1,2,4-Triazole-based anticonvulsant agents with additional ROS scavenging activity are effective in a model of pharmacoresistant epilepsy
There are numerous studies supporting the contribution of oxidative stress to the pathogenesis of epilepsy. Prolonged oxidative stress is associated with the overexpression of ATP-binding cassette transporters, which results in antiepileptic drugs resistance. During our studies, three 1,2,4-triazole...
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| Veröffentlicht in: | Journal of enzyme inhibition and medicinal chemistry 2020-01, Vol.35 (1), p.993-1002 |
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| creator | Kaproń, Barbara Czarnomysy, Robert Wysokiński, Mariusz Andrys, Rudolf Musilek, Kamil Angeli, Andrea Supuran, Claudiu T. Plech, Tomasz |
| description | There are numerous studies supporting the contribution of oxidative stress to the pathogenesis of epilepsy. Prolonged oxidative stress is associated with the overexpression of ATP-binding cassette transporters, which results in antiepileptic drugs resistance. During our studies, three 1,2,4-triazole-3-thione derivatives were evaluated for the antioxidant activity and anticonvulsant effect in the 6 Hz model of pharmacoresistant epilepsy. The investigated compounds exhibited 2-3 times more potent anticonvulsant activity than valproic acid in 6 Hz test in mice, which is well-established preclinical model of pharmacoresistant epilepsy. The antioxidant/ROS scavenging activity was confirmed in both single-electron transfer-based methods (DPPH and CUPRAC) and during flow cytometric analysis of total ROS activity in U-87 MG cells. Based on the enzymatic studies on human carbonic anhydrases (CAs), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), one can assume that the herein investigated drug candidates will not impair the cognitive processes mediated by CAs and will have minimal off-target cholinergic effects. |
| doi_str_mv | 10.1080/14756366.2020.1748026 |
| format | Article |
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Prolonged oxidative stress is associated with the overexpression of ATP-binding cassette transporters, which results in antiepileptic drugs resistance. During our studies, three 1,2,4-triazole-3-thione derivatives were evaluated for the antioxidant activity and anticonvulsant effect in the 6 Hz model of pharmacoresistant epilepsy. The investigated compounds exhibited 2-3 times more potent anticonvulsant activity than valproic acid in 6 Hz test in mice, which is well-established preclinical model of pharmacoresistant epilepsy. The antioxidant/ROS scavenging activity was confirmed in both single-electron transfer-based methods (DPPH and CUPRAC) and during flow cytometric analysis of total ROS activity in U-87 MG cells. Based on the enzymatic studies on human carbonic anhydrases (CAs), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), one can assume that the herein investigated drug candidates will not impair the cognitive processes mediated by CAs and will have minimal off-target cholinergic effects.</description><identifier>ISSN: 1475-6366</identifier><identifier>EISSN: 1475-6374</identifier><identifier>DOI: 10.1080/14756366.2020.1748026</identifier><identifier>PMID: 32253957</identifier><language>eng</language><publisher>England: Taylor & Francis</publisher><subject>6 Hz psychomotor seizures ; Acetylcholinesterase ; Acetylcholinesterase - metabolism ; Animals ; Anticonvulsants ; Anticonvulsants - chemical synthesis ; Anticonvulsants - chemistry ; Anticonvulsants - pharmacology ; Antiepileptic agents ; Antioxidants ; Antioxidants - chemical synthesis ; Antioxidants - chemistry ; Antioxidants - pharmacology ; ATP-binding protein ; Biphenyl Compounds - antagonists & inhibitors ; Butyrylcholinesterase - metabolism ; Carbonic Anhydrase Inhibitors - chemical synthesis ; Carbonic Anhydrase Inhibitors - chemistry ; Carbonic Anhydrase Inhibitors - pharmacology ; Carbonic anhydrases ; Carbonic Anhydrases - metabolism ; Cell Line, Tumor ; Cell Survival - drug effects ; cholinesterase inhibitors ; Cholinesterase Inhibitors - chemical synthesis ; Cholinesterase Inhibitors - chemistry ; Cholinesterase Inhibitors - pharmacology ; Cognitive ability ; Dose-Response Relationship, Drug ; Drug development ; Drug resistance ; Electron transfer ; Epilepsy ; Epilepsy - drug therapy ; Epilepsy - metabolism ; Flow cytometry ; Humans ; Mice ; mitochondrial potential ; Models, Molecular ; Molecular Structure ; Oxidative stress ; Oxidative Stress - drug effects ; Picrates - antagonists & inhibitors ; Reactive Oxygen Species - metabolism ; Research Paper ; Structure-Activity Relationship ; total ROS activity ; Triazoles - chemical synthesis ; Triazoles - chemistry ; Triazoles - pharmacology ; Valproic acid</subject><ispartof>Journal of enzyme inhibition and medicinal chemistry, 2020-01, Vol.35 (1), p.993-1002</ispartof><rights>2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. 