Academic literature on the topic '1;3-oxazole-4-yl-phosphonic acid derivative'

The number of patients with arterial hypertension (AH) continues to increase. Significant negative effects of arterial hypertension are structural, metabolic and functional disorders in the tissues of the myocardium, vessels and other organs, in particular, changes in the content of fatty acids (FA) and their correlation. The purpose of the study is to investigate the change in fatty acid composition of lipids in blood serum and tissues of rats with arterial hypertension under the influence of a new original compound, 1,3-oxazole-4-yl-phosphonic acid derivative (abbreviated name - oxazole derivative). <strong>Materials and methods.</strong>&nbsp;The studies were conducted on white, sexually mature rats. Arterial hypertension was modeled by salt load - salt drink (1 % solution of sodium chloride) with free access to it for 21 days. Animals from the 14th day received oxazole derivative at a dose of 25 mg / kg intraperitoneally, once daily, for 7 days. The content of fatty acids of centrifuged blood serum and homogenized in 0.9 % saline NaCl tissue was determined by gas chromatographic analysis. <strong>Results and discussion.</strong>&nbsp;The administration of oxazole derivative in the background of increased blood pressure in rats did not significantly affect the amount of SFA and USFA in serum in contrast to the group of rats with hypertension due to the tendency to restore the stearic acid content, but the changed content of linoleic and arachidonic acids practically did not differ from the values in the blank group. There was a restoration of the content of palmitic, stearic, linoleic and arachidonic acids in aorta. In heart, the change in the content of linoleic and arachidonic acids in the reverse direction compared with the blank group was established. <strong>Conclusions.</strong><strong>&nbsp;</strong>The administration of 25 mg/kg (ED₅₀) of oxazole derivative intravenous intraperitoneally once daily for 7 days with simultaneous simulation of arterial hypertension by salt load did not cause any adverse changes and led to the restoration of lipid parameters of SFA, USFA and PUFA

Introduction: The determination of biotransformation products is an essential part of the preclinical trial of original medicines. These studies have not been conducted before for the new drug 5-[5-(trifluoromethyl)-1,2-oxazole-3-yl]-furan-2-sulfonamide. Identification and synthesis of metabolite substances are necessary for subsequent tests of bioavailability, linearity of pharmacokinetics, accumulation, distribution and excretion. Materials and methods: The study was carried out on Wistar rats and rabbits of the Soviet Chinchilla breed. The substance of the drug was administered to animals intraperitoneally. The collection of animal blood samples was performed before administration and 1 h, 2 h, 4 h, 24 h after administration into K3EDTA-tubes. A part of each sample was centrifuged to separate the plasma. Rat urine samples were taken before administration and at intervals of 0-2 h, 2-4 h, 4-6 h, 6-24 h after administration of the drug. The HPLC-MS/MS method was used to identify metabolites in biological fluids. The assumed biotransformation products were synthesized after preliminary analysis. The structure of the obtained substances was confirmed by NMR spectroscopy and high-resolution mass spectrometry. Then, a comparison was carried out with the compounds identified in biological fluids by retention time, ratios of chromatographic peak areas at the main MRM-transitions using HPLC-MS/MS. Results and discussion: A metabolite formed by addition an oxygen atom to a drug molecule, as well as an acylated metabolite were detected during the analysis of plasma and blood samples. A compound with an increased molecular weight of 1 dalton compared to the drug substance was also present in a rat urine. N-hydroxy-5-[5-(trifluoromethyl)-1,2-oxazole-3-yl]-furan-2-sulfonamide, 5-[5-(trifluoromethyl)-1,2-oxazole-3-yl]-furan-2-sulfonic acid, which could potentially be obtained during biotransformation, as well as N-acetyl-5-[5-(trifluoromethyl)-1,2-oxazole-3-yl]-furan-2-sulfonamide were synthesized. Repeated HPLC-MS/MS tests confirmed the correctness of the initial hypothesis. It was found that a sulfonic acid derivative is formed in urine as a result of decomposition of N-hydroxymetabolite during sample collection. Conclusion: The studied drug is metabolized by formation of two metabolites: N-hydroxy-5-[5-(trifluoromethyl)-1,2-oxazole-3-yl]-furan-2-sulfonamide and N-acetyl-5-[5-(trifluoromethyl)-1,2-oxazole-3-yl]-furan-2-sulfonamide. N-hydroxymetabolite is able to decompose in biological fluids samples with formation of 5-[5-(trifluoromethyl)-1,2-oxazole-3-yl]-furan-2-sulfonic acid.

