scholarly journals Screening of anxiolytic properties and analysis of structure-activity relationship of new derivatives of 6-(4-methoxy)-7H-[1,2,4]triazolo[3,4-a][2,3]benzodiazepine under the code RD

2021 ◽  
Vol 7 (2) ◽  
pp. 31-37
Author(s):  
Maria O. Skripka ◽  
Alexander A. Spasov ◽  
Dmitriy V. Maltsev ◽  
Mikhail V. Miroshnikov ◽  
Dmitriy S. Yakovlev ◽  
...  
Keyword(s):  
Muscle Tone ◽  
Anxiolytic Activity ◽  
New Drugs ◽  
Test Models ◽  
Benzodiazepine Derivatives ◽  
New Compounds ◽  
Relationship Of ◽  
Leading Compounds ◽  
Derivatives Of

Introduction: Searching for new compounds with anti-anxiety activity resulting from the combination of privileged scaffolds is a promising direction in medicinal chemistry and in the development of new drugs. Anxiolytic potential and cytotoxic properties of previously synthesized molecules, containing fragments of 2,3-benzodiazepine and 1,2,4-triazole – 6-(4-methoxyphenyl)-7H-[1,2,4]triazolo[3,4-A][2,3]benzodiazepines under the generic code RD were studied. Materials and methods: Screening for anxiolytic activity was performed on elevated plus maze (EPM) and open field (OF) test models. Structural and functional analysis of the anti-anxiety activity of the studied substances was carried out. A degree of muscle relaxant effect of the substances was assessed in the tests Grid, Wire, and Rotarod. A cytotoxicity study of RD compounds was carried out using an MTT assay on human hepatocellular carcinoma cells HepG2. Results and discussion: For a number of novel triazolo[3,4-a][2,3]benzodiazepine derivatives, a prominent anxiolytic activity was manifested in terms of EPM test. The results of OF test were consistent with the obtained data and confirmed the presence of the sought activity in the leading compounds. There was no significant effect on muscle tone for the compounds under study. It was observed that RD compounds possessed no cytotoxic properties and were safe for further studies in vivo. Conclusion: Among the new derivatives of 6-(4-methoxyphenyl)-7H-[1,2,4]triazolo[3,4-a][2,3]benzodiazepine under the code RD, substances (RD-4, 12, 13) with a high anxiolytic activity comparable to diazepam and tofisopam were found. The most promising compound is RD-4 due to its pronounced anxiolytic and low cytotoxic properties.

scholarly journals Exploration of in vitro thrombolytic, anthelminthic, cytotoxic and in vivo anxiolytic potentials with phytochemical screening of flowers of Brassica nigra

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Mohammad Sarowar Uddin ◽  
Md. Shalahuddin Millat ◽  
Mohammad Safiqul Islam ◽  
Md. Saddam Hussain ◽  
Md. Giash Uddin ◽  
...  
Keyword(s):  
Brassica Nigra ◽  
Anxiolytic Activity ◽  
Clot Lysis ◽  
Dependent Manner ◽  
Standard Drug ◽  
Lead Compounds ◽  
Lysis Activity ◽  
Test Models

Abstract Background Brassica nigra is a plant of Brassicaceae family, which possesses numerous medicinal values. Our present study is intended to assess the potential in vitro thrombolytic, anthelminthic, cytotoxic and in vivo anxiolytic properties of MCE of B. nigra flowers. MCE was fractioned for separating the compound on the basis of polarity by using chloroform, n-hexane and ethyl acetate solvent. Thrombolytic and anthelminthic activities were explained by collecting human erythrocytes and earthworms as test models, respectively. Anxiolytic activity was evaluated by elevated plus maze and hole board models while cytotoxic test was conducted through brine shrimp lethality bioassay. Results MCE revealed the presence of alkaloids, flavonoids, tannin, diterpenes, glycosides, carbohydrates, phenols, fixed oils and fat. In case of thrombolytic test, the MCE, CSF, ASF and n-HSF had produced maximum clot lysis activity at 5 and 10 mg/ml dose conditions. Two different concentrations (10 and 20 mg/ml) of MCE and its fractions showed significant (p < 0.05) anthelminthic activities in a dose-dependent manner. Significant anxiolytic activity was observed for all fractions which was comparable to the standard drug diazepam (p < 0.05). Again, the cytotoxic screening also presented good potentials for all fractions. Conclusion From the findings of present study, we can conclude that MCE of B. nigra flowers and its fraction possess significant anxiolytic, anthelmintic, anticancer and thrombolytic properties which may be a good candidate for treating these diseases through the determination of bio-active lead compounds.

