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At least 19 recordsLinked to original sources
PubMed1996

Benzoxazines. II. Synthesis, conformational analysis, and structure--activity relationships of 3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide derivatives as potent and long-acting serotonin-3 (5-HT3) receptor antagonists.

A series of 3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide derivatives was synthesized and evaluated for serotonin-3 (5HT3) receptor antagonistic activities by means of assays of 5-HT3 receptor binding and the ability to antagonize the von Bezold-Jarisch reflex in rats. Replacement of the 1,4-benzoxazine ring with a 1,4-benzthiepine ring or seven-membered ring (i.e., 1,5-benzoxepine or 1,5-benzthiepine) resulted in decreased affinity for 5-HT3 receptor. Introduction of substituents at the 2 position of the 1,4-benzoxazine ring increased the antagonistic activities (dimethyl > methyl > dihydro > phenyl). The compounds bearing a 9-methyl-9-azabicyclo[3.3.1]non-3-yl moiety as the basic part of 3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide derivatives were equipotent to those bearing 1-azabicyclo[2.2.2]oct-3-yl moiety. The 9-methyl-9-azabicyclo[3.3.1]non-3-yl moiety was confirmed to adopt a boat-chair conformation on the basis of both NMR studies and X-ray analysis. In this series, endo-6-chloro-3,4-dihydro-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2,2, 4-trimethyl-2H-1,4-benzoxazine-8-carboxamide showed the highest affinity for 5-HT3 receptors (Ki = 0.019 nM), and a long-lasting 5-HT3 receptor antagonistic activity as evidenced by antagonism to the von Bezold--Jarisch reflex in rats. Such a long-lasting 5-HT3 receptor antagonism would be attributed to the introduction of both two methyl groups at the 2 position of the benzoxazine ring and the 9-methyl-9-azabicyclo[3.3.1]non-3-yl moiety, which adopts the boat-chair conformation.

Amides↗
PubMed2001

Palladium-catalyzed heteroannulation leading to heterocyclic structures with two heteroatoms: a highly regio- and stereoselective synthesis of (Z)-4-alkyl-2-alkyl(aryl)idene-3,4-dihydro-2H-1,4-benzoxazines and (Z)-3-alkyl(aryl)idene-4-tosyl-3,4-dihydro-2H-1,4-benzoxazines.

A highly convenient method has been developed for the synthesis of (Z)-4-alkyl-2-alkyl(aryl)idene-3,4-dihydro-2H-1,4-benzoxazines 9 and (Z)-3-alkyl(aryl)idene-4-tosyl-3,4-dihydro-2H-1,4-benzoxazines 34-38 through palladium-copper-catalyzed reactions. Aryl halides 7 reacted with 2-[N-alkyl(benzyl)-N-prop-2'-ynyl]aminophenyl tosylate 6 in the presence of (PPh3)2PdCl2 (3 mol %), CuI(5 mol %) in triethylamine at room temperature to yield 2-[N-alkyl(benzyl)-N-(3-aryl-prop-2'-ynyl)]-aminophenyl tosylates 8 in extremely good yields (72-96%). The latter could then be cyclized with KOH in ethanol-water to Z-9 in a highly regio- and stereoselective manner. Similarly, palladium-copper-catalyzed reaction of 2-(prop-2'-ynyloxy)aniline (21) with aryl iodides 7 led to 22-26 which after tosylation and cyclization with cuprous iodide in CH3CN in the presence of K2CO3 and Bu4-NBr led to the (Z)-3-alkyl(aryl)idene-4-tosyl 3,4-dihydro-2H-1,4-benzoxazines 34-38 in good overall yields. The Z-stereochemistry of the products was established from 1H NMR spectra, 3JCH values (between vinylic proton and methylenic carbon of the heterocyclic ring), NOE experiments, and X-ray analysis. The method was also found to be suitable for the synthesis of bis(benzoxazinylated) derivatives 17, 39, and 2-alkyl-3,4-dihydro-2H-1,4-benzoxazines 18. Our method for the synthesis of 3,4-dihydro-2H-1,4-benzoxazines is highly efficacious, using easily available starting materials under very mild conditions. Also the synthesis of some novel 5-substituted uracil derivatives 40 and 41 containing the benzoxazinyl moiety and of potential biological interest is being reported.

