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At least 19 recordsLinked to original sources
PubMed1977

The pharmacology of benoxaprofen (2-[4-chlorophenyl]-alpha-methyl-5-benzoxazole acetic acid), LRCL 3794, a new compound with antiinflammatory activity apparently unrelated to inhibition of prostaglandin synthesis.

Benoxaprofen is a potent and long-acting anti-inflammatory and antipyretic compound. Its anti-inflammatory activity has been demonstrated in carrageenan-induced oedema, in cellulose pellet granuloma and in both developing and established adjuvant arthritis tests in rats. Its antipyretic activity is greater than either aspirin or paracetamol in tests inducing pyrexia with yeast of 'E' pyrogen in rats and rabbits. Benoxaprofen has analgesic activity in tests where pain is accompanied by inflammation but not in other experimental models of pain. The weak prostaglandin synthetase inhibiting properties of this compound differentiate it from other acid anti-inflammatory compounds. The low ulcerogenic potential of benoxaprofen seen in animal models may be related to its relative inability to inhibit PG synthetase.

Analgesics↗
PubMed1976

Ionophore A23187. Solution conformations of the calcium complex and free acid deduced from proton and carbon-13 nuclear magnetic resonance studies.

Proton and carbon-13 nuclear magnetic resonance (NMR) spectra have been used to deduce possible biologically relevant conformations of ionophore A23187 as the free acid, and as the calcium complex, in solution. By analysis of coupling constants and dihedral angles obtained from 270-MHz proton NMR, A23187 free acid molecules and individual A23187 anions which comprise the calcium complex are found to differ principally by the rotational state of a carbon-carbon single bond near the benzoxazole ring. Proton Tl relaxation data and measurements of rotational correlation times confirm the dimeric nature of the calcium complex vs. the free acid monomer. Using the deduced pseudocyclic conformation for the A23187 anion, in conjunction with model-building studies, a conformation for the calcium complex is proposed, in which the benzoxazole carboxylate oxygen, the ketopyrrole oxygen, and the benzoxazole (ring) nitrogen atom of each molecule are the major participants in calcium binding. Additional stabilization of the structure is possible through the formation of a postulated hydrogen bond bridge between the pyrrole NH proton and benzoxazole carboxylate oxygen.

Anti-Bacterial Agents↗
PubMed1977

Synthesis and antiinflammatory activity of some 2-aryl-6-benzoxazoleacetic acid derivatives.

Various approaches to the synthesis of 2-aryl-6-substituted benzoxazoles are described. The products, which included the 6-methyl derivative 4a, ethylamines 10 and 19, ethanols 12 and 14, the acetic and alpha-methylacetic acids 9 and 16a--f, and the acetic ester 11, were screened for antiinflammatory activity on the carrageenan-induced rat paw edema test. Some of the compounds possessed activity superior to that of phenylbutazone and of the same order as that of benoxaprofen.

Adrenalectomy↗
PubMed1979

The effect of crystal size on the bioavailability of benoxaprofen: studies utilizing deuterium labeled drug.

A study of the effect of crystal size on the bioavailability of benoxaprofen, 2-[4-chlorophenyl]-alpha-methyl-5-benzoxazoleacetic acid, in man is reported. The technique utilized comparison of either the plasma concentrations or urine levels, resulting from administration of deuterium labeled (2H7) drug in solution coadministered with a test capsule formulation. Drug concentrations were determined by gas chromatography, and the ratio of labeled to unlabeled drug was obtained by gas chromatography mass spectrometry. Measurements following coadministration of labeled and unlabeled drug in solution established the absence of an isotope effect due to the presence of deuterium. The dry formulations consisted of either a 3.17--100 micron fraction (mean = 18.5 microns) or a 32--1000 micron fraction (mean = 610 microns) formulated with starch powder. The results in three subjects indicate an almost complete availability (0.95--0.98) of the small crystals as measured by comparison of either area under the plasma level curves or urine excretion (0.94--0.97) of labeled versus unlabeled drug measured to 168 hours. The larger crystals exhibited a lower availability as shown by plasma levels (0.41--0.46) or urine recovery (0.39--0.43). A higher dose of the large crystal formulation resulted in decreased relative availability with a fourfold dose dropping availability to 0.22 in a single subject.