scholarly journals SYNTHESIS, ANTIAGGREGATION AND ANTITROMBOTIC ACTIVITIES OF NEW DERIVATIVES OF HYDROXYBENZOIC ACIDS WITH TAURIC FRAGMENT

2021 ◽  
Vol 9 (3) ◽  
pp. 222-234
Author(s):  
A. K. Brel ◽  
N. V. Atapina ◽  
Yu. N. Budaeva ◽  
S. V. Lisina ◽  
S. S. Tsaruk ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Acetylsalicylic Acid ◽  
Antiplatelet Activity ◽  
Dipotassium Salt ◽  
Hydroxybenzoic Acids ◽  
New Compounds ◽  
Derivatives Of ◽  
Salt Forms

A high prevalence of thrombotic disorders, insufficient effectiveness or safety of antithrombotic therapy is an urgent problem of modern healthcare. The main means of preventing thrombosis is acetylsalicylic acid. Despite its long history, aspirin attracts researchers in the fields of medicinal chemistry, biology, and medicine. The development of new antiplatelet agents, including chemical modification of the acetylsalicylic acid molecule, remains relevant. Modification of the acetylsalicylic acid molecule using amino acids and obtaining their salt forms makes it possible to maintain antiplatelet or antithrombotic properties, as well as to impart additional pharmacodynamic effects. In modern science, a lot of attention is paid to the sulfur-containing amino acid taurine. An analysis of modern scientific literature revealed the protective effect of taurine in diabetes mellitus and cardiovascular diseases, liver dysfunction, gastrointestinal tract, and kidney diseases.The aim of the article is to study synthesis of new compounds, determination of their physical characteristics and assessment of their antiplatelet and antithrombotic activities in vitro and in vivo.Materials and methods. To confirm the structure of the synthesized new derivatives of hydroxybenzoic acids with a taurine fragment by the acelation method, thin layer chromatography and NMR spectra were used. In vitro studies were carried out on the model of ADP-induced platelet aggregation according to the Born G. methods modified by V.A. Gabbasov. In vivo, the studies were carried out on the model of arterial thrombosis induced by the application of iron chloride in the following groups of animals: intact, with experimental diabetes mellitus and three-year-olds; the rate of bleeding from the tail vein was also evaluated.Results. New compounds – derivatives of ortho-, meta- and para-hydroxybenzoic acids with a taurine residue – were synthesized. A procedure for the preparation of N-hydroxybenzoyl taurine compounds and their salt forms have been described; their spectral characteristics and melting points have been determined. The synthesized compounds are superior to acetylsalicylic acid in solubility and are not inferior to it in antiplatelet and antithrombotic activities. The results of the in vitro antiplatelet activity assessment in a wide concentration range from 10-4M to 10-8M, are presented. It has been revealed that the dipotassium salt of N-(2-hydroxybenzoyl)taurine exhibits a less antiplatelet activity than the dipotassium salt of N-(3-hydroxybenzoyl)taurine. The most pronounced antiplatelet activity is exhibited by the compound N-(4-hydroxybenzoyl)taurine. In in vivo experiments on the model of arterial thrombosis in 3-year-olds or animals with experimental diabetes mellitus, carotid artery thrombosis occurred faster than in young or intact animals. A single preliminary oral administration of the test compounds prolonged the time of the thrombus formation, which makes it possible to conclude that they have an antithrombotic effect. In this study, the dipotassium salt of N-(3-hydroxybenzoyl)taurine exhibits a more pronounced activity than that of acetylsalicylic acid.Conclusion. Against the background of the modeled pathologies, the studied drugs showed the expected antithrombotic activity, in terms of the severity not inferior to that found in acetylsalicylic acid.