Journal Article↗
PubMed2003

[New groups of potential antitubercular agents: 3-(4-ethoxythiocarbonylphenyl)-2-H-benzoxazin-2,4(3H)-diones and 3-(4-ethoxythiocarbonylphenyl)-4-thioxy-2H-benzoxazin-2(3H)-ones].

In connection with the search for new antituberculotics, the present authors prepared a group of derivatives of 3-(4-ethoxythiocarbonylphenyl)-2H-benzoxazin-2,4(3H)-dithione and 3-(4-ethoxythiocarbonylphenyl)-4-thioxy-2H-benzoxazin-2,4(3H)-one. The modifications of substituents were carried out on the benzoxazine ring. The study was based on the present authors' previous assumption that the substitution of the oxo group for the thioxo group was connected with an increase in antimycobacterial activity. The prepared substances were evaluated by the activity against Mycobacterium tuberculosis, Mycobacterium kansasii, and Mycobacterium avium. However, it was concluded that there was no assumed increase in antimycobacterial activity in the groups of 3-(4-ethoxythiocarbonylphenyl)-4-thioxy-2H-benzoxazin-2,4(3H)-one and 3-(4-ethoxythiocarbonylphenyl)-2H-benzoxazin-2,4(3H)-dithione derivatives.

Antitubercular Agents↗
PubMedDate not supplied

New groups of antimycobacterial agents: 6-chloro-3-phenyl-4-thioxo-2H-1,3-benzoxazine-2(3H)-ones and 6-chloro-3-phenyl-2H-1,3-benzoxazine-2,4(3H)-dithiones.

A series of 6-chloro-3-phenyl-4-thioxo-2H-1,3-benzoxazine-2(3H)-ones 3 and a series of 6-chloro-3-phenyl-2H-1,3-benzoxazine-2, 4(3H)-dithiones 4 were synthesized by melting 6-chloro-3-phenyl-2H-1, 3-benzoxazine-2,4(3H)-dione and its derivatives substituted on the phenyl ring 2 with tetraphosphorus decasulfide. Compounds 2c-e, 3 and 4 exhibited in vitro activity against Mycobacterium tuberculosis, M. kansasii (two strains) and M. avium better than or comparable to that of isoniazid. Replacement of the oxo group by a thioxo group at position 4 led to improvement in activity against M. tuberculosis and M. kansasii. The Free-Wilson method and procedure developed by the authors were used to analyse the structure-activity and structure-antimycobacterial profile relationships, respectively.

Anti-Bacterial Agents↗
PubMed2006

Dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA) and 2,4-dihydroxy-1,4-benzoxazin-3-one (DIBOA), two naturally occurring benzoxazinones contained in sprouts of Gramineae are potent aneugens in human-derived liver cells (HepG2).

Benzoxazinoids (BAs) are toxic constituents of sprouts of Gramineae such as wheat, maize and rye and are part of the plant defence system against pests. In the last years, sprouts have been increasingly consumed as health foods and are also used for the production of dietary supplements. In the present study we investigated the mutagenic activities of the two most abundant BAs, namely 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA) and 2,4-dihydroxy-1,4-benzoxazin-3-one (DIBOA) in the Salmonella/microsome assay and additionally, in micronucleus (MN) assay and single cell gel electrophoresis (SCGE) assay in a human-derived liver cell line (HepG2). DIBOA caused significant induction of his(+) revertants in all three strains in the range between 0.02 and 0.50 mg/plate; the highest activity was observed in TA100 (fivefold increase over the background at the highest dose level). The effect in YG1024 (a derivative of TA98 with increased acetyltransferase activity) was only slightly higher than the effect in the parental strain indicating that acetylation plays no crucial role in the activation of this BA. DIMBOA was in general less active and a positive result was only seen in the base substitution strain (TA100). Addition of rat liver homogenate (S9-mix) led to a significant (ca. twofold) increase of the mutagenic activities of both BAs. In SCGE assays with HepG2 cells consistently negative results were obtained with both compounds whereas in MN assays significant dose dependent effects were observed under similar experimental conditions. DIMBOA caused significant effects already at concentrations > or =1 microM; at the highest dose (20 microM) the MN frequency was sevenfold higher than the background level. DIBOA caused weaker effects and was positive at doses > or =2.5 microM, the maximal induction (twofold over background) was observed with 20 microM. Overall, DIMBOA was ca. 30-fold more active as DIBOA. Subsequent experiments with pancentromeric probes showed that >80% of the MN induced at the highest doses gave a centromere positive signal indicating that both BAs are aneugenic. This is an interesting observation as it is assumed that aneuploidy is a key event in cancer induction and at present no other aneugenic plant-derived substances of dietary relevance are known.