2020</rights><rights>2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This work is licensed under the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. 2020 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c562t-229aca0a89323a3e5dd0219ddbdf65bb9331ef96bb1a123deb1486c1fb8fc2df3</citedby><cites>FETCH-LOGICAL-c562t-229aca0a89323a3e5dd0219ddbdf65bb9331ef96bb1a123deb1486c1fb8fc2df3</cites><orcidid>0000-0002-1470-7192 ; 0000-0002-8162-8435 ; 0000-0003-4262-0323 ; 0000-0002-7520-3238</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178883/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178883/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,27502,27924,27925,53791,53793,59143,59144</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32253957$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kaproń, Barbara</creatorcontrib><creatorcontrib>Czarnomysy, Robert</creatorcontrib><creatorcontrib>Wysokiński, Mariusz</creatorcontrib><creatorcontrib>Andrys, Rudolf</creatorcontrib><creatorcontrib>Musilek, Kamil</creatorcontrib><creatorcontrib>Angeli, Andrea</creatorcontrib><creatorcontrib>Supuran, Claudiu T.</creatorcontrib><creatorcontrib>Plech, Tomasz</creatorcontrib><title>1,2,4-Triazole-based anticonvulsant agents with additional ROS scavenging activity are effective in a model of pharmacoresistant epilepsy</title><title>Journal of enzyme inhibition and medicinal chemistry</title><addtitle>J Enzyme Inhib Med Chem</addtitle><description>There are numerous studies supporting the contribution of oxidative stress to the pathogenesis of epilepsy. Prolonged oxidative stress is associated with the overexpression of ATP-binding cassette transporters, which results in antiepileptic drugs resistance. During our studies, three 1,2,4-triazole-3-thione derivatives were evaluated for the antioxidant activity and anticonvulsant effect in the 6 Hz model of pharmacoresistant epilepsy. The investigated compounds exhibited 2-3 times more potent anticonvulsant activity than valproic acid in 6 Hz test in mice, which is well-established preclinical model of pharmacoresistant epilepsy. The antioxidant/ROS scavenging activity was confirmed in both single-electron transfer-based methods (DPPH and CUPRAC) and during flow cytometric analysis of total ROS activity in U-87 MG cells. Based on the enzymatic studies on human carbonic anhydrases (CAs), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), one can assume that the herein investigated drug candidates will not impair the cognitive processes mediated by CAs and will have minimal off-target cholinergic effects.</description><subject>6 Hz psychomotor seizures</subject><subject>Acetylcholinesterase</subject><subject>Acetylcholinesterase - metabolism</subject><subject>Animals</subject><subject>Anticonvulsants</subject><subject>Anticonvulsants - chemical synthesis</subject><subject>Anticonvulsants - chemistry</subject><subject>Anticonvulsants - pharmacology</subject><subject>Antiepileptic agents</subject><subject>Antioxidants</subject><subject>Antioxidants - chemical synthesis</subject><subject>Antioxidants - chemistry</subject><subject>Antioxidants - pharmacology</subject><subject>ATP-binding protein</subject><subject>Biphenyl Compounds - antagonists & inhibitors</subject><subject>Butyrylcholinesterase - metabolism</subject><subject>Carbonic Anhydrase Inhibitors - chemical synthesis</subject><subject>Carbonic Anhydrase Inhibitors - chemistry</subject><subject>Carbonic Anhydrase Inhibitors - pharmacology</subject><subject>Carbonic anhydrases</subject><subject>Carbonic Anhydrases - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival - drug effects</subject><subject>cholinesterase inhibitors</subject><subject>Cholinesterase Inhibitors - chemical synthesis</subject><subject>Cholinesterase Inhibitors - chemistry</subject><subject>Cholinesterase Inhibitors - pharmacology</subject><subject>Cognitive ability</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug development</subject><subject>Drug resistance</subject><subject>Electron transfer</subject><subject>Epilepsy</subject><subject>Epilepsy - drug therapy</subject><subject>Epilepsy - metabolism</subject><subject>Flow cytometry</subject><subject>Humans</subject><subject>Mice</subject><subject>mitochondrial potential</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Oxidative stress</subject><subject>Oxidative Stress - drug effects</subject><subject>Picrates - antagonists & inhibitors</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Research Paper</subject><subject>Structure-Activity Relationship</subject><subject>total ROS activity</subject><subject>Triazoles - chemical synthesis</subject><subject>Triazoles - chemistry</subject><subject>Triazoles - pharmacology</subject><subject>Valproic acid</subject><issn>1475-6366</issn><issn>1475-6374</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>0YH</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>DOA</sourceid><recordid>eNp9Uk1v1DAQjRCIlsJPAFni2hR_JE5yQaCKQqVKlaCcrYk9znrljRc7u9XyD_jXddjtil44eTx-855n5hXFW0YvGG3pB1Y1tRRSXnDKc6qpWsrls-J0zpdSNNXzYyzlSfEqpSWlnHFWvSxOBOe16OrmtPjDzvl5Vd5FB7-Dx7KHhIbAODkdxu3GpxwSGHCcErl304KAMW5yYQRPvt_-IEnDFsfBjQMBPbmtm3YEIhK0Fuc7EjcSIKtg0JNgyXoBcQU6REwuTTM5rp3Hddq9Ll5Y8AnfHM6z4ufVl7vLb-XN7dfry883pa4ln0rOO9BAoe0EFyCwNia31RnTGyvrvu-EYGg72fcMGBcGe1a1UjPbt1ZzY8VZcb3nNQGWah3dCuJOBXDqbyLEQUHM7XtUVa8tE5y1FbQVZomu1g1veJ62oRZ55vq451pv-hUanccUwT8hffoyuoUawlY1rGnbVmSC9weCGH5tME1qGTYxDzcpXklRN7STXUbVe5SOIaWI9qjAqJrdoB7doGY3qIMbct27f793rHpcfwZ82gPcaEPey32I3qgJdj5EG2HULinxf40H167HnQ</recordid><startdate>20200101</startdate><enddate>20200101</enddate><creator>Kaproń, Barbara</creator><creator>Czarnomysy, Robert</creator><creator>Wysokiński, Mariusz</creator><creator>Andrys, Rudolf</creator><creator>Musilek, Kamil</creator><creator>Angeli, Andrea</creator><creator>Supuran, Claudiu T.</creator><creator>Plech, Tomasz</creator><general>Taylor & Francis</general><general>Taylor & Francis Ltd</general><general>Taylor & Francis Group</general><scope>0YH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-1470-7192</orcidid><orcidid>https://orcid.org/0000-0002-8162-8435</orcidid><orcidid>https://orcid.org/0000-0003-4262-0323</orcidid><orcidid>https://orcid.org/0000-0002-7520-3238</orcidid></search><sort><creationdate>20200101</creationdate><title>1,2,4-Triazole-based anticonvulsant agents with additional ROS scavenging activity are effective in a model of pharmacoresistant epilepsy</title><author>Kaproń, Barbara ; Czarnomysy, Robert ; Wysokiński, Mariusz ; Andrys, Rudolf ; Musilek, Kamil ; Angeli, Andrea ; Supuran, Claudiu T. ; Plech, Tomasz</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c562t-229aca0a89323a3e5dd0219ddbdf65bb9331ef96bb1a123deb1486c1fb8fc2df3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>6 Hz psychomotor seizures</topic><topic>Acetylcholinesterase</topic><topic>Acetylcholinesterase - metabolism</topic><topic>Animals</topic><topic>Anticonvulsants</topic><topic>Anticonvulsants - chemical synthesis</topic><topic>Anticonvulsants - chemistry</topic><topic>Anticonvulsants - pharmacology</topic><topic>Antiepileptic agents</topic><topic>Antioxidants</topic><topic>Antioxidants - chemical synthesis</topic><topic>Antioxidants - chemistry</topic><topic>Antioxidants - pharmacology</topic><topic>ATP-binding protein</topic><topic>Biphenyl Compounds - antagonists & inhibitors</topic><topic>Butyrylcholinesterase - metabolism</topic><topic>Carbonic Anhydrase Inhibitors - chemical synthesis</topic><topic>Carbonic Anhydrase Inhibitors - chemistry</topic><topic>Carbonic Anhydrase Inhibitors - pharmacology</topic><topic>Carbonic anhydrases</topic><topic>Carbonic Anhydrases - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival - drug effects</topic><topic>cholinesterase inhibitors</topic><topic>Cholinesterase Inhibitors - chemical synthesis</topic><topic>Cholinesterase Inhibitors - chemistry</topic><topic>Cholinesterase Inhibitors - pharmacology</topic><topic>Cognitive ability</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug development</topic><topic>Drug resistance</topic><topic>Electron transfer</topic><topic>Epilepsy</topic><topic>Epilepsy - drug therapy</topic><topic>Epilepsy - metabolism</topic><topic>Flow cytometry</topic><topic>Humans</topic><topic>Mice</topic><topic>mitochondrial potential</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Oxidative stress</topic><topic>Oxidative Stress - drug effects</topic><topic>Picrates - antagonists & inhibitors</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Research Paper</topic><topic>Structure-Activity Relationship</topic><topic>total ROS activity</topic><topic>Triazoles - chemical synthesis</topic><topic>Triazoles - chemistry</topic><topic>Triazoles - pharmacology</topic><topic>Valproic acid</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kaproń, Barbara</creatorcontrib><creatorcontrib>Czarnomysy, Robert</creatorcontrib><creatorcontrib>Wysokiński, Mariusz</creatorcontrib><creatorcontrib>Andrys, Rudolf</creatorcontrib><creatorcontrib>Musilek, Kamil</creatorcontrib><creatorcontrib>Angeli, Andrea</creatorcontrib><creatorcontrib>Supuran, Claudiu T.