Adult↗
PubMed1979

Liquid chromatography in pharmaceutical analysis X: Determination of chlorzoxazone and hydroxy metabolite in plasma.

A method for the high-pressure liquid chromatographic determination of chlorzoxazone and its hydroxy metabolite in human plasma samples is presented. The separation of the compounds is achieved on an octadecylsilane column with a mobile phase of absolute methanol-distilled water (40:60) at a flow rate of 2.0 ml/min (3100 psig). The chromatographic separation is achieved within 10 min. The overall analysis time is about 45 min, which includes extraction of the drug and metabolite from plasma followed by high-pressure liquid chromatographic separation and quantification. The accuracy of the procedure is in the 1-5% range.

Benzoxazoles↗
PubMed1979

Benoxaprofen, a new anti-inflammatory agent: particle-size effect on dissolution rate and oral absorption in humans.

The particle-size effect of benoxaprofen, a new nonsteroidal anti-inflammatory agent, on the in vitro dissolution rate and oral absorption in humans was evaluated. Ten normal subjects participated in a randomized crossover-designed absorption study with two sieved particle-size formulations: one with crystals larger than 60 mesh (mean equivalent spherical diameter = 640 micron) and the other with crystals smaller than 100 mesh (mean equivalent spherical diameter = 67 micron). Plasma drug concentrations and urinary drug excretion were used to determine the relative absorption of the two formulations. The standard USP procedure was used for the dissolution study. Particle size had a dramatic effect on both the in vitro drug dissolution and its oral absorption in humans. In vitro, the smaller crystals dissolved more rapidly and more efficiently than the larger crystals. In vivo, the smaller crystals produced higher plasma concentrations, more rapid peak concentration attainment, and more drug excreted in the urine.

Anti-Inflammatory Agents↗
PubMed1979

Fluorometric determination of chlorzoxazone in tablets and biological fluids.

A fluorometric determination for chlorzoxazone was developed based on the intrinsic drug fluorescence in chloroform using excitation and emission wavelengths of 286 and 310 nm, respectively. A calibration curve for chlorzoxazone in chloroform gave a linear working range of 0.027-2.3 microgram/ml (r = 0.9999) with the minimum detectability at 27 ng/ml. The procedure was applied to chlorzoxazone analysis in spiked plasma and urine samples. Minimum detectable drug levels in these samples were 60 and 130 ng/ml, respectively. Data revealed that chlorzoxazone could be determined in plasma and urine even in the presence of 20-fold molar excesses of its major metabolite, 6-hydroxychlorzoxaxone, and acetaminophen. The method also was applicable to chlorzoxazone analysis in a commercial dosage form containing acetaminophen.

Adult↗
PubMed1979

Electrostatic interaction between merocyanine 540 and liposomal and mitochondrial membranes.

The fluorescence of merocyanine 540 (MC) in liposomal and mitochondrial suspensions was measured under various conditions. Under a given condition, both the amount of dye bound to the membrane and the zeta potential were determined simultaneously. It was found that the fluorescence intensity was proportional to the amount of bound dye and correlated with the zeta potential of particles. The fluorescence intensity was represented quantiatively in terms of the Langmuir adsorption isotherm, when the electrostatic interaction acting between MC and membrane surface was properly taken into account. It was concluded that the changes in MC fluorescence in the liposomal and mitochondrial suspensions are mainly attributed to the changes in the surface potential of the membranes.

Animals↗
PubMed1978

Effects of fenoprofen and benoxaprofen on human lymphocytes: inhibition of tritiated thymidine uptake.

