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PubMed1996

Design and synthesis of 6-chloro-3,4-dihydro-4-methyl-2H-1,4-benzoxazine-8-carboxamide derivatives as potent serotonin-3 (5-HT3) receptor antagonists.

Several 3-substituted 5-chloro-2-methoxybenzamides were synthesized and evaluated for serotonin-3 (5-HT3) receptor binding affinity. The 5-HT3 receptor antagonistic activity of zacopride, a representative 5-HT3 receptor antagonist, was unchanged by the replacement of the 4-amino substituent on the aromatic moiety by a 3-dimethyl-amino substituent. This finding prompted a structural modification of azasetron, another 5-HT3 receptor antagonist. Consequently, a new series of 3,4-dihydro-2H-1,4-benzoxazine-8-carboxamides was obtained and these compounds were found to be more potent than 3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8-carboxamides. In particular, (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-3,4-dihydro-4-methyl-2H-1,4 -benzoxazine-8-carboxamide showed a high affinity for 5-HT3 receptors K(i) = 0.051 nM) and especially potent antagonistic activity against the von Bezold-Jarisch reflex (ED50 = 0.089 micrograms/kg i.v.) in rats.

Animals↗

PubMed2003

Antimycobacterial 3-aryl-2H-1,3-benzoxazine-2,4(3H)-diones.

A series of 153 derivatives of 3-phenyl-2H-benzoxazine-2,4(3H)-dione substituted in position 6 or 7 on benzoxazine and on the phenyl ring was synthesized. The compounds were evaluated in vitro for antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii and Mycobacterium avium. The activity of the compounds increases with increasing hydrophobicity and electron-withdrawing properties of the substituents on the phenyl ring, whereas the effect of the substituents on the benzoxazine ring seems to be more complex.

Algorithms↗

PubMed1991

Hydrolysis kinetics of 1,3-benzoxazine-2,4-dione (a potential salicylamide prodrug) and various N-substituted derivatives.

The kinetics and mechanism of hydrolysis of 1,3-benzoxazine-2,4-dione and its N-methyl and N-benzoyl derivatives were studied in aqueous solution to provide basic information on the reactivity of the benzoxazinedione structure and to assess the potential of unsubstituted 1,3-benzoxazine-2,4-dione as a prodrug for salicylamide. The compounds were found to hydrolyze quantitatively to the parent salicylamide. The pH-rate profiles obtained at pH 1-11 were accounted for by a spontaneous or water-catalyzed reaction which predominated at pH 1-4 and a hydroxide ion-catalyzed reaction. The rates of hydrolysis were catalyzed slightly in the presence of human plasma and rat liver homogenate, the exception being the N-benzoyl derivative which was hydrolyzed very fast in plasma solutions to N-benzoylsalicylamide. The aqueous solubility and lipophilicity characteristics of 1,3-benzoxazine-2,4-dione were determined. The results obtained suggest that the latter may function as a prodrug for salicylamide with the potential of depressing the extensive first-pass metabolism of salicylamide following oral or rectal administration.

Animals↗

PubMed2005

The 3D structure of the binding pocket of the human oxytocin receptor for benzoxazine antagonists, determined by molecular docking, scoring functions and 3D-QSAR methods.

Molecular docking and 3D-QSAR studies were performed to determine the binding mode for a series of benzoxazine oxytocin antagonists taken from the literature. Structural hypotheses were generated by docking the most active molecule to the rigid receptor by means of AutoDock 3.05. The cluster analysis yielded seven possible binding conformations. These structures were refined by using constrained simulated annealing, and the further ligands were aligned in the refined receptor by molecular docking. A good correlation was found between the estimated deltaG(bind) and the pKi values for complex F. The Connolly-surface analysis, CoMFA and CoMSIA models q2(CoMFA) = 0.653, q2(CoMSA) = 0.630 and r2(pred,CoMFA) = 0.852 , r2(pred,CoMSIA) = 0.815) confirmed the scoring function results. The structural features of the receptor-ligand complex and the CoMFA and CoMSIA fields are in closely connected. These results suggest that receptor-ligand complex F is the most likely binding hypothesis for the studied benzoxazine analogs.

Benzoxazines↗

PubMed2004

Synthesis by microwave irradiation of a substituted benzoxazine parallel library with preferential relaxant activity for guinea pig trachealis.

