The Identification and synthesis of metabolites of 4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonamide

Authors

DOI:

https://doi.org/10.18413/rrpharmacology.10.498

Abstract

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.

Graphical Abstract

Keywords:

biotransformation, selective carbonic anhydrase II inhibitor, HPLC-MS/MS, N-hydroxysulfonamide

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Author Contribution

Alexander L. Khokhlov, Yaroslavl State Medical University

Doctor Habil. of Medical Sciences, Professor, Member of The Russian Academy of Sciences, Head of the Department of Pharmacology and Clinical Pharmacology, rector of Yaroslavl State Medical University; e-mail: al460935@yandex.ru, ORCID ID: https://orcid.org/0000-0002-0032-0341. The author’s contribution: formulation and development of the aim and objectives; analysis and interpretation of the obtained data; critical review of the draft copy and provision of valuable comments.

Ilya I. Yaichkov, Yaroslavl State Pedagogical University named after K.D. Ushinsky

Candidate of Pharmaceutical Sciences, research fellow of the Department of Analytical Development and Quality Control of M.V. Dorogov Pharmaceutical Technology Transfer Center of Yaroslavl State Pedagogical University named after K.D. Ushinsky; research fellow of the Institute of Pharmacy of Yaroslavl State Medical University; e-mail: i.yaichkov@yspu.org, ORCID ID: https://orcid.org/0000-0002-0066-7388. The author’s contribution: concept development; development of design of biotransformation study; development of bioanalytical methods; analysis of samples; analysis and interpretation of the obtained data; writing the bioanalytical part and editing the manuscript.

Anton A. Shetnev, Yaroslavl State Pedagogical University named after K.D. Ushinsky

Candidate of Chemical Sciences, Head of the Department of Pharmaceutical Development of M.V. Dorogov Pharmaceutical Technology Transfer Center of Yaroslavl State Pedagogical Universitynamed after K.D. Ushinsky; e-mail: a.shetnev@list.ru, ORCID ID: https://orcid.org/0000-0002-4389-461X. The author’s contribution: formulation and development of the aim and objectives; development of synthesis technology of the drug and its metabolite; writing the synthesis part and interpretation of the obtained data.

Valeria A. Panova, Yaroslavl State Pedagogical University named after K.D. Ushinsky

Junior research fellow of the Department of Pharmaceutical Development of M.V. Dorogov Pharmaceutical Technology Transfer Center of Yaroslavl State Pedagogical University named after K.D. Ushinsky; e-mail: v.panova@yspu.org, ORCID ID: https://orcid.org/0000-0002-4775-5326. The author’s contribution: synthesis of the drug and its metabolites.

Julia A. Efimova, Yaroslavl State Pedagogical University named after K.D. Ushinsky

Engineer of the Department of Pharmaceutical Development of M.V. Dorogov Pharmaceutical Technology Transfer Center of Yaroslavl State Pedagogical University named after K.D. Ushinsky, post-graduate student of Department of Organic Chemistry of A.N. Kosygin State University of Russia; e-mail: yua.efimova@yspu.org, ORCID ID: https://orcid.org/0000-0003-3027-0223. The author’s contribution: synthesis of the drug and its metabolites.

Sergey A. Ivanovskiy , Yaroslavl State Pedagogical University named after K.D. Ushinsky

Candidate of Chemical Sciences, Head of the Department of Analytical Development and Quality Control of M.V. Dorogov Pharmaceutical Technology Transfer Center of Yaroslavl State Pedagogical University named after K.D. Ushinsky; e-mail: main_engine@mail.ru, ORCID ID:https://orcid.org/0000-0002-1421-9236. The author’s contribution: quality control and characterization of structure of the drug and its metabolites.

Mikhail K. Korsakov, Yaroslavl State Pedagogical University named after K.D. Ushinsky

Doctor Habil. of Chemical Sciences, Professor of the Department of Chemistry, Theory and Methods of Teaching Chemistry, Head of The Center of Transfer of Pharmaceutical Technology named after M.V. Dorogov of Yaroslavl State Pedagogical University named after K.D. Ushinsky; e-mail: m.korsakov@yspu.org, ORCID ID: https://orcid.org/0000-0003-0913-2571. The author’s contribution: formulation and development of the aim and objectives; analysis and interpretation of the obtained data; critical review of the draft copy and provision of valuable comments.

Nikita N. Volkhin, Yaroslavl State Pedagogical University named after K.D. Ushinsky

Junior research fellow of the Department of Pharmacological Studies of M.V. Dorogov Pharmaceutical Technology Transfer Center of Yaroslavl State Pedagogical University named after K.D. Ushinsky; e-mail: nnvolkhin@ysmu.ru, ORCID ID: https://orcid.org/0000-0002-4275-9037.  The author’s contribution: blood and plasma sample collection; analysis and interpretation of the data obtained.

Sergey S. Petukhov, Yaroslavl State Pedagogical University named after K.D. Ushinsky

Engineer of the Department of Pharmacological Studies of M.V. Dorogov Pharmaceutical Technology Transfer Center of Yaroslavl State Pedagogical University named after K.D. Ushinsky; junior research fellow of the Institute of Pharmacy of Yaroslavl State Medical University; e-mail: sspp465@mail.ru, ORCID ID: https://orcid.org/0009-0007-8435-7689. The author’s contribution: blood and plasma sample collection; analysis and interpretation of the obtained data.

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Published

21-11-2024

How to Cite

Khokhlov AL, Yaichkov II, Шетнев A, Panova VA, Efimova YA, Ivanovskiy SA, Korsakov M, Volkhin NN, Petukhov SS (2024) The Identification and synthesis of metabolites of 4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonamide. Research Results in Pharmacology 10(4): 15–27. https://doi.org/10.18413/rrpharmacology.10.498

Issue

Vol. 10 No. 4 (2024)

Section

Experimental Pharmacology

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Copyright (c) 2024 Khokhlov AL, Yaichkov II, Shetnev AA, Panova VA, Efimova YA, Ivanovskiy SA, Korsakov MK, Vol’khin NN, Petukhov SS

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