Nikolina Sibinčić, Stanislav Kalinin, Vladimir Sharoyko, Julia Efimova, Olga A Gasilina, Mikhail Korsakov, Maxim Gureev, Mikhail Krasavin
{"title":"一系列三氟甲基异恶唑基和三氟甲基吡唑基取代(杂)芳族磺酰胺碳酸酐酶抑制剂:合成和进一步体内研究的便捷优先排序工作流程","authors":"Nikolina Sibinčić, Stanislav Kalinin, Vladimir Sharoyko, Julia Efimova, Olga A Gasilina, Mikhail Korsakov, Maxim Gureev, Mikhail Krasavin","doi":"10.2174/1573406418666220831112049","DOIUrl":null,"url":null,"abstract":"<p><strong>Aims: </strong>To synthesize novel sulfonamide inhibitors of carbonic anhydrase and develop in vitro prioritization workflow to select compounds for in vivo evaluation.</p><p><strong>Background: </strong>Carbonic anhydrase (CA) inhibitors gain significant attention in the context of drug discovery research for glaucoma, hypoxic malignancies, and bacterial infections. In previous works, we have successfully used direct sulfochlorination approach to develop diverse heterocyclic primary sulfonamides with remarkable activity and selectivity against therapeutically relevant CA isoforms.</p><p><strong>Objective: </strong>Synthesis and investigation of the CA inhibitory properties of novel trifluoromethylisoxazolyl- and trifluoromethylpyrazolyl-substituted (hetero)aromatic sulfonamides.</p><p><strong>Methods: </strong>Thirteen trifluoromethylisoxazolyl- and thirteen trifluoromethylpyrazolyl-substituted (hetero) aromatic sulfonamides were synthesized by direct sulfochlorination of hydroxyisoxazolines and pyrazoles followed by reaction with ammonia. The compound structures were confirmed by <sup>1</sup>H and <sup>13</sup>C NMR as well as element analysis. The obtained compounds were evaluated, using the CA esterase activity assay, for their potential to block the catalytic activity of bovine CA (bCA).</p><p><strong>Results: </strong>Eight most potent compounds selected based on the esterase activity assay data were tested for direct affinity to the enzyme using the thermal shift assay (TSA). These compounds displayed Kd values (measured by TSA) in the double-digit nanomolar range, thus showing comparable activity to the reference drug acetazolamide.</p><p><strong>Conclusion: </strong>Coupling the bCA esterase activity assay with thermal shift assay represents a streamlined and economical strategy for the prioritization of sulfonamide CA inhibitors for subsequent evaluation in vivo.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":1.9000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"1","resultStr":"{\"title\":\"A Series of Trifluoromethylisoxazolyl- and Trifluoromethylpyrazolyl- Substituted (Hetero)aromatic Sulfonamide Carbonic Anhydrase Inhibitors: Synthesis, and Convenient Prioritization Workflow for Further <i>In Vivo</i> Studies.\",\"authors\":\"Nikolina Sibinčić, Stanislav Kalinin, Vladimir Sharoyko, Julia Efimova, Olga A Gasilina, Mikhail Korsakov, Maxim Gureev, Mikhail Krasavin\",\"doi\":\"10.2174/1573406418666220831112049\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Aims: </strong>To synthesize novel sulfonamide inhibitors of carbonic anhydrase and develop in vitro prioritization workflow to select compounds for in vivo evaluation.</p><p><strong>Background: </strong>Carbonic anhydrase (CA) inhibitors gain significant attention in the context of drug discovery research for glaucoma, hypoxic malignancies, and bacterial infections. In previous works, we have successfully used direct sulfochlorination approach to develop diverse heterocyclic primary sulfonamides with remarkable activity and selectivity against therapeutically relevant CA isoforms.</p><p><strong>Objective: </strong>Synthesis and investigation of the CA inhibitory properties of novel trifluoromethylisoxazolyl- and trifluoromethylpyrazolyl-substituted (hetero)aromatic sulfonamides.</p><p><strong>Methods: </strong>Thirteen trifluoromethylisoxazolyl- and thirteen trifluoromethylpyrazolyl-substituted (hetero) aromatic sulfonamides were synthesized by direct sulfochlorination of hydroxyisoxazolines and pyrazoles followed by reaction with ammonia. The compound structures were confirmed by <sup>1</sup>H and <sup>13</sup>C NMR as well as element analysis. The obtained compounds were evaluated, using the CA esterase activity assay, for their potential to block the catalytic activity of bovine CA (bCA).</p><p><strong>Results: </strong>Eight most potent compounds selected based on the esterase activity assay data were tested for direct affinity to the enzyme using the thermal shift assay (TSA). These compounds displayed Kd values (measured by TSA) in the double-digit nanomolar range, thus showing comparable activity to the reference drug acetazolamide.</p><p><strong>Conclusion: </strong>Coupling the bCA esterase activity assay with thermal shift assay represents a streamlined and economical strategy for the prioritization of sulfonamide CA inhibitors for subsequent evaluation in vivo.</p>\",\"PeriodicalId\":18382,\"journal\":{\"name\":\"Medicinal Chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.9000,\"publicationDate\":\"2023-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.2174/1573406418666220831112049\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2174/1573406418666220831112049","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
A Series of Trifluoromethylisoxazolyl- and Trifluoromethylpyrazolyl- Substituted (Hetero)aromatic Sulfonamide Carbonic Anhydrase Inhibitors: Synthesis, and Convenient Prioritization Workflow for Further In Vivo Studies.
Aims: To synthesize novel sulfonamide inhibitors of carbonic anhydrase and develop in vitro prioritization workflow to select compounds for in vivo evaluation.
Background: Carbonic anhydrase (CA) inhibitors gain significant attention in the context of drug discovery research for glaucoma, hypoxic malignancies, and bacterial infections. In previous works, we have successfully used direct sulfochlorination approach to develop diverse heterocyclic primary sulfonamides with remarkable activity and selectivity against therapeutically relevant CA isoforms.
Objective: Synthesis and investigation of the CA inhibitory properties of novel trifluoromethylisoxazolyl- and trifluoromethylpyrazolyl-substituted (hetero)aromatic sulfonamides.
Methods: Thirteen trifluoromethylisoxazolyl- and thirteen trifluoromethylpyrazolyl-substituted (hetero) aromatic sulfonamides were synthesized by direct sulfochlorination of hydroxyisoxazolines and pyrazoles followed by reaction with ammonia. The compound structures were confirmed by 1H and 13C NMR as well as element analysis. The obtained compounds were evaluated, using the CA esterase activity assay, for their potential to block the catalytic activity of bovine CA (bCA).
Results: Eight most potent compounds selected based on the esterase activity assay data were tested for direct affinity to the enzyme using the thermal shift assay (TSA). These compounds displayed Kd values (measured by TSA) in the double-digit nanomolar range, thus showing comparable activity to the reference drug acetazolamide.
Conclusion: Coupling the bCA esterase activity assay with thermal shift assay represents a streamlined and economical strategy for the prioritization of sulfonamide CA inhibitors for subsequent evaluation in vivo.
期刊介绍:
Aims & Scope
Medicinal Chemistry a peer-reviewed journal, aims to cover all the latest outstanding developments in medicinal chemistry and rational drug design. The journal publishes original research, mini-review articles and guest edited thematic issues covering recent research and developments in the field. Articles are published rapidly by taking full advantage of Internet technology for both the submission and peer review of manuscripts. Medicinal Chemistry is an essential journal for all involved in drug design and discovery.