An efficient, facile, and practical parallel combinatorial synthesis of substituted-benzoxazines under microwave irradiation was described. The procedure involved the use of a microwave oven especially designed for organic synthesis suitable for parallel synthesis of solution libraries. A demonstration 19-membered library of substituted N,N-dimethyl- and N-methyl-benzoxazine amide derivatives, structurally related to the potassium channel opener cromakalim, was generated by both conventional and microwave procedures, achieving a reduction from 7 h to 30-36 min in library generation time for the microwave approach. All the synthesized compounds were tested using the in vitro models of rat aorta and guinea pig trachea rings pre-contracted with phenylephrine and carbachol, respectively. All N,N-dimethyl amide derivatives showed a relaxant activity higher on guinea pig trachea rings than on rat aorta rings.

Animals↗

PubMed2001

Induced accumulation of 2-hydroxy-4,7-dimethoxy-1,4-benzoxazin-3-one glucoside (HDMBOA-Glc) in maize leaves.

Accumulation of 2-(2-hydroxy-4,7-dimethoxy-1,4-benzoxazin-3-one)-beta-D-glucopyranose (HDMBOA-Glc) was induced in maize leaves by treatment with CuCl2, chitopentaose, penta-N-acetylchitopentaose, or jasmonic acid (JA). The accumulation of HDMBOA-Glc was accompanied by a decrease in level of 2-(2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one)-beta-D-glucopyranose (DIMBOA-Glc). When the leaf segments were treated with JA in the presence of [Me-2H3]L-methionine, the label was efficiently incorporated into HDMBOA-Glc, while no incorporation into DIMBOA-Glc or HMBOA-Glc was detected, suggesting the conversion of constitutive DIMBOA-Glc to HDMBOA-Glc by methylation at the 4-position. Levels of endogenous JA and its leucine conjugate transiently increased prior to the accumulation of HDMBOA-Glc in leaf segments treated with CuCl2 and chitopentaose. The lipoxygenase inhibitor ibuprofen suppressed the accumulation of HDMBOA-Glc induced by CuCl2 treatment, and the reduced accumulation of HDMBOA-Glc was recovered by addition of JA. These findings suggested that JA functions as a signal transducer in the induction of HDMBOA-Glc accumulation.

Benzoxazines↗

PubMed2001

Studies on the biosynthesis of 2-hydroxy-1,4-benzoxazin-3-one (HBOA) from 3-hydroxyindolin-2-one in Zea mays.

The ring expansion of 3-hydroxyindolin-2-one to 2-hydroxy-1,4-benzoxazin-3-one (HBOA) was investigated by labelling experiments. Action of the cytochrome P450 enzyme BX4 from maize on 3-hydroxyindolin-2-one under an 18O2 atmosphere induced production of 2-hydroxy-1,4-benzoxazin-3-one in which the ring oxygen--but not the 2-hydroxy group of HBOA--is labelled. A mechanism for this transformation is proposed.

Benzoxazines↗

PubMed2005

Degradation studies on benzoxazinoids. Soil degradation dynamics of (2R)-2-O-beta-D-glucopyranosyl-4-hydroxy-(2H)- 1,4-benzoxazin-3(4H)-one (DIBOA-Glc) and its degradation products, phytotoxic allelochemicals from Gramineae.

Wheat (Triticum aestivum L.) has been found to possess allelopathic potential and studies have been conduced to apply wheat allelopathy for biological weed control. 2,4-Dihydroxy-(2H)-1,4-benzoxazin-3(4H)-one (DIBOA) is a common product found in wheat, corn, and rye exudates and it can be released to the environment by that way. In this report, the stability of DIBOA is studied in two soils from crop lands of wheat cv. Astron and cv. Ritmo. These varieties were selected by their concentrations of DIBOA and 2,4-dihydroxy-7-methoxy-(2H)-1,4-benzoxazin-3(4H)-one (DIMBOA) from aerial parts and by the bioactivities of their aqueous extracts in the growth of wheat coleoptile sections. The degradation rate of DIBOA in these soils was measured in laboratory tests during 90 h by high-pressure liquid chromatography methods. These analyses demonstrate that DIBOA was transformed primarily into 2-benzoxazolinone (BOA). This transformation was similar in both soil types with an average half-life of 43 h. The degradation studies for BOA show its biotransformation to 2-aminophenoxazin-3-one (APO) with a half-life of 2.5 days. Therefore, BOA is an intermediate product in the biotransformation from DIBOA to APO in these wheat crop soils and is consistent with previous findings. APO was not degraded after three months in soil, suggesting that its degradation rate in soil is very slow.

Benzoxazines↗

PubMed2005

Novel 2-alkylamino-1,4-benzoxazine derivatives as potent neuroprotective agents: structure-activity relationship studies.

