SEARCH · PubMed Health
Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
The synthesis, unambiguous proof of structure and benzodiazepine receptor affinity and efficacy of 2-phenyl-1,2,4-triazolo[1,5-c][1,3]benzoxazin-5-one 1 are reported. The in vitro biological data indicate that 1 may be the lead compound of a new class of benzodiazepine antagonist-inverse agonist ligands.
New 1-arylpiperazine (series d-f) and 1,2,3,4-tetrahydroisoquinoline (series g) derivatives of 1,4-benzoxazin-3(4H)-one 1, 1,2-benzoxazolin-3-one 2, and 1,3-benzoxazolin-2,4-dione 3 with an n-butyl chain were synthesized in order to explore the effect of spacer elongation on their binding affinity and in vivo functional activity at 5-HT1A and 5-HT2A receptors in comparison with trimethylene analogues (a, bc). 5-HT1A receptor binding constants of derivatives 1d-g, 2d-f, and 3d-f were very high (Ki = 1.25-54 nM), and 5-HT2A affinities were maintained at a similar, high level (Ki = 27-85 nM) for series d and e, and moderate (Ki = 246-495 nM) for series f. In respect of a spacer, the obtained results showed either no effect or a slight increase in the 5-HT1A/5-HT2A affinity in case of derivatives of 1 and 2, respectively. A striking effect was observed for derivatives 3d and 3f, whose 5-HT1A affinity was reinforced by two orders of magnitude with a simultaneous decrease in 5-HT2A binding constants in comparison with trimethylene analogues. As shown by X-ray crystallography, this phenomenon may be attributed to the position of non-carbonyl oxygen atom in the amide moiety. In vivo studies demonstrated that compounds 1e-g, 2d-f, and 3f behaved like typical postsynaptic 5-HT1A receptor antagonists, whereas 3d and 3e might be qualified as their potential partial agonists. Moreover, 1e, 2e, and 3e demonstrated 5-HT2A receptor antagonistic properties. Of the tested compounds, two derivatives showed some very outstanding properties: 3e may be regarded as a potential anxiolytic and/or antidepressant agent, while 3f as a new potent 5-HT1A antagonist.
Four 7a-methyl octa(or hexa)hydrocyclopenta[d][1,3]oxazines, five 8a-methyl octa(or hexa)hydro[3,1]benzoxazines, two 6-phenyl hexahydro[3,1]benzoxazinones, and 8a-methyl hexahydro[1,3]benzoxazinone, all cis-fused, were prepared and their stereostructures studied by various one- and two-dimensional (1)H, (13)C, and (15)N NMR spectroscopic methods. In solution, the cyclopentane-fused 2-oxo derivatives and the 1,3-benzoxazinone were found to attain exclusively the N-in/O-in conformation, whereas the 6-phenyl 2-oxo/thioxo derivatives were found to be present predominantly in the N-out conformation. The C-2 unsubstituted and the 2-oxo/thioxo 7a/8a-methyl derivatives were all present in solution as a rapidly interconverting equilibrium of the N-in and N-out conformations. The C-2 methyl derivatives were each found to be interconvertable mixtures of epimers (at C-2) with the N-in conformer predominating for one epimer and the N-out conformer predominating for the other, with both predominating conformers having the C-2 methyl group equatorially orientated. The substituent on the nitrogen (H or Me) was found to be always predominantly equatorial with respect to the heteroring, except for the epimeric 2-methyl derivatives with N-out conformations where steric constraints and the generalized anomeric effect resulted in the axial orientation of the C-2 methyl being favored.