Analysis of Variance↗
PubMedDate not supplied

Distribution and variations of three 1,4-benzoxazin-3-ones in maize induced by the Asian corn borer, Ostrinia furnacalis (Guenée).

Contents of three 1,4-benzoxazin-3-ones in tissue samples from different parts (young leaf, second leaf, old leaf, stem and root) of young maize plants of 4-leaves stage, fed by the third instar larvae of the Asian corn borer, Ostrinia furnacalis (Guenée), were analyzed by high-performance liquid chromatography-mass spectroscopy (HPLC-MS). Samples were taken immediately (set A) or 48 h (set B) after larvae had fed on the second leaf for 48 h. The three 1,4-benzoxazin-3-ones investigated in our experiments were 2,4-dihydroxy-7-methoxy-1,4(2H)-benzoxazin-3-one (DIMBOA), 2,4-dihydroxy-1,4(2H)-benzoxazin-3-one (DIBOA) and 2-hydroxy-7-methoxy-1,4(2H)-benzoxazin-3-one (HMBOA). In samples of set A, the levels of DIMBOA and HMBOA were significantly lifted in the old leaf (L3) and young leaf (L1), respectively, while amounts of these two chemicals in other plant parts were not significantly different between larvae-fed plants and intact plants. Concentrations of DIBOA in each plant part remained unchanged. In samples of set B, no concentration differences for any of these three 1,4-benzoxazin-3-ones between larvae-fed plants and controls were observed in any plant part. The feeding of the Asian corn borer seems to have limited effects on induction of these three 1,4-benzoxazin-3-ones in young maize plants of the variety investigated.

Animals↗
PubMed1979

Identification of 1,4-Benzoxazin-3-ones in Maize Extracts by Gas-Liquid Chromatography and Mass Spectrometry.

Gas-liquid chromatography-mass spectrometry (GLC-MS) has been used for the separation, detection, and identification of 1,4-benzoxazin-3-ones (hydroxamic acids and lactams) and benzoxazolinones found in maize (Zea mays L.) extracts. Compounds of interest were partitioned into ethyl acetate from aqueous maize seedling extracts. For analysis by GLC-MS, trimethylsilyl derivatives were prepared, chromatographed on a column of 3% OV-1, and detected in the mass spectrometer. Mass spectra were obtained for all peaks present in extracts of four maize lines. A data comparison system was developed for relating unidentified spectra to the spectra of the reference compounds. Based on spectral comparisons, three hydroxamic acids (2,4-dihydroxy-2H-1, 4-benzoxazin-3(4H)-one; 2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one; and 2,4-dihydroxy-7,8-dimethoxy-2H-1,4-benzoxazin-3(4H)-one), three lactams (2-hydroxy-2H-1,4-benzoxazin-3(4H)-one; 2,7-dihydroxy-2H-1,4-benzoxazin-3(4H)-one; and 2-hydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one), one benzoxazolinone (6-methoxybenzoxazolinone), and two organic acids (malic and aconitic) were identified in the extracts. In addition, one other hydroxamic acid and one other related compound were tentatively identified based on mass spectral evidence.

