The Identification and synthesis of metabolites of 4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonamide
Introduction: 4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonamide is a new selective type II carbonic anhydrase inhibitor with local action through instillation into the eyes. For a complete pharmacokinetic study of this drug, it is necessary to detect and synthesize its metabolites for their syst...
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Belgorod National Research University
2024-11-01
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| Series: | Research Results in Pharmacology |
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| Online Access: | https://rrpharmacology.ru/index.php/journal/article/view/498 |
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| author | Alexander L. Khokhlov Ilya I. Yaichkov Anton A. Shetnev Valeria A. Panova Julia A. Efimova Sergey A. Ivanovskiy Mikhail K. Korsakov Nikita N. Volkhin Sergey S. Petukhov |
| author_facet | Alexander L. Khokhlov Ilya I. Yaichkov Anton A. Shetnev Valeria A. Panova Julia A. Efimova Sergey A. Ivanovskiy Mikhail K. Korsakov Nikita N. Volkhin Sergey S. Petukhov |
| author_sort | Alexander L. Khokhlov |
| collection | DOAJ |
| description | Introduction: 4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonamide is a new selective type II carbonic anhydrase inhibitor with local action through instillation into the eyes. For a complete pharmacokinetic study of this drug, it is necessary to detect and synthesize its metabolites for their systemic exposure evaluation.
Materials and Methods: The investigation was performed on 6 Wistar rats and 6 Soviet Chinchilla rabbits. The drug in the form of a 1% suspension was administered by intraperitoneal injection. Blood was sampled in a volume of 0.2 mL at the following time points: before administration and 1 h, 2 h, 4 h, 24 h after administration. Then 150 µL of each sample was centrifuged to produce plasma. Urine was simultaneously sampled in rats using metabolic cells: before administration and at intervals of 0-2 h, 2-4 h, 4-6 h, 6-24 h after administration of the drug. The identification of metabolites in these objects was performed using HPLC-MS/MS. Then the detected biotransformation products were synthesized. The structure of the obtained substances was confirmed by NMR spectroscopy and high-resolution mass spectrometry. At the final stage, animal biological fluids and model samples with the addition of the synthesized compounds were analyzed using HPLC-MS/MS to establish the structure of metabolites.Results and Discussion: N-hydroxy-4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonamide, 4-(5-(hydroxymethyl)-1,3,4-oxadiazole-2-yl)-benzenesulfonamide and 4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonic acid were identified and synthesized. The complete coincidence of the structure of metabolites and the synthesized substances was established as a result of their comparison in retention time, the ratio of the areas of chromatographic peaks at the main MRM transitions, as well as mass spectra.Conclusion: N-hydroxy-4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonamide and 4-(5-(hydroxymethyl)-1,3,4-oxadiazole-2-yl)-benzenesulfonamide are products of biotransformation of the studied drug. It was found that 4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonic acid is formed by decomposition of N-hydroxymetabolite in urine samples during the collection process. |
| format | Article |
| id | doaj-art-79708070fa7c43778d8d914640ff9a75 |
| institution | Kabale University |
| issn | 2658-381X |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Belgorod National Research University |
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| series | Research Results in Pharmacology |
| spelling | doaj-art-79708070fa7c43778d8d914640ff9a752025-01-08T12:51:24ZengBelgorod National Research UniversityResearch Results in Pharmacology2658-381X2024-11-01104152710.18413/rrpharmacology.10.498The Identification and synthesis of metabolites of 4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonamideAlexander L. Khokhlov0https://orcid.org/0000-0002-0032-0341Ilya I. Yaichkov1https://orcid.org/0000-0002-0066-7388Anton A. Shetnev2https://orcid.org/0000-0002-4389-461XValeria A. Panova3https://orcid.org/0000-0002-4775-5326Julia A. Efimova4https://orcid.org/0000-0003-3027-0223Sergey A. Ivanovskiy5https://orcid.org/0000-0002-1421-9236Mikhail