytes and human embryonic kidney cells. Some of these substances, especially carvacrol, were highly potent on GABAA receptors composed of α1β2 and α1β2γ2 subunits. All effects measured were independent from the presence of the γ2 subunit. As Sideritis extracts contain a high amount of terpenes, 13 terpenes with similar structure elements were tested in the same way. Following a prescreening on α1β2 GABAA receptors, a high-throughput method was used for identification of the most effective terpenoid substances on GABA-affinity of α1β2γ2 receptors expressed in transfected cell lines. Isopulegol, pinocarveol, verbenol, and myrtenol were the most potent modifiers of GABAA receptor function.ConclusionComparing the chemical structures, the action of terpenes on GABAA receptors is most probably due to the presence of hydroxyl groups and a bicyclic character of the substances tested. We propose an allosteric modulation independent from the γ2 subunit and similar to the action of alcohols and anesthetics.

How aliphatic alcohols and pH affect reactivity of horse blood serum cholinesterase at its interaction with organophosphorus inhibitors

There was studied action of aliphatic alcohols (ethanol, propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol), and pH on various kinds of serum cholinesterase. At inhibition of the cholinesterase hydrolytic activity under effect of alcohols the key role was played not by the total number of carbon atoms in the alcohol molecule, but by the “efficient length” of the carbohydrate chain. The fact that the presence of alcohols did not affect parameters of reversible inhibition of cholinesterase by onium ions tetramethylammonium and choline allows suggesting the absence of action of solvents on specific sorption of acetylcholine in the enzyme active center. With aid of two sets of hydrophobic organophosphorus inhibitors (OPI) (12 compounds), we have managed to estimate both the degree and the character itself of serum cholinesterase.

Functional Modulation of the ELIC by General Anesthetics and Alcohols

ELIC is a prokaryotic pentameric ligand gated ion channel (pLGIC) homologous to Cys-loop receptors, which are molecular targets of general anesthetics and alcohols. Crystal structures of ELIC and its complex with the antagonist acetylcholine have been resolved recently, suggesting the possibility of using ELIC to understand the structural basis of anesthetic and alcohol modulation on pLGICs. However, the pharmacological profiles of ELIC for modulation by general anesthetics and alcohols have not been well defined. In this study, we characterized these profiles for ELIC expressed in Xenopus laevis oocytes with two-electrode voltage clamp techniques. We found that the ELIC current elicited by the agonist propylamine could be inhibited by both volatile and intravenous general anesthetics at clinically relevant concentrations. ELIC is also inhibited by ethanol and other n-alcohols with potency increasing with the number of carbons until n-nonanol, where inhibition is cut off. Alcohol modulation on ELIC is similar to that on GABAR-ρ1 but different from nAChRs, which are potentiated by ethanol. In addition, ELIC is inhibited by the benzodiazepine drug diazepam. In summary, ELIC shares some pharmacological characteristics of cation-conducting eukaryotic pLGICs and is a suitable model for the structural study of the actions of general anesthetics and alcohols on pLGICs. Supported by NIH (R01GM066358, R01GM056257, and R37GM049202).

Effect of sugar alcohols, antioxidants and activators of systemically acquired resistance on severity of bacterial angular leaf spot (Xanthomonas fragariae) of strawberry in controlled environment conditions

Bacterial angular leaf spot of strawberry caused by Xanthomonas fragariae is an increasingly important disease for which few management strategies are available. The resistance status of most cultivars is unknown and of those cultivars tested, few have significant levels of resistance. Copper formulations are available and have limited effectiveness but phytotoxicity is a problem with repeated applications. This controlled environment study examined the efficacy of foliar applications of various antioxidants, such as α-tocopherol and mannitol, along with the plant activators acetylsalicylic acid and acibenzolar-S-methyl, and the fungicide fosetyl-Al, for disease control. Mannitol and acibenzolar-S-methyl consistently provided excellent control of disease, while fosetyl-Al and α-tocopherol were significantly less effective. Other antioxidants and sugar alcohols similar to mannitol did not provide the same level of angular leaf spot control. Interestingly, interactions were observed between various sugar alcohols and strawberry cultivars in suppressing disease. The mode of action of sugar alcohols against angular leaf spot is likely not related to their antioxidant activity. Sugar alcohols, especially mannitol, may represent a new and non-toxic approach to bacterial angular leaf spot control.