Journal Article↗
PubMed1979

Quantitation of 1,4-Benzoxazin-3-ones in Maize by Gas-Liquid Chromatography.

A gas-liquid chromatographic (GLC) procedure is reported for the quantitation of the trimethylsilyl (TMS) derivatives of substituted 2-hydroxy-2H-1,4-benzoxazin-3(4H)-ones (2-hydroxy-2H-1,4-benzoxazin-3(4H)-one[HBOA]; 2-hydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one[HMBOA];2,4- dihydroxy-2H-1,4-benzoxazin-3(4H)-one[DIBOA]; 2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one[DIMBOA]; and 2,4-dihydroxy-7,8-dimethoxy-2H-1,4-benzoxazin-3(4H)-one[DIM (2)BOA]) found in maize (Zea mays L.) extracts. Derivatized samples were chromatographed on columns with liquid phases of 2% DC-11 and 3% OV-17 and detected by flame ionization. Internal standards were methyl palmitate and methyl stearate on DC-11 and methyl behenate on OV-17. Detector response was linear to at least 5 nanomoles for TMS(2)-HBOA and TMS(2)-DIBOA and to 19 nanomoles for TMS(2)-DIMBOA. Standard errors of 2% or less were obtained when four replicate samples were analyzed. For each of the 15 maize lines examined, the amount of DIMBOA determined by GLC was directly proportional to the amount of ferric chloride-reactive material determined colorimetrically.

Journal Article↗
PubMed1999

Synthesis of oxypropanolamine derivatives of 3,4-dihydro-2H-1,4-benzoxazine, beta-adrenergic affinity, inotropic, chronotropic and coronary vasodilating activities.

Aseries of oxypropanolamine derivatives of 3,4-dihydro-2H-1,4-benzoxazine were synthesized and evaluated for inotropic, chronotropic and coronary vasodilating activities in the canine heart, affinity to beta(1)-adrenergic receptor in turkey erythrocytes and affinity to the beta(2)-adrenergic receptor in the rat lung. Among these compounds, 4-acetyl-6-(3-tert-butylamino-2-hydroxy)propoxy-3,4-dihydro-2H-1,4-benzoxazine showed 2.1-fold more potent affinity to the beta(1) receptor than propranolol and 7-(3-tert-butylamino-2-hydroxy)propoxy-N-butyryl-3,4-dihydro-2H-1,4-benzoxazine showed 2.5-fold more potent affinity to the beta(2) receptor and furthermore 4386-fold more potent selectivity to the beta(2) receptor than propranolol. In addition, 4-acetyl-6-[3-(3,4-dimethoxybenzyl)amino-2-hydroxy]propoxy-3,4-dihydro-2H-1,4-benzoxazine showed 1.1-fold more potent affinity to the beta(1) receptor than propranolol and also 1147-fold more potent selectivity to the beta(1) receptor. With a few exceptions, negative inotropic and chronotropic actions of these compounds were dependent on the size of the 4-substituent obeying the order: unsubstituted < acetyl < propanoyl < butanoyl, while the benzoyl substituent conferred even stronger negative actions in the 6-oxypropanolamine derivatives. Neither negative inotropic and chronotropic actions related with affinity to beta(1)-adrenoceptor nor coronary vasodilator action related with affinity to beta(2)-adrenoceptor were observed. 4-acetyl-7-[3-(3,4-dimethoxybenzyl)amino-2-hydroxy]propoxy-3,4-dihydro-2H-1,4-benzoxazine exerted potent positive inotropic, chronotropic and coronary vasodilating actions. The inotropic and chronotropic actions of the latter compound may be attributed to the release of intrinsic catecholamines, as concluded by the absence of beta(1)-adrenoceptor affinity and disappearance of activity in the presence of a beta-blocker.

Journal Article↗
PubMed2001

Asymmetric mono-oxazine: an inevitable product from Mannich reaction of benzoxazine dimers.

