The in Vitro and in Vivo Metabolism of Morantel in Cattle and Toxicology Species

Lynch, Martin J.; Mosher, Franklyn R; Levesque, W. R.; Newby, T.J.

doi:10.3109/03602538708998308

Cited by 13 publications

(3 citation statements)

References 12 publications

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“…Whereas the formation of all these products can be rationalized by an initial oxidation of the sulfur atom of thiophene ( 1 ), the mechanism behind the formation of thiophen-2-one ( 4 ) is less evident. Aromatic hydroxylations are commonly described in the cytochrome P450-catalyzed biotransformations of thiophene-containing drugs. ,− Their exact mechanism of formation and particularly the nature of the primary reactive intermediate are still a matter of scientific debate. Reports on the direct hydroxylation of thiophene derivatives by chemical means are rare.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of the Aromatic Hydroxylation of Thiophene by Acid-Catalyzed Peracid Oxidation

Treiber

2002

J. Org. Chem.

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The oxidation of thiophene (1) with peracids in a strongly acidic environment yielded thiophen-2-one (4) as the product of an apparent direct hydroxylation of the thiophene aromatic ring together with the anticipated thiophene-S-oxide dimers, 2a,b, as the main products. Formation of the latter dimers can be rationalized in a straightforward manner by initial oxidation at the sulfur atom of thiophene (1) to yield thiophene-S-oxide followed by subsequent dimerization in a Diels-Alder type reaction. Trapping experiments in the presence of a competing dienophile indicated that thiophen-2-one (4) did not originate from the monomeric thiophene-S-oxide but was the product of an independent reaction pathway. The extent of thiophen-2-one (4) formation correlated with the acidity of the reaction medium and was suppressed in the presence of water, the latter presumably acting as a competing base. As evidenced by the use of 2,5-dideuterated thiophene (1-D), its mechanism of formation involved a 1,2-hydride shift, a feature commonly described in the peracid-mediated epoxidation of aromatic hydrocarbons and indicative for the occurrence of cationic intermediates. In agreement with all these observations we propose a mechanism involving initial protonation of thiophene followed by nucleophilic attack of the peracid in position 2 of the thiophene ring. Intramolecular epoxidation may lead to the formation of thiophene 2,3-epoxide as a highly reactive intermediate that then undergoes heterolytic ring opening and a 1,2-hydride shift to yield thiophen-2-one (4) after a final, acid-catalyzed, isomerization of the double bond.

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Section: Discussionmentioning

confidence: 99%

Mechanism of the Aromatic Hydroxylation of Thiophene by Acid-Catalyzed Peracid Oxidation

Treiber

2002

J. Org. Chem.

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“…The oxidative metabolism of a 3-aroylthiophene analog of tienilic acid also leads to metabolites deriving from reactions of glutathione with its S-oxide intermediate [5]. In vivo and in vitro oxidation of several 2aroylthiophenes mainly leads to metabolites resulting from their hydroxylation at position 5 [8][9][10][11][12][13][14]. These 5-hydroxy metabolites could result from an isomerization of either a thiophene-S-oxide intermediate, or a 4,5-epoxide intermediate [15].…”

mentioning

confidence: 99%

First evidence that cytochrome P450 may catalyze both S-oxidation and epoxidation of thiophene derivatives

Dansette

Bertho

Mansuy

2005

Biochemical and Biophysical Research Communications

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Oxidation of 2-phenylthiophene (2PT) by rat liver microsomes, in the presence of NADPH and glutathione (GSH), led to three kinds of metabolites whose structures were established by 1H NMR and mass spectrometry. The first ones were 2PT-S-oxide dimers formed by Diels-Alder type dimerization of 2PT-S-oxide, while the second ones were GSH adducts derived from the 1,4-Michaël-type addition of GSH to 2PT-S-oxide. The third metabolites were GSH adducts resulting from a nucleophilic attack of GSH to the 4,5-epoxide of 2PT. Oxidation of 2PT by recombinant, human cytochrome P4501A1, in the presence of NADPH and GSH, also led to these three kinds of metabolites. These results provide the first evidence that cytochrome P450 may catalyze the oxidation of thiophene compounds with the simultaneous formation of two reactive intermediates, a thiophene-S-oxide and a thiophene epoxide.

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“…Other thiophene-containing drugs, tiquizium bromide 1w, morantel 1x, and tenoxicam 1y, were also oxidized in microsomal incubations in the thiophene ring, but the position of oxidation was not determined [132][133][134]. For two thiophene-containing drugs, duloxetine and eprosartan, and one benzothiophene-containing drug, raloxifene, metabolic oxidation of the thiophene ring was researched and not detected, other parts of the molecules being oxidized [57].…”

Section: Cyp450-catalyzed Epoxidation Of Monocyclic Thiophenesmentioning

confidence: 99%

Monooxygenase- and Dioxygenase-Catalyzed Oxidative Dearomatization of Thiophenes by Sulfoxidation, cis-Dihydroxylation and Epoxidation

Boyd

Sharma

Stevenson

et al. 2022

IJMS

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Enzymatic oxidations of thiophenes, including thiophene-containing drugs, are important for biodesulfurization of crude oil and drug metabolism of mono- and poly-cyclic thiophenes. Thiophene oxidative dearomatization pathways involve reactive metabolites, whose detection is important in the pharmaceutical industry, and are catalyzed by monooxygenase (sulfoxidation, epoxidation) and dioxygenase (sulfoxidation, dihydroxylation) enzymes. Sulfoxide and epoxide metabolites of thiophene substrates are often unstable, and, while cis-dihydrodiol metabolites are more stable, significant challenges are presented by both types of metabolite. Prediction of the structure, relative and absolute configuration, and enantiopurity of chiral metabolites obtained from thiophene enzymatic oxidation depends on the substrate, type of oxygenase selected, and molecular docking results. The racemization and dimerization of sulfoxides, cis/trans epimerization of dihydrodiol metabolites, and aromatization of epoxides are all factors associated with the mono- and di-oxygenase-catalyzed metabolism of thiophenes and thiophene-containing drugs and their applications in chemoenzymatic synthesis and medicine.

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The in Vitro and in Vivo Metabolism of Morantel in Cattle and Toxicology Species

Cited by 13 publications

References 12 publications

Mechanism of the Aromatic Hydroxylation of Thiophene by Acid-Catalyzed Peracid Oxidation

Mechanism of the Aromatic Hydroxylation of Thiophene by Acid-Catalyzed Peracid Oxidation

First evidence that cytochrome P450 may catalyze both S-oxidation and epoxidation of thiophene derivatives

Monooxygenase- and Dioxygenase-Catalyzed Oxidative Dearomatization of Thiophenes by Sulfoxidation, cis-Dihydroxylation and Epoxidation

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