Unfolding Action of Alcohols on a Highly Negatively Charged State of Cytochrome c

It is well-known that hydrophobic effect play a major role in alcohol-protein interactions leading to structure unfolding. Studies with extremely alkaline cytochrome c (U(B) state, pH 13) in the presence of the first four alkyl alcohols suggests that the hydrophobic effect persistently overrides even though the protein carries a net charge of -17 under these conditions. Equilibrium unfolding of the U(B) state is accompanied by an unusual expansion of the chain involving an intermediate, I(alc), from which water is preferentially excluded, the extent of water exclusion being greater with the hydrocarbon content of the alcohol. The mobility and environmental averaging of side chains in the I(alc) state are generally constrained relative to those in the U(B) state. A few nuclear magnetic resonance-detected tertiary interactions are also found in the I(alc) state. The fact that the I(alc) state populates at low concentrations of methanol and ethanol and the fact that the extent of chain expansion in this state approaches that of the U(B) state indicate a definite influence of electrostatic repulsion severed by the low dielectric of the water/alcohol mixture. Interestingly, the U(B) ⇌ I(alc) segment of the U(B) ⇌ I(alc) ⇌ U equilibrium, where U is the unfolded state, accounts for roughly 85% of the total number of water molecules preferentially excluded in unfolding. Stopped-flow refolding results report on a submillisecond hydrophobic collapse during which almost the entire buried surface area associated with the U(B) state is recovered, suggesting the overwhelming influence of hydrophobic interaction over electrostatic repulsions.

Alcohol-Binding Sites in Distinct Brain Proteins: The Quest for Atomic Level Resolution

Defining the sites of action of ethanol on brain proteins is a major prerequisite to understanding the molecular pharmacology of this drug. The main barrier to reaching an atomic-level understanding of alcohol action is the low potency of alcohols, ethanol in particular, which is a reflection of transient, low-affinity interactions with their targets. These mechanisms are difficult or impossible to study with traditional techniques such as radioligand binding or spectroscopy. However, there has been considerable recent progress in combining X-ray crystallography, structural modeling, and site-directed mutagenesis to define the sites and mechanisms of action of ethanol and related alcohols on key brain proteins. We review such insights for several diverse classes of proteins including inwardly rectifying potassium, transient receptor potential, and neurotransmitter-gated ion channels, as well as protein kinase C epsilon. Some common themes are beginning to emerge from these proteins, including hydrogen bonding of the hydroxyl group and van der Waals interactions of the methylene groups of ethanol with specific amino acid residues. The resulting binding energy is proposed to facilitate or stabilize low-energy state transitions in the bound proteins, allowing ethanol to act as a "molecular lubricant" for protein function. We discuss evidence for characteristic, discrete alcohol-binding sites on protein targets, as well as evidence that binding to some proteins is better characterized by an interaction region that can accommodate multiple molecules of ethanol.

Structural Basis for Alcohol Modulation of a Ligand-Gated Ion Channel Homolog

The molecular mechanisms underlying direct effects of ethanol and other n-alcohols on the nervous system, including intoxication and anesthesia, are poorly understood. Although physiological and behavioral evidence implicates ligand-gated ion channels in the action of alcohols and other general anesthetics, a lack of high-resolution structural information for these receptors has limited structural characterization of alcohol modulation. Recent structural and functional studies of the prokaryotic ligand-gated ion channel homolog GLIC show it to be a valuable model for structure, function, and modulation of these receptors. We are investigating the effects of alcohols on GLIC, and identifying specific protein sites underlying alcohol modulation. Our results demonstrate that GLIC exhibits differential modulation by short- and long-chain n-alcohols, similar to homologous cys-loop receptors. Mutations at putative alcohol binding sites modify alcohol modulation, while labeling with MTS reagents mimics alcohol effects. Our work supports a role for specific residues in the GLIC transmembrane domain in mediating alcohol binding and modulation.

Alcohol Effects on Lipid Bilayer Properties as Measured using a Gramicidin-Based Fluorescence Assay

Alcohols are known modulators of lipid bilayer properties and their anesthetic action was for long sole attributed to their bilayer modifying effects. More recently, it has been shown that alcohols can alter protein function through direct alcohol-membrane protein interactions. This raises the question to what extent the anesthetic/intoxicating action(s) of alcohols result from direct protein-alcohol interactions or from general changes in membrane properties. The efficacy of alcohols of varying chain lengths (different number of carbon atoms) studied in very different assays tend to exhibit a so-called “cut off” effect - increased potency with increased chain length, which then levels off and maybe declines above a certain chain length.