Über 3‐Chlor‐1.2‐benzisoxazole

Böshagen, Horst

doi:10.1002/cber.19671001022

Cited by 20 publications

(7 citation statements)

References 3 publications

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“…Each fluorine atom ortho to the acetyl group of 15a and 15b was displaced by the anion of acetone oxime, and treatment with aqueous acid hydrolyzed both the oxime and silyl ether, enabling subsequent cyclization to the corresponding benzisoxazoles. 33 Oxidation with MnO 2 afforded aldehydes 16a and 16b. The final Treaction was achieved by heating barbituric acid with the corresponding aldehyde at the appropriate temperature.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…To this end, salicylic acid 24 was converted to 26 by procedures set out in the literature for the synthesis of chlorobenzisoxazoles. 33,34 eomers could not be isolated due to instability relative to configurational isomerization. Compound inhibitory potency against Escherichia coli DNA gyrase was determined in an assay where differential binding of a fluorescence tagged DNA chain with relaxed and supercoiled DNA was monitored.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Novel DNA Gyrase Inhibiting Spiropyrimidinetriones with a Benzisoxazole Scaffold: SAR and in Vivo Characterization

et al. 2014

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The compounds described herein with a spirocyclic architecture fused to a benzisoxazole ring represent a new class of antibacterial agents that operate by inhibition of DNA gyrase as corroborated in an enzyme assay and by the inhibition of precursor thymidine into DNA during cell growth. Activity resided in the configurationally lowest energy (2S,4R,4aR) diastereomer. Highly active compounds against Staphylococcus aureus had sufficiently high solubility, high plasma protein free fraction, and favorable pharmacokinetics to suggest that in vivo efficacy could be demonstrated, which was realized with compound (-)-1 in S. aureus mouse infection models. A high drug exposure NOEL on oral dosing in the rat suggested that a high therapeutic margin could be achieved. Importantly, (-)-1 was not cross-resistant with other DNA gyrase inhibitors such as fluoroquinolone and aminocoumarin antibacterials. Hence, this class shows considerable promise for the treatment of infections caused by multidrug resistant bacteria, including S. aureus.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Novel DNA Gyrase Inhibiting Spiropyrimidinetriones with a Benzisoxazole Scaffold: SAR and in Vivo Characterization

et al. 2014

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“…General methods. 3-Chloro-1,2-benzisoxazoles were prepared as previously described (Boshagen, 1967). All reagents and solvents were obtained from Sigma-Aldrich and were used without further purification.…”

Section: Methodsmentioning

confidence: 99%

SUBSTITUENT EFFECT ON THE REDUCTIVEN-DEARYLATION OF 3-(INDOL-1-YL)-1,2-BENZISOXAZOLES BY RAT LIVER MICROSOMES

Tschirret-Guth

Wood²

2003

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:The reductive metabolism of a series of 3-(indol-1-yl)-1,2-benzisoxazoles was examined in vitro using rat liver microsomes. 3-(Indol-1-yl)-1,2-benzisoxazole was reduced to the corresponding amidine (resulting from N-O bond cleavage) under anaerobic conditions. The reaction required viable microsomes and NADPH and was inhibited by carbon monoxide, air, and ketoconazole, suggesting the involvement of cytochrome P450 enzymes. The amidine was subsequently nonenzymatically hydrolyzed to 1-salicylindole, which in turn was hydrolyzed to indole. Addition of electron-withdrawing substituents (Cl ؊ , MeSO 2 ؊ ) at the 6-position of the benzisoxazole ring resulted in a significant increase in the rate of substrate reduction. Introduction of electron-withdrawing substituents on the indole ring likewise increased the rate of substrate consumption but caused a substituent-dependent shift of the site of bond cleavage from the 1,2-isoxazole N-O bond to the C-N bond linking the 1,2-benzisoxazole to the indole moiety. In the case of 3-(2-chloro-3-methanesulfoxylindol-1-yl)-1,2-benzisoxazole, C-N bond cleavage was nearly quantitative, and products resulting from N-O bond reduction were not observed. The overall rates of 3-(indol-1-yl)-1,2-benzisoxazoles reduction were found to be substrate concentration-dependent and observed Michaelis-Mententype behavior. The apparent V max of substrate reduction by rat liver microsomes correlated negatively with the free energy of the lowest unoccupied molecular orbitals (E LUMO ) calculated semiempirically using a parameterized model 3 (PM3), and suggested that the initial electron transfer was rate-determining and that the E LUMO could be used as an indication of the susceptibility of 1,2-isoxazoles to undergo reductive metabolism.The 1,2-isoxazole heterocycle is found in several marketed drugs including the anticonvulsant zonisamide and the antipsychotic iloperidone. One particular feature of the 1,2-isoxazole ring is that it is prone to reductive metabolism resulting in cleavage of the N-O bond (Dalvie et al., 2002). The susceptibility of 1,2-isoxazoles to reductive N-O bond cleavage was first observed when the insecticide isoxathion [O,O-diethyl O-(5-phenyl-3-1,2-isoxazolyl)-phosphorothioate] was administered orally to rats (Ando et al., 1975) and hippuric acid was isolated from urine. In vitro studies indicated that 3-hydroxy-5-phenyl-1,2-isoxazole, a metabolite found in urine as well, was reduced to benzoylacetamide and further metabolized to benzoic acid when incubated with rat liver S9 fractions in the presence of NADPH. More recently, it was shown that zonisamide undergoes extensive reductive metabolism in vivo and in vitro. In the rat, 2-(sulfamoylacetyl)-phenol glucuronide and 2-(1-aminosulfamoylethyl)-phenol, two metabolites identified in rat urine, were most likely formed from a common imine intermediate that resulted from N-O bond cleavage (Stiff and Zemaitis, 1990). It was subsequently shown that metaboli...

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“…trichloroanthranil) (310) may be prepared by reduction of 3,4,5-trichloro-2-nitrobenzaldehyde with tin and acid [666], and that 3,5,7-trichloro-l,2-benzisoxazole (311) is obtained when 5,7dichloro-3-hydroxy-l,2-benzisoxazole is treated with phosphorus oxychloride at 140-150° in the presence of triethylamine [667].…”

Section: 35-trichloro-p-benzoquinonedipivalimidementioning

confidence: 99%

Polychloroheteroaromatic Compounds

Iddon¹,

Suschitzky²

1974

Polychloroaromatic Compounds

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Über 3‐Chlor‐1.2‐benzisoxazole

Abstract: 3-Hydroxy-1.2-benzisoxazole lassen sich glatt in 3-Chlor-1.2-benzisoxazole umwandeln. In diesen Verbindungen ist das Chloratom in 3-Stellung m5iBig reaktiv und kann einige nucleophile Austauschreaktionen eingehen.

Cited by 20 publications

References 3 publications

Novel DNA Gyrase Inhibiting Spiropyrimidinetriones with a Benzisoxazole Scaffold: SAR and in Vivo Characterization

Novel DNA Gyrase Inhibiting Spiropyrimidinetriones with a Benzisoxazole Scaffold: SAR and in Vivo Characterization

SUBSTITUENT EFFECT ON THE REDUCTIVEN-DEARYLATION OF 3-(INDOL-1-YL)-1,2-BENZISOXAZOLES BY RAT LIVER MICROSOMES

Polychloroheteroaromatic Compounds

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