The Mannich reaction is detailed, which was carried out on benzoxazine dimers under various conditions, that is, temperature, reaction time, and solvents. Against our expectation, in any condition, instead of generating a disubstitution oxazine compound, the reaction gives a product with only a single oxazine ring, a mono-oxazine benzoxazine dimer, as characterized by FT-IR, 1H NMR, 13C NMR, 2D-NMR (1H-1H COSY, 1H-13C HMQC, and 1H-13C HMBC), and EA. The asymmetrical reaction is found to be based on the original structure of the benzoxazine dimer which has two phenol rings in a different stability as clarified by X-ray structure analysis of the single crystal. All types of benzoxazine dimers indicate the specific structure with a pair of inter- and intramolecular hydrogen bonds. The bond distance indicates that the intramolecular hydrogen bonding is very strong, while the packing structure emphasizes the high stability of the dimer unit and implies the deactivation of one phenol ring in the benzoxazine dimer. In this contribution, we demonstrate one of the quite rare examples, showing how the stereostructure of the reactant molecule is an important factor to control the reaction and give an asymmetric product which we never expected when considering only the chemical formula.

Journal Article↗
PubMed2003

4H-1,2-benzoxazines with electron-withdrawing substituents on the benzene ring: synthesis and application as potent intermediates for oxygen-functionalized aromatic compounds.

A new general method for synthesizing functionalized 4H-1,2-benzoxazine derivatives is described. Although 4H-1,2-benzoxazine is one of the fundamental structure of the oxazine group, no general synthetic method for the heterocycle has been established. We found that 3-methoxycarbonyl-4H-1,2-benzoxazine was obtained in good yield when methyl 2-nitro-3-phenylpropionate was treated with an excess amount of trifluoromethanesulfonic acid. This methodology was also applicable for the synthesis of 4H-1,2-benzoxazine rings functionalized with various electron-withdrawing substituents on the benzene ring. Furthermore, we also show that the resulting 4H-1,2-benzoxazines can be used as precursors of functionalized o-quinone methides and multisubstituted phenols. This type of heterocycle can be a potent intermediate to oxygen-fuctionalized aromatic compounds.

Journal Article↗
PubMed1999

Synthesis and in vitro evaluation of new 8-amino-1,4-benzoxazine derivatives as neuroprotective antioxidants.

A series of new 8-amino-1,4-benzoxazine derivatives 5a-o was synthesized and examined for their intrinsic cytotoxicity and their capacity to inhibit oxidative stress-mediated neuronal degeneration in neuronal cell cultures. In particular, substituent effects at the 3- and 8-positions of the 1,4-benzoxazine ring were investigated by in vitro evaluation. In this aim, 3-alkyl substituents seemed to be essential for efficient neuroprotective activity. Furthermore, within the subseries of substituted 3-alkyl benzoxazines, the most active derivatives were those bearing an 8-benzylamino substituent. From the combined results of both toxicity and neuroprotection expressed in terms of the safety index, 8-benzylamino-substituted-3-alkyl-1,4-benzoxazines were identified as the most promising compounds, owing to their potent neuroprotective activity without the manifestation of intrinsic cytotoxicity.

Animals↗
PubMed2004

Similarity approach to QSAR. Application to antimycobacterial benzoxazines.

The antimycobacterial activity in six series of substituted 3-phenyl-2H-benzoxazine-2,4(3H)-dithiones and 3-(phenyl)-4-thioxo-2H-benzoxazine-2,4(3H)-diones has been studied using a quantum molecular similarity approach. The approach is based on the use of fragment self-similarity measures as new universal molecular descriptors applicable for the design of novel theoretical QSAR models. Using this approach it was possible to show that while traditional QSAR models were able to describe the activity only within each of the six sets of studied molecules individually, the proposed approach is much more general and a single universal QSAR model describing the activity of all the 39 studied molecules in all the studied series together was built. The replacement of the oxo group by the thioxo group in position 4 on the benzoxazine ring of the antitubercular 3-(phenyl)-2H-benzoxazine-2,4(3H)-diones increases the activity, as well as the similar replacement in position 2.

Anti-Bacterial Agents↗