Structural and Biological Overview of Boron-containing Amino Acids in the Medicinal Chemistry Field

2019 ◽  
Vol 26 (26) ◽  
pp. 5077-5089 ◽  
Author(s):  
Antonio Abad García ◽  
Alexey Rayevsky ◽  
E. Andrade-Jorge ◽  
José G. Trujillo-Ferrara
Keyword(s):  
Amino Acids ◽  
Biological Activity ◽  
Biological Effect ◽  
Drug Targets ◽  
New Drugs ◽  
Toxicological Profile ◽  
Therapeutic Tools ◽  
The Stability ◽  
Relationship Of ◽  
Derivatives Of

Background: Amino acids are the basic structural units of proteins as well as the precursors of many compounds with biological activity. The addition of boron reportedly induces changes in the chemical-biological profile of amino acids. Methods: We compiled information on the biological effect of some compounds and discussed the structure-activity relationship of the addition of boron. The specific focus presently is on borinic derivatives of α-amino acids, the specific changes in biological activity caused by the addition of a boron-containing moiety, and the identification of some attractive compounds for testing as potential new drugs. Results: Borinic derivatives of α-amino acids have been widely synthesized and tested as potential new therapeutic tools. The B-N (1.65 A°) or B-C (1.61 A°) or B-O (1.50 A°) bond is often key for the stability at different pHs and temperatures and activity of these compounds. The chemical features of synthesized derivatives, such as the specific moieties and the logP, polarizability and position of the boron atom are clearly linked to their pharmacodynamic and pharmacokinetic profiles. Some mechanisms of action have been suggested or demonstrated, while those responsible for other effects remain unknown. Conclusion: The increasing number of synthetic borinic derivatives of α-amino acids as well as the recently reported crystal structures are providing new insights into the stability of these compounds at different pHs and temperatures, their interactions on drug targets, and the ring formation of five-membered heterocycles. Further research is required to clarify the ways to achieve specific synthesis, the mechanisms involved in the observed biological effect, and the toxicological profile of this type of boron-containing compounds (BCCs).

Design, Synthesis and Anxiolytic Activity Evaluation of N-Acyltryptophanyl- Containing Dipeptides, Potential TSPO Ligands#

2019 ◽  
Vol 15 (4) ◽  
pp. 383-399 ◽  
Author(s):  
Tatiana A. Gudasheva ◽  
Olga A. Deeva ◽  
Grigory V. Mokrov ◽  
Alina S. Dyabina ◽  
Milada A. Yarkova ◽  
...  
Keyword(s):  
Open Field ◽  
Design Method ◽  
Anxiolytic Effect ◽  
Benzodiazepine Receptor ◽  
Anxiolytic Activity ◽  
Translocator Protein ◽  
In Vivo Studies ◽  
Inner Mitochondrial Membrane ◽  
New Compounds

