Pharmacological properties of sulfonamide derivatives — new inhibitors of carbonic anhydrase

Khokhlov, A. L.; Shetnev, A. A.; Korsakov, M. K.; Fedorov, V. N.; Tyushina, A. N.; Volkhin, N. N.; Vdovichenko, V. P.

doi:10.47056/0365-9615-2023-175-2-166-170

Cited by 3 publications

(1 citation statement)

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“…Determination of pharmacokinetic parameters of active substance and its biotransformation products is required during preclinical study of each original drug. The qualitative composition of metabolites of a newly created pharmacologically active substance is unknown, but can be predicted "in-silico" (Mironov 2012; Khokhlov et al 2019). The modeling of a process of microsomal oxidation and conjugation of xenobiotics is possible using microsomes, S9 fraction or hepatocytes (Khokhlov and Pyatigorskaya 2019;Alseekh et al 2021).…”

Section: Introductionmentioning

confidence: 99%

Identification and synthesis of metabolites of the new antiglaucoma drug

Khokhlov,

Yaichkov,

Shetnev

et al. 2023

RRP

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Introduction: The determination of biotransformation products is an essential part of the preclinical trial of original medicines. These studies have not been conducted before for the new drug 5-[5-(trifluoromethyl)-1,2-oxazole-3-yl]-furan-2-sulfonamide. Identification and synthesis of metabolite substances are necessary for subsequent tests of bioavailability, linearity of pharmacokinetics, accumulation, distribution and excretion. Materials and methods: The study was carried out on Wistar rats and rabbits of the Soviet Chinchilla breed. The substance of the drug was administered to animals intraperitoneally. The collection of animal blood samples was performed before administration and 1 h, 2 h, 4 h, 24 h after administration into K3EDTA-tubes. A part of each sample was centrifuged to separate the plasma. Rat urine samples were taken before administration and at intervals of 0-2 h, 2-4 h, 4-6 h, 6-24 h after administration of the drug. The HPLC-MS/MS method was used to identify metabolites in biological fluids. The assumed biotransformation products were synthesized after preliminary analysis. The structure of the obtained substances was confirmed by NMR spectroscopy and high-resolution mass spectrometry. Then, a comparison was carried out with the compounds identified in biological fluids by retention time, ratios of chromatographic peak areas at the main MRM-transitions using HPLC-MS/MS. Results and discussion: A metabolite formed by addition an oxygen atom to a drug molecule, as well as an acylated metabolite were detected during the analysis of plasma and blood samples. A compound with an increased molecular weight of 1 dalton compared to the drug substance was also present in a rat urine. N-hydroxy-5-[5-(trifluoromethyl)-1,2-oxazole-3-yl]-furan-2-sulfonamide, 5-[5-(trifluoromethyl)-1,2-oxazole-3-yl]-furan-2-sulfonic acid, which could potentially be obtained during biotransformation, as well as N-acetyl-5-[5-(trifluoromethyl)-1,2-oxazole-3-yl]-furan-2-sulfonamide were synthesized. Repeated HPLC-MS/MS tests confirmed the correctness of the initial hypothesis. It was found that a sulfonic acid derivative is formed in urine as a result of decomposition of N-hydroxymetabolite during sample collection. Conclusion: The studied drug is metabolized by formation of two metabolites: N-hydroxy-5-[5-(trifluoromethyl)-1,2-oxazole-3-yl]-furan-2-sulfonamide and N-acetyl-5-[5-(trifluoromethyl)-1,2-oxazole-3-yl]-furan-2-sulfonamide. N-hydroxymetabolite is able to decompose in biological fluids samples with formation of 5-[5-(trifluoromethyl)-1,2-oxazole-3-yl]-furan-2-sulfonic acid.

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Section: Introductionmentioning

confidence: 99%

Identification and synthesis of metabolites of the new antiglaucoma drug

Khokhlov,

Yaichkov,

Shetnev

et al. 2023

RRP

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Synthesis, Antibacterial, and Antimonooxidase Activity of 4-(2-Methyl-1,3-oxazol-5-yl)benzenesulfonamide

Gasilina,

Romanycheva,

Shetnev

et al. 2023

Russ J Gen Chem

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Synthesis, antibacterial and antimonooxidase activity of 4-(2-methyl-1,3-oxazol-5-yl)benzenesulfonamide

Gasilina,

Romanycheva,

Shetnev

et al. 2023

Žurnal obŝej himii

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A new method for obtaining 4-(2-methyl-1,3-oxazol-5-yl)benzenesulfonamide an antiglaucomatous drug candidate oxazopt was developed using a diazotization reaction. A combined potentiated effect of the antimicrobial action of carbapenems (meropenem) and aminoglycosides (gentamicin) against antibiotic-resistant gram-positive bacteria Enterococcus faecium, Enterococcus faecalis and gram-negative bacteria Escherichia coli and antimonooxidase effect in vitro was revealed for this compound.

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Pharmacological properties of sulfonamide derivatives — new inhibitors of carbonic anhydrase

Cited by 3 publications

References 0 publications

Identification and synthesis of metabolites of the new antiglaucoma drug

Identification and synthesis of metabolites of the new antiglaucoma drug

Synthesis, Antibacterial, and Antimonooxidase Activity of 4-(2-Methyl-1,3-oxazol-5-yl)benzenesulfonamide

Synthesis, antibacterial and antimonooxidase activity of 4-(2-methyl-1,3-oxazol-5-yl)benzenesulfonamide

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