2-Alkylamino-substituted-1,4-benzoxazine derivatives, a new class of potential neuroprotective agents, were synthesized and examined for their intrinsic cytotoxicity and their capacity to inhibit oxidative stress-mediated neuronal degeneration in vitro. Through structure-activity relationship studies, the 3,3-diphenyl-substituted-1,4-benzoxazine derivative 3l was identified as the optimal candidate, owing to its potent neuroprotective activity, without the manifestation of intrinsic cytotoxicity. Accordingly, 3l proved to be effective in an animal model of excitotoxic lesions in newborn mice.

Animals↗

PubMed2006

Electrochemically induced cascade reaction for the assembly of libraries of biologically relevant 1,4-benzoxazine derivatives.

The scope and mechanism of an electrochemically induced cascade reaction, which leads to highly substituted 1,4-benzoxazine derivatives, have been explored through the variation of the structure of the o-azaquinone mediator. This reaction sequence, wherein both cycloaddition partners are generated in situ, at room temperature, under metal-free conditions, allows the regiospecific inverse-electron-demand Diels-Alder (IEDDA) reaction of an o-azaquinone heterodiene and a secondary alkylenamine dienophile, two chemically nonaccessible unstable entities. The cascade reaction was found to be general with electron-poor o-azaquinone entities generated from substituted 2-aminoresorcinol substrates. In the case of o-aminophenol derivatives which lack the 2-hydroxyl group, the generated o-azaquinone species failed to catalyze the oxidation of the amine to the corresponding imine, precursor of the enamine dienophile, because the absence of an intramolecular hydrogen bond at the origin of a highly reactive Schiff base cyclic transition state. To overcome this problem, a tandem oxidation-IEDDA reaction, in which the o-azaquinone is generated in the presence of a preformed enamine, has been developed as an alternative. These one-pot methodologies, which offer the opportunity to introduce variations in both cycloaddition partners, should be particularly useful for the development of libraries of biologically relevant 1,4-benzoxazine derivatives.

Benzoxazines↗

PubMed1998

Relationships between the chemical structure of antimycobacterial substances and their activity against atypical strains. Part 14: 3-Aryl-6,8-dihalogeno-2H-1,3-benzoxazine-2,4(3H)-diones.

A set of eight derivatives of 6,8-dichloro-3-phenyl-2H-benzoxazine-2,4(3H)-dione and nine derivatives of 6,8-dibromo-3-phenyl-2H-1, 3-benzoxazine-2,4(3H)-dione, substituted on the phenyl ring, was prepared by the reaction of the corresponding salicylanilides with ethyl chloroformate. The compounds were evaluated in vitro for antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii, and Mycobacterium avium. Their activity increases with increasing hydrophobicity and electron-withdrawing ability of the substituents on the phenyl ring.

Anti-Bacterial Agents↗

PubMed1996

Structure-activity relationship studies of novel pyrazolo[1,5-c][1,3]benzoxazines: synthesis and benzodiazepine receptor affinity.

Some 2-arylpyrazolo[1,5-c][1,3]benzoxazin-5-ones 1 and 5- oxopyrazolo[1,5-c][1,3]benzoxazin-2-carboxylates 2 were prepared and biologically evaluated for their binding at benzodiazepine receptor (BZR) in rat cortical membranes. Structure-activity relationship studies suggest that, although proton donor d and proton acceptor a1 are both optional pharmacophoric descriptors, at least one of them must be present for good BZR affinity. When the proton donor d is not present, the heteroatom acceptor a1 is necessary either in the tricyclic core or in the appended substituent at the C-2 to obtain sub-micromolar BZR affinity.

Animals↗

PubMed2002

Mass spectrometric studies of benzoxazine resorcarenes.

Eleven differently substituted 3,4-dihydro-2H-1,3-benzoxazine resorcarenes were studied by electrospray ionisation (ESI) and matrix-assisted laser desorption/ionisation (MALDI) mass spectrometry, using Fourier transform ion cyclotron resonance (FT-ICR) and time-of-flight (TOF) mass spectrometers, respectively. Under ESI conditions it was possible to transfer the intact resorcarenes from solution to the gas phase, yielding [M + H](+) and [M + 2H](+) ions as the main ions observed. Energy increase of the ions induced ready decomposition through successive eliminations of four CH(2)NR groups. Ion-molecule reactions showed that the ionising proton was situated somewhere inside the molecule and could not be reached with neutral reagent gases. In the host-guest complexation experiments, the benzoxazine resorcarenes studied turned out to be poor hosts for alkali metal and ammonium ions. In MALDI experiments, 2,5-dihydroxybenzoic acid proved to be the best matrix for these compounds. However, the intensity of the [M + H](+) ions was low for all compounds, and extensive fragmentation with consecutive elimination of CH(2)NR groups was observed.