Background:The 18 kDa translocator protein (TSPO), previously known as the peripheral- type benzodiazepine receptor, plays a key role for the synthesis of neurosteroids by promoting transport of cholesterol from the outer to the inner mitochondrial membrane, which is the ratelimiting step in neurosteroid biosynthesis. Neurosteroids interact with nonbenzodiazepine site of GABAa receptor causing an anxiolytic effect without the side effects.Methods:Using the original peptide drug-based design strategy, the first putative dipeptide ligand of the TSPO N-carbobenzoxy-L-tryptophanyl-L-isoleucine amide (GD-23) was obtained. Molecular docking of GD-23 in the active pocket of the TSPO receptor using Glide software was carried out. The lead compounds GD-23 and its analogues were synthesized using activated succinimide esters coupling method. The anxiolytic activity of GD-23 and its analogues was investigated in vivo, using two validated behavioral tests, illuminated open field and elevated plus-maze.Results:he in vivo studies revealed that the following parameters are necessary for the manifestation of anxiolytic activity of new compounds: the L-configuration of tryptophan, the presence of an amide group at the C-terminus, the specific size of the N-acyl substituent at the Nterminus. Compound GD-23 (N-carbobenzoxy-L-tryptophanyl-L-isoleucine amide) demonstrated a high anxiolytic-like effect in the doses of 0.05–1.0 mg/kg i.p. comparable with that of diazepam. Compound GD-23 was also active in the open field test when was administered orally in the doses of 0.1-5.0 mg/kg. The involvement of TSPO receptor in the mechanism of anxiolytic-like activity of new compounds was proved by the antagonism of compound GD-23 with TSPO selective inhibitor PK11195 as well as with inhibitors of enzymes which are involved in the biosynthesis of neurosteroids, trilostane and finasteride.Conclusion:A series of N-acyl-tryptophanyl-containing dipeptides were designed and synthesized as 18 kDa translocator protein (TSPO) ligands. Using a drug-based peptide design method a series of the first dipeptide TSPO ligands have been designed and synthesized and their anxiolytic activity has been evaluated. In general, some of the compounds displayed a high level of anxiolytic efficacy comparable with that of diazepam. The involvement of TSPO receptor in the mechanism of anxiolytic activity of new compounds was proved using two methods. On this basis, the N-acyl-Ltryptophanyl- isoleucine amides could potentially be a novel class of TSPO ligands with anxiolytic activity.

Synthesis of Water Soluble Spin Labeled Glucose Derivatives as Potential NMR Contrast Enhancing Agents

1986 ◽  
Vol 41 (10) ◽  
pp. 1293-1305 ◽  
Author(s):  
George Sosnovsky ◽  
N. Uma Maheswara Rao ◽  
Jan Lukszo ◽  
Robert C. Brasch
Keyword(s):  
Glucuronic Acid ◽  
Water Soluble ◽  
Spin Labels ◽  
Proton Relaxation ◽  
Spin Lattice ◽  
Synthetic Methodologies ◽  
New Compounds ◽  
Derivatives Of ◽  
Glucose Derivatives

AbstractSynthetic methodologies for the preparation of nitroxyl labeled derivatives of D -(+)-glucose, α -D -(+)-m ethylglycoside, 2-amino-2-deoxy-D -(+)-glucose, and D -(+)-glucuronic acid are presented. The spin labels in these compounds are attached variably at the 1, 2, 3, and 6 positions of the glucose framework. These new compounds, being water soluble and producing marked en­hancement of spin-lattice (T ,) and spin-spin (T2) proton relaxation in deionized water and human plasma have potential utility as contrast altering pharmaceuticals for magnetic resonance imaging and as spin probes in biomolecular research. These spin labeled carbohydrates may demonstrate in vivo biodistribution characteristics reflecting tissue-specific differences in glucose metabolism .

Defibrotide Inhibits Platelet Activation by Cathepsin G Released From Stimulated Polymorphonuclear Leukocytes

1992 ◽  
Vol 67 (06) ◽  
pp. 660-664 ◽  
Author(s):  
Virgilio Evangelista ◽  
Paola Piccardoni ◽  
Giovanni de Gaetano ◽  
Chiara Cerletti
Keyword(s):  
Platelet Activation ◽  
Polymorphonuclear Leukocytes ◽  
Direct Interaction ◽  
Cathepsin G ◽  
In Vivo Test ◽  
Cell Functions ◽  
Test Models ◽  
Antithrombotic Effects

SummaryDefibrotide is a polydeoxyribonucleotide with antithrombotic effects in experimental animal models. Most of the actions of this drug have been observed in in vivo test models but no effects have been reported in in vitro systems. In this paper we demonstrate that defibrotide interferes with polymorphonuclear leukocyte-induced human platelet activation in vitro. This effect was not related to any direct interaction with polymorphonuclear leukocytes or platelets, but was due to the inhibition of cathepsin G, the main biochemical mediator of this cell-cell cooperation. Since cathepsin G not only induces platelet activation but also affects some endothelial cell functions, the anticathepsin G activity of defibrotide could help to explain the antithrombotic effect of this drug.