Introduction: 3-(2-butyl-5-chloro-1H-imidazole-4-yl)-N-[4-methoxy-3-(trifluoromethyl)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxamide is new antirheumatic drug. It is necessary to identify and synthesize the biotransformation products for its complete pharmacokinetic study. Materials and Methods: A biotransformation study was carried out by intraperitoneal administration of the drug to Wistar rats and Soviet Chinchilla breed rabbits. Animal blood sampling was performed before the injection and 0.5 h, 1 h, 2 h, 4 h, 24 h after the injection of the investigated compound. The samples were immediately centrifuged for plasma separation. Urine was simultaneously collected from rats before the administration and at intervals of 0-2 h, 2-4 h, 4-6 h, 6-24 h after administration, faeces – before administration and at intervals of 0-12 h and 12-24 h after administration. The samples were analyzed by HPLC-MS/MS after immediate preparation by adding acetonitrile. Results and Discussion: 3-(2-butyl-5-chloro-1H-imidazole-4-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid and 4-methoxy-3-(trifluoromethyl)aniline – hydrolysis products of the active substance were found during the analysis of plasma, urine and fecal samples. The 4,5-dihydro-1,2-oxazole-5-carboxylic acid derivative has been synthesized. The second metabolite is a raw material for production of active pharmaceutical substance. During comparative tests, no significant difference between the retention times, ratio areas of chromatographic peaks at the main MRM-transitions and mass spectra of these metabolites on chromatograms of standard and animal samples was found, which indicates the correct identification of biotransformation products. Conclusion: The studied drug undergoes biotransformation by hydrolysis to form two main metabolites: 3-(2-butyl-5-chloro-1H-imidazole-4-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid and 4-methoxy-3-(trifluoromethyl)aniline. The structure of the metabolites was confirmed by comparison with the synthesized standard samples using HPLC-MS/MS.

In primary cultures of cerebellar granule cells kainate produced marked influx of 45Ca2+, partially sensitive to the N-methyl-D-aspartate (NMDA) antagonist, 3-(+/-)-2-carboxypiperazin-4-yl)- propyl-1-phosphonic acid (CPP), indicating involvement of an NMDA receptor-sensitive component that may be secondary to kainate-induced glutamate release. Sodium removal partially inhibited kainate's effect. Quisqualate also produced influx of 45Ca2+, but with lower efficacy and higher potency than kainate. This action of quisqualate was unaffected by CPP and by sodium removal. Preincubation of cells with the plant lectin concanavalin A (Con A), but not with its succinyl derivative, enhanced quisqualate-induced calcium influx, and to a lesser extent kainate's effect. Inclusion of quisqualate in preincubation medium antagonized Con A potentiation of quisqualate response. Also Con A was ineffective when included in the incubation medium only, without preincubation. Preincubation of rat brain cortical membranes with Con A but not with succinyl Con A increased the binding of the AMP A receptor agonist, [3H]alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([3H]AMPA). The results suggest that Con A enhancement of quisqualate response possibly involves the modification of an AMPA recognition site and requires preincubation in the absence of an agonist (here quisqualate).

Introduction. 3-(2-butyl-5-chloro-1H-imidazole-4-yl)-N-[4-methoxy-3-(trifluoromethyl)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxamide (R004) is a prospective new molecule for the treatment of rheumatoid arthritis. This compound is at the stage of preclinical research, during which its pharmacokinetics must be studied along with efficacy and safety. In this case, it is necessary to establish the main pharmacokinetic parameters of the drug and its metabolites in blood plasma after a single administration.Aim. Evaluation of linearity of pharmacokinetics and relative bioavailability of 3-(2-butyl-5-chloro-1H-imidazole-4-yl)-N-[4-methoxy-3-(trifluoromethyl)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxamide and its main metabolites in plasma after a single administration of the substance to rats.Materials and methods. Substance R004 was administered to rats once orally at dosages of 10 mg/kg, 20 mg/kg and 40 mg/kg and intraperitoneally at a dosage of 10 mg/kg. The study was carried out using 24 Wistar rats: 6 rats were used for each of the dosage. Blood samples were collected before administration and 30 min, 1 h, 1 h, 30 min, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h after administration of the drug. The obtained plasma was stabilized with a 250 mM ammonium acetate solution to prevent hydrolysis of R004. Plasma samples were prepared by means proteins precipitation by acetonitrile solution of internal standards. Measurement of the concentration of R004 and its metabolites 3-(2-butyl-5-chloro-1H-imidazole-4-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (M1) and 4-methoxy-3-(trifluoromethyl)aniline (M2) was performed using HPLC-MS/MS. A non-compartment approach was applied for evaluation pharmacokinetic parameters.Results and discussion. The developed bioanalytical method has been fully validated in accordance with the requirements of the EAEU guideline for conducting bioequivalence study and ICH M10 guideline. The analytical range of determination in plasma of R004 was 2–2000 ng/ml, M1 and M2 – 1–1000 ng/ml. The dependence of the parameters Cmax and AUC0–t of the studied compound and its metabolites on the administered dose was linear. Thus, the value of the correlation coefficient of Cmax R004 was 0.9995, and value of the correlation coefficient of AUC0–t was 0.9991. The presence of enterohepatic recirculation R004 has been determined. The relative bioavailability of R004 was 21.26%.Conclusion. The developed method was successfully applied for the pharmacokinetic research. R004 and its metabolites have linear pharmacokinetics in case of oral administration.