The absorption and metabolic fate of 7-chloro-3,3a-dihydro-2-methyl-2H,9H-isoxazolo-(3,2-b)(1,3)-benzoxazin-9-one (I) was studied in rats, dogs, and humans. Orally administered I was readily absorbed by all species. In the rat, orally administered I was converted to its metabolite, 5-chlorosalicylic acid, by the intestinal wall. The half-lives of blood radioactivity, after the oral administration of I-9-14C, were about 18 and 12 hr in the rat and beagle hound, respectively. In human subjects, no intact I was detected in the bloodstream; however, the clearance of the metabolite, 5-chlorosalicylic acid, had a half-life of about 33 hr. Cleavage of the oxazine ring of I generated 5-chlorosalicylic acid, which was excreted both in the free form and conjugated with glycine and glucuronic acid. The isoxazole moiety was converted to beta-hydroxybutyric acid and its metabolites carbon dioxide and fumaric, citric, alpha-ketoglutaric, succinic, and malic acids. Binding of I to plasma proteins was extensive but was less than that of 5-chlorosalicylic acid.
Evidence is presented which indicates that 7-chloro-3,3a-dihydro-2-methyl-2H,9H-isoxazolo-(3,2-b) (1,3)-benzoxazin-9-one (I) and 5-chlorosalicylic acid, its major metabolic end-product, are equally effective as anti-inflammatory and antipyretic agents, while the former is a somewhat more effective analgesic than its metabolite in the rat. However, at the equimolar doses used in this study, I is not ulcerogenic, while 5-chlorosalicylic acid does possess this untoward effect in the fasted rat. Moreover, the LD50 for 5-chlorosalicylic acid (261.0 mg/kg) is approximately 6.5 times less than that of I (1710.0 mg/kg) in the nonfasted rat. These results support the postulation that 5-chlorosalicylic acid is most likely responsible for the pharmacological activity displayed by I; i.e., the latter acts as a carrier or delivery system, allowing attenuation of the toxic properties of its active metabolite.
A simple NMR method was developed for the determination of the enantiomers of 7-chloro-3,3a-dihydro-2-methyl-2H,9H-isoxazolo[3,2-b][1,3]benzoxazin-9-one. Chiral shift reagent, tris[3-(heptafluoroburyryl)-d-camphorato]europium(III), causes the doublet assigned to the protons of the 2-methyl group, which normally appears at about 1.5 ppm, to split into two pairs of doublets and to shift downfield to about 2.0-3.5 ppm. The downfield pair of doublets represents the two enantiomers present in one racemate, designated as the beta-form, while the upfield pair represents the enantiomers of the racemate designated as the alpha-form. From the integration of the area under the doublets, the relative concentration of all four enantiomers was determined.
A series of 3,4-dihydro-1,3-benzoxazine and 3,4-dihydro-1,3-pyridooxazine derivatives was synthesized, and the hydrolysis of the derivatives was studied with proton nuclear magnetic resonance spectroscopy. The oxazine derivatives underwent various degrees of hydrolysis when H2O was added to dimethyl sulfoxide solutions of the compounds. The rates and extents of decomposition of the oxazine ring systems depended on the electronic effects of substituents within the molecules. Examination of the proton nuclear magnetic resonance spectra that were generated during decomposition of the oxazines and trends in stability of the oxazine derivatives suggest the formation of an intermediate in the hydrolysis mechanism.
7-Substituted 5-methyl-2-isopropylamino-4H-3,1-benzoxazin-4-ones (BOZNs) were prepared and tested as inhibitors of human sputum elastase (HSE). The BOZNs with certain amino acid residues at the 7-position proved to be potent inhibitors of HSE. Some of the compounds also showed a high selectivity for HSE versus chymotrypsin. In a hamster model in which acute injury was induced by intratracheal administration of HSE (1.0 mg/kg), these compounds, when administered intratracheally (1.0 mg/kg) either 30 or even 240 min before challenge with HSE, significantly suppressed pulmonary hemorrhage. These findings suggest that 7-substitution of BOZN by amino acid residues can produce strong and HSE-specific inhibitors, with potential use in elastase-mediated disorders.