The effects of the related nonsteroidal anti-inflammatory agents, fenoprofen and benoxaprofen, on in vitro responses of normal human peripheral blood lymphocytes were examined. Drugs caused dose-related inhibition of stimulated cell responses. Fifty percent inhibition occurred at 400 microgram/ml calcium fenoprofen and 250 microgram/ml sodium benoxaprofen. Drugs affected not only responses to soluble phytomitogens but also responses to specific antigens and allogeneic lymphocytes. Numbers of viable cells in cultures with and without mitogens and drugs were similar at beginnings and ends of experiments, excluding drug-related cytotoxicity. Inhibition by drugs was greater when cells were cultured in medium alone than in medium with plasma. Cells that were exposed overnight to drugs and then washed and stimulated did not respond as well as did cells not exposed to drugs. These data indicated that fenoprofen and benoxaprofen exhibited noncytotoxic, incompletely reversible inhibition of nonspecific, specific, soluble and insoluble, mitogen-stimulated lymphocyte responses. These findings may pertain to the anti-inflammatory efficacy of these drugs.

Anti-Inflammatory Agents↗
PubMed1978

Fluorescent probes in model membranes. II. Monolayer studies of 2,2'-(vinylenedi-p-phenylene)bisbenzoxazole, d-3-aminodesoxyequilenin and N-octadecylnaphthyl-2-amino-6-sulfonic acid with host-lipid tetradecanoic acid.

Film studies at the air-water interface have been carried out for pure films of 2,2'-(vinylenedi-p-phenylene)bisbenzoxazole (VPBO), d-3-aminodesoxyequilenin (EQ) and N-octadecylnapthyl-2-amino-6-sulfonic acid (ONS), and for mixed films with tetradecanoic acid for the first two fluorescent probes. Pure film isotherms indicate highly rigid non-monomolecular films for both VPBO and EQ, revealing the presence of strong intermolecular forces. In mixed films with tetradecanoic acid VPBO rapidly segregates with resultant film loss over a wide concentration range. EQ, however, can be stabilized by the host-lipid at low concentrations. This, coupled with an ability to only slightly affect the host-lipid liquid-condensed/liquid-expanded phase change, suggests that EQ can be regarded as "non-perturbing" and should be retained in condensed lipid phases. ONS, because of its unusual polar headgroup, resembled hexadecanoic acid more than octadecanoic acid. While difficulties in spreading ONS precluded the study of mixed films, the indications are that it would be a satisfactory expanded lipid state probe if mixing can be brought about.

17-Ketosteroids↗
PubMed1978

Merocyanine 540 as a fluorescent probe of membranes: staining of electrically excitable cells.

With the exception of certain blood cells considered in the accompanying paper (Valinsky, Easton and Reich, 1978), merocyanine 540 (MC 540), a fluorescent membrane probe, selectively strains the membranes of a wide variety of electrically excitable cells, but not those of nonexcitable cells. This reaction is Ca2+-dependent when staining is performed in buffered iso-osmotic sucrose, Ca2+-independent when staining proceeds at high ionic strength, inhibited by La3+ and sodium Suramin, enhanced by controlled, low level photosensitization of cell-associated dye and essentially irreversible. These characteristics of the staining reaction depend upon the maintenance of both cell viability and a normal unperturbed membrane structure. Although the mechanisms involved in the staining specificity remain unknown, observation of MC 540 partitioning between benzene and water in model reactions indicates that dye transport into hydrophobic solvents is accompanied by the formation of stoichiometric complexes with cations and phospholipids. These results may suggest the existence of specific, possibly phospholipid-rich membrane domains that mediate complex formation with MC 540 in excitable cells; comparable domains either would not exist, or would be inaccessible at the external surfaces of nonexcitable cells.

Benzoxazoles↗
PubMed1978

Merocyanine 540 as a fluorescent probe of membranes: selective staining of leukemic and immature hemopoietic cells.

We have reported (Easton, Valinsky and Reich, 1978) that merocyanine 540 (MC 540) specifically stains a variety of living excitable cells, but not nonexcitable cells. This paper describes the exceptional permeability to MC 540 of leukemic leukocytes and immature hemopoietic precursor cells. We have used fluorescence microscopy and uptake of radioactive dye to study MC 540 staining of peripheral blood leukocytes from 80 leukemic and 34 normal individuals; leukemic leukocytes stain, whereas normal leukcytes do not. The leukocyte staining reaction differs from that previously described for excitable cells since it is independent of the ionic composition of the staining medium, kinetically complex, enhanced by light, enhanced by oxygen and essentially irreversible. Virtually all circulating nucleated cells from leukemic individuals are stained to approximately the same extent, and there is no qualitative or quantitative distinction between the various forms of leukemia. We have also found that MC 540 interacts with granulopoietic colony-forming cells (CFU-C) and with spleen colony-forming cells derived from mouse bone marrow (CFU-S). We cannot as yet identify a specific property of leukocyte plasma membranes that determines MC 540 permeability; since changes in MC 540 uptake appear to be correlated with cellular maturation during normal hemopoiesis, the retention of staining by leukemic cells, some of which appear morphologically normal, may indicate of failure in membrane maturation during leukemic blood cell development.