We have investigated the reactivity of rhodium(III) complex-functionalized TiO2 nanoparticles and demonstrate a proof-of-principle study of their catalytic activity in an alcohol oxidation carried out under aqueous conditions water in air. TiO2 nanoparticles (NPs) have been treated with (4-([2,20:60,200- terpyridin]-40-yl)phenyl)phosphonic acid, 1, to give the functionalized NPs (1)@TiO2. Reaction between (1) @TiO2 NPs and either RhCl3$3H2O or [Rh2(m-OAc)4(H2O)2] produced the rhodium(III) complexfunctionalized NPs Rh(1)2@TiO2. The functionalized NPs were characterized using thermogravimetric analysis (TGA), matrix-assisted laser desorption ionization (MALDI) mass spectrometry, 1H NMR and FT-IR spectroscopies; the single crystal structures of [Rh(1)2][NO3]3$1.25[H3O][NO3]$2.75H2O and of a phosphonate ester derivative were determined. 1H NMR spectroscopy was used to follow the reaction kinetics and to assess the recyclability of the NP-supported catalyst. The catalytic activity of the Rh(1)2@TiO2 NPs was compared to that of a homogeneous system containing [Rh(1)2]3+, confirming that no catalytic activity was lost upon surface-binding. Rh(1)2@TiO2 NPs were able to withstand reaction temperatures of up to 100 C for 24 days without degradation.

This investigation deals with the design and synthesis of new derivatives of pyrrole consisting of modifying atoms of chlorine, amide, and 1,3-oxazole fragments. These compounds can be interesting in the context of research of new antimicrobial agents. Ethyl 5-chloro-4-formyl-1H-pyrrole-3-carboxylates were used as a key substrate for further transformation into target compounds. This process was realized as a direct transformation of an aldehyde fragment into a 1,3-oxazole cycle by van Leusen’s reaction followed by hydrolysis of an ester group, which finally converted a reactant into the corresponding pyrrole-3-carboxylic acid. This acid has been found to be an efficient construction block for the further development of antimicrobial agents. The preparative potential of these compounds has been verified by way of their transformation into a series of carbamides through consecutive reactions with thionyl chloride and alkyl-, aryl, and heterylamines under mild reaction conditions. According to bio screening results, the following two compounds have been chosen as those exhibiting a high anti-staphylococcus activity: 1-butyl-5-chloro-2-methyl-4-(1,3-oxazol-5-yl)-N-[(1,3-thiazol-2-yl]-1H-pyrrole-3-carboxamide and 1-butyl-5-chloro-N-[(3-dimethylaminosulfonyl)phenyl]-2-methyl-4-(1,3-oxazol-5-yl)-1H-pyrrole-3-carboxamide (МІС=7.8 µg/ml), while another one – 5-сhloro-N-(4-chlorophenyl)-4-(1,3-oxazol-5-yl)-2-phenyl-1-propyl-1H-pyrrole-3-carboxamide was selected as a compound exhibiting high antifungal activity (МІС=7.8 µg/ml) against the reference strains Candida albiсans АТСС 885/653 and Aspergillus niger K9.

AbstractEcto‐nucleotidase CD73 inhibits immune function by overproducing adenosine. A series of important studies have shown that CD73 is over‐expressed in many cancers, and CD73 inhibitors are promising drugs for cancer (immunotherapy). Here, we describe the structure optimization of a hit compound obtained through screening an in‐house chemical library, (3‐(4‐(3‐aminophenyl)‐1H‐1,2,3‐triazol‐1‐yl)phenyl‐(naphthalen‐1‐yl)methyl)phosphonic acid (1). A series of ((diphenylmethyl) phosphonic acid) derivatives were synthesized, and all target compounds were characterized by nuclear magnetic resonance (NMR) and mass spectrometry (MS). Then structure–activity relationship analysis using the in vitro enzymatic inhibition assay was performed, which led to the discovery of a number of compounds (11, 13, 14, 17, 19, 23, and 27) that exhibited greater inhibitory activity than the lead compound 1. Among them, the compounds 14 and 23, with p‐Cl and p‐ethyl substitution on the terminal phenyl ring respectively, showed the strongest inhibitory activity against CD73, with IC50 values of 2.35 and 2.55 μM respectively. And we believe that compounds 14 and 23 can serve as lead compounds for further research on specific CD73 inhibitors.