A high-performance liquid chromatographic method for the determination of a new fluoroquinolone antimicrobial agent, (S)-10-[(S)-(8-amino-6-azaspiro[3,4]octan-6-yl)]-9-fluoro-2,3- dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid hemihydrate (DV-7751a, I) in human serum and urine has been developed. Compound I and the internal standard were extracted from serum and urine by means of Bond Elut C8 LRC column. The extracts were chromatographed on a reversed-phase Inertsil ODS-2 column using tetrahydrofuran-50 mM KH2PO4 (pH2)-1 M ammonium acetate (19:81:1, v/v) as the mobile phase at a flow-rate of 1.0 ml/min. Fluorescence detection at an excitation wavelength of 305 nm and an emission wavelength of 530 nm resulted in a limit of quantitation of 0.0098 microgram/ml for serum and 0.098 microgram/ml for urine. The method showed satisfactory sensitivity, precision, accuracy, recovery and selectivity. Stability studies showed that I was stable in serum and urine for at least 1 month at -20 degrees C and for at least 48 h at room temperature.
A series of 6-amino-2-phenyl-4H-3,1-benzoxazin-4-one aminoacyl and dipeptidyl derivatives, in which aminoacids and dipeptides are linked to the benzoxazinone moiety via an amide bond, were synthesized and tested in vitro for their inhibitory activity towards human leukocyte elastase (HLE). When compared to their values without inhibitors, the residual enzymatic activities decrease with time, indicating a time-dependent inhibition. The most potent inhibitions were obtained when Z-Arg-(Pmc), Z-Val-Phe, Z-Ala-Val or Z-Val-Ala are linked to the 6-amino group. Twenty-five new compounds were synthesized.
Some 4-hydroxy-2H-1,4-benzoxazin-3(4H)-ones were synthesized and evaluated for their antimicrobial activities against Staphylococcus aureus, Escherichia coli and Candida albicans. Compounds 9, and 10 exhibited the best activity against Candida albicans.
The synthesis of a series of novel 2-aryl substituted 4H-3,1-benzoxazin-4-ones and their evaluation as specific inhibitors of the Tissue Factor (TF)/Factor VIIa (FVIIa)-induced pathway of coagulation is reported. Inhibitory activities (IC50 values) in the range 0.17 to > 40 microM on the activation of Factor X (FX) by the TF/FVIIa complex were found for compounds having one or two electronegative substituents such as F, Cl and NO2 in the 2-aryl substituent. Different substitutions both electron-attracting and donating groups were allowed in the 5, 6, 7 and 8 positions. Several of the compounds showed a selectivity ratio towards FX and thrombin of > 50, thus being the first small molecules described as potential drugs for oral antithrombotic treatment without side effects such as bleeding which is observed especially with thrombin inhibitors. The best substituent pattern being the 2-aryl group substituted with: 2-F; 2,6-F2; or 2-FX; 6-Cl; together with electronegative substitution in the 5, 6, 7, or 8 positions. 2-Heteroaryl substituents like thienyl and furanyl were of low activity while some 2-(2-chloro-3-pyridyl) derivatives had inhibitory activity < 10 microM and a good selectivity.
We have recently described the synthesis and antifungal activity of a series of 1,4-benzothiazine and 1,4-benzoxazine imidazole derivatives that mainly showed in vivo activity against a murine experimental model of candidiasis but that very often lacked in vitro activity. Here, we report a docking study of a representative set of our molecules in a 3D model of CYP51 of Candida albicans (CA-CYP51). The model was constructed on the basis of the sequence homology relationship with the recently reported crystal structure of the CYP51 of Mycobacterium tuberculosis (MT- CYP51).
As part of a search for a new potassium channel opener, the 1,4-benzoxazine skeleton derived from the benzopyran skeleton of cromakalim, was transformed into other fused rings such as 1,4-benzothiazine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroquinoxaline, indoline, and 1,5-benzoxazepine. The 1,4-benzothiazine derivative displayed approximately 20 times more potent vasorelaxant activity than cromakalim.
