1,2,4-Triazole-based anticonvulsant agents with additional ROS scavenging activity are effective in a model of pharmacoresistant epilepsy.

Tytuł:: 1,2,4-Triazole-based anticonvulsant agents with additional ROS scavenging activity are effective in a model of pharmacoresistant epilepsy.
Autorzy:: Kaproń B; Department of Clinical Genetics, I Faculty of Medicine with Dentistry Division, Medical University of Lublin, Lublin, Poland.
Czarnomysy R; Department of Synthesis and Technology of Drugs, Faculty of Pharmacy, Medical University of Białystok, Bialystok, Poland.
Wysokiński M; Department of Basic Nursing and Medical Teaching, Chair of Development in Nursing, Faculty of Health Sciences, Medical University of Lublin, Lublin, Poland.
Andrys R; Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic.
Musilek K; Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic.
Angeli A; Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Firenze, Italy.
Supuran CT; Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Firenze, Italy.
Plech T; Department of Pharmacology, Faculty of Health Sciences, Medical University of Lublin, Lublin, Poland.
Źródło:: Journal of enzyme inhibition and medicinal chemistry [J Enzyme Inhib Med Chem] 2020 Dec; Vol. 35 (1), pp. 993-1002.
Typ publikacji:: Journal Article
Język:: English
Imprint Name(s):: Original Publication: Basingstoke, UK : Taylor & Francis, c2002-
MeSH Terms:: Anticonvulsants/*pharmacology
Antioxidants/*pharmacology
Carbonic Anhydrase Inhibitors/*pharmacology
Cholinesterase Inhibitors/*pharmacology
Epilepsy/*drug therapy
Triazoles/*pharmacology
Acetylcholinesterase/metabolism ; Animals ; Anticonvulsants/chemical synthesis ; Anticonvulsants/chemistry ; Antioxidants/chemical synthesis ; Antioxidants/chemistry ; Biphenyl Compounds/antagonists & inhibitors ; Butyrylcholinesterase/metabolism ; Carbonic Anhydrase Inhibitors/chemical synthesis ; Carbonic Anhydrase Inhibitors/chemistry ; Carbonic Anhydrases/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Cholinesterase Inhibitors/chemical synthesis ; Cholinesterase Inhibitors/chemistry ; Dose-Response Relationship, Drug ; Epilepsy/metabolism ; Humans ; Mice ; Models, Molecular ; Molecular Structure ; Oxidative Stress/drug effects ; Picrates/antagonists & inhibitors ; Reactive Oxygen Species/metabolism ; Structure-Activity Relationship ; Triazoles/chemical synthesis ; Triazoles/chemistry
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Contributed Indexing:: Keywords: 6 Hz psychomotor seizures; carbonic anhydrases; cholinesterase inhibitors; mitochondrial potential; total ROS activity
Substance Nomenclature:: 0 (Anticonvulsants)
0 (Antioxidants)
0 (Biphenyl Compounds)
0 (Carbonic Anhydrase Inhibitors)
0 (Cholinesterase Inhibitors)
0 (Picrates)
0 (Reactive Oxygen Species)
0 (Triazoles)
288-88-0 (1,2,4-triazole)
DFD3H4VGDH (1,1-diphenyl-2-picrylhydrazyl)
EC 3.1.1.7 (Acetylcholinesterase)
EC 3.1.1.8 (Butyrylcholinesterase)
EC 4.2.1.1 (Carbonic Anhydrases)
Entry Date(s):: Date Created: 20200408 Date Completed: 20201221 Latest Revision: 20240330
Update Code:: 20240330
PubMed Central ID:: PMC7178883
DOI:: 10.1080/14756366.2020.1748026
PMID:: 32253957
: Czasopismo naukowe

Pełny tekst

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.

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