K. Korsakov6https://orcid.org/0000-0003-0913-2571Nikita N. Volkhin7https://orcid.org/0000-0002-4275-9037Sergey S. Petukhov8https://orcid.org/0009-0007-8435-7689Yaroslavl State Medical UniversityYaroslavl State Pedagogical University named after K.D. UshinskyYaroslavl State Pedagogical University named after K.D. UshinskyYaroslavl State Pedagogical University named after K.D. UshinskyYaroslavl State Pedagogical University named after K.D. UshinskyYaroslavl State Pedagogical University named after K.D. UshinskyYaroslavl State Pedagogical University named after K.D. UshinskyYaroslavl State Pedagogical University named after K.D. UshinskyYaroslavl State Pedagogical University named after K.D. UshinskyIntroduction: 4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonamide is a new selective type II carbonic anhydrase inhibitor with local action through instillation into the eyes. For a complete pharmacokinetic study of this drug, it is necessary to detect and synthesize its metabolites for their systemic exposure evaluation. Materials and Methods: The investigation was performed on 6 Wistar rats and 6 Soviet Chinchilla rabbits. The drug in the form of a 1% suspension was administered by intraperitoneal injection. Blood was sampled in a volume of 0.2 mL at the following time points: before administration and 1 h, 2 h, 4 h, 24 h after administration. Then 150 µL of each sample was centrifuged to produce plasma. Urine was simultaneously sampled in rats using metabolic cells: before administration and at intervals of 0-2 h, 2-4 h, 4-6 h, 6-24 h after administration of the drug. The identification of metabolites in these objects was performed using HPLC-MS/MS. Then the detected biotransformation products were synthesized. The structure of the obtained substances was confirmed by NMR spectroscopy and high-resolution mass spectrometry. At the final stage, animal biological fluids and model samples with the addition of the synthesized compounds were analyzed using HPLC-MS/MS to establish the structure of metabolites.Results and Discussion: N-hydroxy-4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonamide, 4-(5-(hydroxymethyl)-1,3,4-oxadiazole-2-yl)-benzenesulfonamide and 4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonic acid were identified and synthesized. The complete coincidence of the structure of metabolites and the synthesized substances was established as a result of their comparison in retention time, the ratio of the areas of chromatographic peaks at the main MRM transitions, as well as mass spectra.Conclusion: N-hydroxy-4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonamide and 4-(5-(hydroxymethyl)-1,3,4-oxadiazole-2-yl)-benzenesulfonamide are products of biotransformation of the studied drug. It was found that 4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonic acid is formed by decomposition of N-hydroxymetabolite in urine samples during the collection process.https://rrpharmacology.ru/index.php/journal/article/view/498biotransformationselective carbonic anhydrase ii inhibitorhplc-ms/msn-hydroxysulfonamide |
| spellingShingle | Alexander L. Khokhlov Ilya I. Yaichkov Anton A. Shetnev Valeria A. Panova Julia A. Efimova Sergey A. Ivanovskiy Mikhail K. Korsakov Nikita N. Volkhin Sergey S. Petukhov The Identification and synthesis of metabolites of 4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonamide Research Results in Pharmacology biotransformation selective carbonic anhydrase ii inhibitor hplc-ms/ms n-hydroxysulfonamide |
| title | The Identification and synthesis of metabolites of 4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonamide |
| title_full | The Identification and synthesis of metabolites of 4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonamide |
| title_fullStr | The Identification and synthesis of metabolites of 4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonamide |
| title_full_unstemmed | The Identification and synthesis of metabolites of 4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonamide |
| title_short | The Identification and synthesis of metabolites of 4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonamide |
| title_sort | identification and synthesis of metabolites of 4 5 methyl 1 3 4 oxadiazole 2 yl benzenesulfonamide |
| topic | biotransformation selective carbonic anhydrase ii inhibitor hplc-ms/ms n-hydroxysulfonamide |
| url | https://rrpharmacology.ru/index.php/journal/article/view/498 |
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