</creatorcontrib><creatorcontrib>Plech, Tomasz</creatorcontrib><collection>Access via Taylor & Francis (Open Access Collection)</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Journal of enzyme inhibition and medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kaproń, Barbara</au><au>Czarnomysy, Robert</au><au>Wysokiński, Mariusz</au><au>Andrys, Rudolf</au><au>Musilek, Kamil</au><au>Angeli, Andrea</au><au>Supuran, Claudiu T.</au><au>Plech, Tomasz</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>1,2,4-Triazole-based anticonvulsant agents with additional ROS scavenging activity are effective in a model of pharmacoresistant epilepsy</atitle><jtitle>Journal of enzyme inhibition and medicinal chemistry</jtitle><addtitle>J Enzyme Inhib Med Chem</addtitle><date>2020-01-01</date><risdate>2020</risdate><volume>35</volume><issue>1</issue><spage>993</spage><epage>1002</epage><pages>993-1002</pages><issn>1475-6366</issn><eissn>1475-6374</eissn><abstract>There are numerous studies supporting the contribution of oxidative stress to the pathogenesis of epilepsy. Prolonged oxidative stress is associated with the overexpression of ATP-binding cassette transporters, which results in antiepileptic drugs resistance. During our studies, three 1,2,4-triazole-3-thione derivatives were evaluated for the antioxidant activity and anticonvulsant effect in the 6 Hz model of pharmacoresistant epilepsy. The investigated compounds exhibited 2-3 times more potent anticonvulsant activity than valproic acid in 6 Hz test in mice, which is well-established preclinical model of pharmacoresistant epilepsy. The antioxidant/ROS scavenging activity was confirmed in both single-electron transfer-based methods (DPPH and CUPRAC) and during flow cytometric analysis of total ROS activity in U-87 MG cells. Based on the enzymatic studies on human carbonic anhydrases (CAs), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), one can assume that the herein investigated drug candidates will not impair the cognitive processes mediated by CAs and will have minimal off-target cholinergic effects.</abstract><cop>England</cop><pub>Taylor & Francis</pub><pmid>32253957</pmid><doi>10.1080/14756366.2020.1748026</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-1470-7192</orcidid><orcidid>https://orcid.org/0000-0002-8162-8435</orcidid><orcidid>https://orcid.org/0000-0003-4262-0323</orcidid><orcidid>https://orcid.org/0000-0002-7520-3238</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 6 Hz psychomotor seizures Acetylcholinesterase Acetylcholinesterase - metabolism Animals Anticonvulsants Anticonvulsants - chemical synthesis Anticonvulsants - chemistry Anticonvulsants - pharmacology Antiepileptic agents Antioxidants Antioxidants - chemical synthesis Antioxidants - chemistry Antioxidants - pharmacology ATP-binding protein Biphenyl Compounds - antagonists & inhibitors Butyrylcholinesterase - metabolism Carbonic Anhydrase Inhibitors - chemical synthesis Carbonic Anhydrase Inhibitors - chemistry Carbonic Anhydrase Inhibitors - pharmacology Carbonic anhydrases Carbonic Anhydrases - metabolism Cell Line, Tumor Cell Survival - drug effects cholinesterase inhibitors Cholinesterase Inhibitors - chemical synthesis Cholinesterase Inhibitors - chemistry Cholinesterase Inhibitors - pharmacology Cognitive ability Dose-Response Relationship, Drug Drug development Drug resistance Electron transfer Epilepsy Epilepsy - drug therapy Epilepsy - metabolism Flow cytometry Humans Mice mitochondrial potential Models, Molecular Molecular Structure Oxidative stress Oxidative Stress - drug effects Picrates - antagonists & inhibitors Reactive Oxygen Species - metabolism Research Paper Structure-Activity Relationship total ROS activity Triazoles - chemical synthesis Triazoles - chemistry Triazoles - pharmacology Valproic acid |
| title | 1,2,4-Triazole-based anticonvulsant agents with additional ROS scavenging activity are effective in a model of pharmacoresistant epilepsy |
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