Acyl-Enzymes as Thrombolytic Agents in Dog Models of Venous Thrombosis and Pulmonary Embolism

1984 ◽  
Vol 51 (02) ◽  
pp. 248-253 ◽  
Author(s):  
R J Dupe ◽  
P D English ◽  
R A G Smith ◽  
J Green
Keyword(s):  
Pulmonary Embolism ◽  
Side Effects ◽  
Venous Thrombosis ◽  
Active Site ◽  
Acute Pulmonary Embolism ◽  
Quantitative Model ◽  
Beagle Dog ◽  
Thrombosis Model ◽  
Derivatives Of

SummaryA quantitative model of venous thrombosis in the beagle dog is described. The model was adapted to permit ageing of isolated experimental clots in vivo. A model of acute pulmonary embolism in this species is also described. In the venous thrombosis model, infusion of streptokinase (SK) or SK-activated human plasmin gave significant lysis but bolus doses of SK. plasmin complex were ineffective. Active site anisoylated derivatives of SK. plasminogen complex, SK-activated plasmin and activator-free plasmin were all active when given as bolus doses in both models. At lytic doses, the acyl-enzymes caused fewer side-effects attributable to plasminaemia than the corresponding unmodified enzymes.

SOME DIRECTIONS IN THE MODIFICATION OF AZOLES

2020 ◽  
Vol 5 (443) ◽  
pp. 85-91
Author(s):  
Ibrayev M.K., ◽  
◽  
Takibayeva A.T., ◽  
Fazylov S.D., ◽  
Rakhimberlinova Zh.B., ◽  
...  
Keyword(s):  
13C Nmr Spectroscopy ◽  
Biologically Active Compounds ◽  
Biologically Active ◽  
Active Compounds ◽  
Synthesis Conditions ◽  
Alkaloid Cytisine ◽  
Azole Ring ◽  
Cyclic Compounds ◽  
New Compounds ◽  
Derivatives Of

This article presents studies on the targeted search for new derivatives of azoles, such as benzthiazole, 3,5-dimethylpyrazole, 1,3,4-oxadiazole-2-thione, 1,3,4-thiadiazole. The possibility of combining in one molecule of the azole ring with other cyclic compounds: the alkaloid cytisine, morpholine, furan and some arenes has been studied. To obtain new compounds, the reactions of bromination, acylation, and interaction with isothiocyanates were studied. Optimal synthesis conditions were studied for all reactions. It was found that the reaction of 4-bromo-3,5-dimethylpyrazole with isothiocyanates, in contrast to the previously written derivatives of anilines, takes a longer time and requires heating the reaction mixture. The combination of a pirasol fragment with halide substituents often results in an enhanced therapeutic effect. The synthesized 2-bromine-N-(6-rodanbenzo[d]thiazole-2-yl)acetamide, due to the alkylbromide group, is an important synth in the synthesis of new benzthiazole derivatives. Its derivatives combine in one molecule the rest of rhodanbenzthiazole with alkaloid cytisine and biogenic amine morpholine and are potentially biologically active compounds, since the molecule structure contains several pharmacophoric fragments: benzthiazole and alkaloid (amine) heterocycles, rhodane and urea groups. The mechanism of formation of 1,3,4-oxadiazole-2-tyons from hydrazides under action on them by carbon disulfide was studied and assumed. It was shown that dithiocarbamates in acidic medium decompose with the release of hydrogen sulfide and the formation of highly reactive isothiocyanate group. Then, intra-molecular cyclization occurs, with the formation of end products - 1,3,4-oxadiazole-2-thions. The structures of the synthesized compounds were studied by 1H and 13C NMR spectroscopy. All synthesized substances are potentially biologically active compounds, since they contain several pharmacophore fragments in their structure.

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