Oxazines↗

PubMed2002

In vitro antifungal activity of 3-phenyl-2H-benzoxazine-2,4(3H)-diones.

A series of 81 3-phenyl-2H-benzoxazine-2,4(3H)-diones with substitution at C(6) on the benzoxazine ring and on the phenyl moiety was synthesized; the compounds were evaluated for antifungal activity against five strains of potentially pathogenic fungi (Absidia corymbifera, Aspergillus fumigatus, Candida albicans, Microsporum gypseum and Trichophyton mentagrophytes). Structure-activity relationships against T. mentagrophytes and M. gypseum were determined using the Free-Wilson method, which was further combined with the approach of Hansch. In vitro antifungal activity becomes higher with increasing electron-accepting ability of the substituents on the phenyl ring, and with increasing lipophilicity.

Antifungal Agents↗

PubMed2002

Potent nonsteroidal progesterone receptor agonists: synthesis and SAR study of 6-aryl benzoxazines.

Novel 6-aryl benzoxazines were prepared and examined as progesterone receptor (PR) modulators. In contrast to the structurally related 6-aryl dihydroquinoline PR antagonists, the 6-aryl benzoxazines were potent PR agonists. Compounds 4e, 5b, and 6a with the 2,4,4-trimethyl-1,4-dihydro-2H-benzo[d][1,3]oxazine core were the most potent PR agonists in the series with sub-nanomolar activities (EC(50) 0.20-0.35nM). Compound 6a was more potent than progesterone (P4) in the in vivo decidualization assay in an ovariectomized female rat model by subcutaneous administration with an ED(50) of 1.5mg/kg (vs 5.62mg/kg for P4).

Animals↗

PubMed2002

Synthesis and vasorelaxant activity of new 1,4-benzoxazine derivatives potassium channel openers.

As part of a search for new potassium channel openers, the synthesis and vasorelaxant activity of new 1,4-benzoxazine derivatives derived from transformation of the benzopyran skeleton of cromakalim were described. Several new 1,4-benzoxazine derivatives were provided with significant vasorelaxant activity with an overall pharmacological behavior similar to CRK (1f, 1i, 2d, 2e, 2f and 2i).

Animals↗

PubMed1997

Inhibition of cathepsin G by 4H-3,1-benzoxazin-4-ones.

A series of 4H-3,1-benzoxazin-4-ones is reported that inhibit the serine proteases human cathepsin G and bovine chymotrypsin. The synthesis and kinetic parameters of the alkaline hydrolysis is described. These compounds act as acyl-enzyme inhibitors of both enzymes. The reaction of cathepsin G with 2-benzylamino-4H-3,1-benzoxazin-4-one (20) was studied in detail. A partition in deacylation of the initially formed acyl-enzyme was observed, leading to the formation of 2-(3-benzylureido)benzoic acid (26) and 3-benzylquinazoline-2,4-(1H,3H)-dione (27). A 6-methyl substitution strongly increased the acylation rate of both proteases. Introduction of an aryl moiety into the 2-substituent led to compounds with Ki values towards cathepsin G in the nanomolar range. Their inhibitory potency is stronger than that of other synthetic inhibitors of cathepsin G.

Animals↗

PubMed2003

Benzoxazine oligomers: evidence for a helical structure from solid-state NMR spectroscopy and DFT-based dynamics and chemical shift calculations.

A combination of molecular modeling, DFT calculations, and advanced solid-state NMR experiments is used to elucidate the supramolecular structure of a series of benzoxazine oligomers. Intramolecular hydrogen bonds are characterized and identified as the driving forces for ring-shape and helical conformations of trimeric and tetrameric units. In fast MAS (1)H NMR spectra, the resonances of the protons forming the hydrogen bonds can be assigned and used for validating and refining the structure by means of DFT-based geometry optimizations and (1)H chemical-shift calculations. Also supporting these proposed structures are homonuclear (1)H[bond](1)H double-quantum NMR spectra, which identify the local proton-proton proximities in each material. Additionally, quantitative (15)N[bond](1)H distance measurements obtained by analysis of dipolar spinning sideband patterns confirm the optimized geometry of the tetramer. These results clearly support the predicted helical geometry of the benzoxazine polymer. This geometry, in which the N...H...O and O...H...O hydrogen bonds are protected on the inside of the helix, can account for many of the exemplary chemical properties of the polybenzoxazine materials. The combination of advanced experimental solid-state NMR spectroscopy with computational geometry optimizations, total energy, and NMR spectra calculations is a powerful tool for structural analysis. Its results provide significantly more confidence than the individual measurements or calculations alone, in particular, because the microscopic structure of many disordered systems cannot be elucidated by means of conventional methods due to lack of long-range order.

Journal Article↗