The 1H and 13C NMR spectra of twelve 4H-3,1-benzoxazine-4-ones and of their acylaminobenzoic acid precursors are presented. Differentiation between these two series of compounds is best achieved through the characteristic J(CH) coupling interactions in the high frequency carbonyl region. Some 4H-pyrido[2,3-d][1,3]oxazin-4-ones have also been studied and some earlier literature assignments revised.
The energies of the preferred conformations of four 7a-methyl octa(or hexa)hydrocyclopenta[d][1,3]oxazines, five 8a-methyl octa(or hexa)hydro[3,1]benzoxazines, and 8a-methyl hexahydro[1,3]benzoxazinone, all cis-fused, were investigated by DFT methods. Following geometry optimization at the B3LYP/6-31G(d,p) level, both the proton chemical shifts and the vicinal coupling constants between H-4a and the H-4 and H-5 protons were calculated at the B3LYP/cc-pVTZ level and compared to the previously experimentally measured values. The agreement between the calculated and the experimental chemical shifts was found to be good. Similarly, the agreement between the calculated and the experimental vicinal coupling constants was also found to be good, thus providing a methodology for determining the conformational equilibria of such systems that is comparable in many respects to experimental approaches such as variable-temperature NMR or to the use of model coupling constant values, when available, from analogous compounds.
4H-3,1-Benzoxazin-4-ones are alternate substrate inhibitors of the serine proteinase human leukocyte elastase (HL elastase) and form acyl enzyme intermediates during enzyme catalysis. We have synthesized a large variety of benzoxazinones using specific methods that have been adapted to achieve the pattern of ring substitution dictated by theoretical considerations. The results of the inhibition of HL elastase by 175 benzoxazinones are reported herein with reference to hydrophobicity constants D, alkaline hydrolysis rates kOH-, inhibition constants Ki, and their component acylation and deacylation rate constants, kon and koff, respectively. The ranges for the compounds are considerable; alkaline hydrolysis rates and kon span 6, koff covers 5, and ki spans 8 orders of magnitude. Multiple regression on this large data set has been used to isolate the contributions of electronic and steric effects, as well as other factors specific to compound stability and elastase inhibition. Essentially, a simple electronic parameter is sufficient to account for almost all the variance in the alkaline hydrolysis data, indicating that electronic factors are the major determinants of this type of benzoxazinone reactivity. Factors that significantly enhance the potency of benzoxazinones I are R5 alkyl groups and electron withdrawal by R2. Bulk in R7 and R8 and compound hydrophobicity are not significant, but substitution in R6 is highly unfavorable as are substituents linked via carbon to C2. The physiochemical factors that underlie these trends in Ki are further analyzed in terms of equations that describe kon and koff. A conclusion that emerges is that chemically stable, potent benzoxazinone inhibitors of HL elastase with inhibition constants in the nanomolar range can be designed with (1) R5 alkyl groups to inhibit enzyme-catalyzed deacylation, (2) small alkyl substituents linked via heteroatoms to C2 to enhance acylation and limit deacylation rates, and (3) strongly electron-donating groups at C7 to stabilize the oxazinone ring to nucleophilic attack. Thus, 2-(isopropylamino)-5-n-propyl-7-(dimethylamino)benzoxazinone 95 has kOH = 0.01 M-1 s-1, which extrapolates to a half-life at pH 7.4 of over 8.5 years, and 2-ethoxy-5-ethylbenzoxazinone 38 has Ki = 42 pM.
Synthesis of several members of the 9-oxaergoline ring system is presented. Both the C/D cis and the C/D trans isomers of 4,6,6a,8,9,10a-hexahydro-7-ethyl-7H-indolo[3,4-gh] [1,4]benzoxazine were prepared, and the C/D trans isomer was resolved into its optical isomers. The enantiomer having the highest affinity for the [3H]apomorphine binding site, (-)-trans-6-ethyl-9-oxaergoline [(-)-6b], was shown to have the same absolute configuration as the natural ergolines, namely, 6aR, 10aR. In vivo and in vitro pharmacological evaluation shows these 9-oxaergolines to possess potent dopamine agonist properties.