Benzoxazoles↗
PubMed2026

Design, synthesis and biological evaluation of hydroxybenzothiazole-linked benzothiazole/benzoxazole conjugates as potent dual α-amylase and α-glucosidase inhibitors.

The current study focuses on the synthesis and evaluation of novel Hydroxybenzothiazole-Linked Benzothiazole/Benzoxazole Conjugates to target Diabetes Mellitus (DM) by inhibiting α-amylase and α-glucosidase. Spectroscopic methods, including 1H and 13C NMR spectroscopy, were employed to confirm the structures of newly synthesized conjugates. The findings of in-vitro analysis displayed that the synthesized derivatives inhibited α-amylase and α-glucosidase enzymes with IC50 values ranging from 3.65 ± 0.20 μM to 32.15 ± 3.20 μM on α-amylase and 5.92 ± 0.80 μM to 35.60 ± 3.40 μM on α-glucosidase, in contrast to the reference drug Acarbose (α-amylase IC50 = 8.25 ± 0.80 μM; α-glucosidase IC50 = 10.75 ± 1.10 μM). Among the series 9a-9f and 10a-10f, analogs 10 f, 10b, 9b, and 9e displayed superior anti-diabetic activity compared to the reference drug Acarbose. The inhibitory activity of these conjugates can be attributed to their favorable and stable interactions with critical amino acid residues of targeted enzymes, as revealed through molecular docking analysis. ADMET predictions and drug-likeness evaluations showed favorable pharmacokinetic features, while DFT investigations revealed electronic insights related to bioactivity. Experimental outcomes and in silico support display that these potent Hydroxybenzothiazole-Linked Benzothiazole/Benzoxazole Conjugates were comparable to an existing diabetic mellitus inhibitor while conserving an acceptable safety profile, specifying potential for further therapeutic development and optimization against diabetic Mellitus.

Benzothiazoles↗
PubMed1978

Determination of benoxaprofen [2-(4-chlorophenyl)-alpha-methyl-5-benzoxazoleacetic acid, LRCL 3794] in biological fluids.

Benoxaprofen, a novel anti-inflammatory compound, is efficiently (greater than 95%) extracted from plasma and urine in the pH range 1 to 5 into either chloroform or ether. The compound is determined either by UV spectroscopy or by gas-liquid chromatography of the methyl ester (formed by reaction with diazomethane) on a column of 3% of silicone gum E-301 on DCMS-treated Chromosorb W, with detection by flame ionisation (limit 0.3 microgram/ml) or electron capture (limit 0.01 microgram/ml). For rapid routine use, the UV method (limit ca. 5 microgram/ml) gives good agreement with the specific methods.

Animals↗
PubMed1979

Studies on 3-substituted 1,2-benzisoxazole derivatives. 6. Syntheses of 3-(sulfamoylmethyl)-1,2-benzisoxazole derivatives and their anticonvulsant activities.

Several 3-(sulfamoylmethyl)-1,2-benzisoxazole derivatives were synthesized from 3-(bromomethyl)-1,2-benzisoxazole by the reaction with sodium bisulfite followed by chlorination and amination. Some of them displayed marked anticonvulsant activity in mice. The introduction of a halogen atom to the 5 position of the benzisoxazole ring caused increased activity and neurotoxicity; the substitution of a sulfamoyl group caused decreased activity. The activity of monoalkylated compounds might be the result of biotransformation. Among these compounds, 3-(sulfamoylmethyl)-1,2-benzisoxazole (1a) was thought to be the most promising as an anticonvulsant from the ratio of NTD50 and ED50.

Animals↗