Development of the 1,2,4-triazole-based anticonvulsant drug candidates acting on the voltage-gated sodium channels. Insights from in-vivo, in-vitro, and in-silico studies

Kaproń, Barbara; Łuszczki, Jarogniew J.; Płazińska, Anita; Siwek, Agata; Karcz, Tadeusz; Gryboś, Anna; Nowak, Gabriel; Makuch-Kocka, Anna; Walczak, Katarzyna; Langner, Ewa; Szalast, Karolina; Marciniak, Sebastian; Paczkowska, Magdalena; Cielecka‐Piontek, Judyta; Cieśla, Łukasz; Plech, Tomasz

doi:10.1016/j.ejps.2018.12.018

Cited by 60 publications

(48 citation statements)

References 28 publications

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“…Therefore, to confirm the antioxidant potency of TP-10, TP-315, and TP-427 in in-vivo conditions, flow cytometric measurements of the total ROS level and mitochondrial potential were performed. Human brain-derived cells (U-87 MG) were exposed to a fixed concentration (10 mg/ml) of the compounds for 24 h. As it has been shown before in studies on TP-315 and TP-427, such a concentration remains non-toxic for human cells (HEK-293, HepG2) and is sufficient to generate the maximal anticonvulsant effect in mice subjected to the MES test 11,12 . As can be seen from Figure 2, there were also no visible changes in the morphology and viability of U-87 MG cells treated and untreated with the investigated 1,2,4-triazole-3-thiones.…”

Section: Discussionmentioning

confidence: 84%

“…Importantly, 4-hexyl-5-substituted-1,2,4-triazole-3-thione derivatives (TP-315, TP-427), apart from their antioxidant activity, were also confirmed to be voltage-gated sodium channel blockers 11,12 . It is suggested by the researchers that compounds combining both antioxidant and sodium channel blocking activities are to be characterised by superior neuroprotective effect as compared to compounds possessing only one of these features 33 .…”

Section: Discussionmentioning

confidence: 99%

“…MES test) and favourable ADME-Tox properties (long-lasting effect, low toxicity, lack of genotoxic properties, etc.) [10][11][12][13][14][15][16] . These compounds exhibited fast onset of action and some of them were able to potentiate the anticonvulsant activity of valproate, which is the most commonly prescribed antiepileptic drug.…”

Section: Introductionmentioning

confidence: 99%

“…These compounds exhibited fast onset of action and some of them were able to potentiate the anticonvulsant activity of valproate, which is the most commonly prescribed antiepileptic drug. The use of patchclamp and radioligand binding techniques allow us to elucidate that voltage-gated sodium channels play crucial role in the anticonvulsant activity of the above-mentioned compounds [10][11][12] . From the 1,2,4-triazole-3-thione derivatives investigated thus far, those with the most favourable properties ( Figure 1) have been selected for further studies in order to examine their ROS scavenging activity and possible protective effect in animal model of pharmacoresistant epilepsy (6 Hz test).…”

Section: Introductionmentioning

confidence: 99%

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

Kaproń

Czarnomysy

Wysokiński

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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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 transferbased 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. ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Kaproń

Czarnomysy

Wysokiński

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…The anticonvulsant activity of the investigated 1,2,4‐triazole‐3‐thione derivatives was evaluated using mice maximal electroshock seizure test. The detailed results of the procedure was published . In the currently presented studies, only ED50 values are quoted.…”

Section: Methodsmentioning

confidence: 99%

Thermodynamic study of new antiepileptic compounds by combining chromatography on the phosphatidylcholine biomimetic stationary phase and differential scanning calorimetry

Flieger

Trębacz

Pizoń

et al. 2019

J of Separation Science

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Liquid chromatography coupled to spectrophotometric detection of new antiepileptic compounds, 1,2,4‐triazole‐3‐thione derivatives, on immobilized artificial membrane phosphatidylcholine is reported. The curves representing the relationship between ln k versus 1/T generated under isocratic conditions by the use of methanol and acetonitrile‐containing eluent systems have been constructed in order to determine the thermodynamic parameters: the enthalpies, entropies and the relative free energies. The hydrocarbon chains of analytes significantly influenced the membrane behavior of the whole molecules. Excellent correlations of the theoretical lipophilicity with the experimental thermodynamic descriptors, have confirmed contribution of the hydrophobic interactions in the retention process. However, presence of sulfur or oxygen as heteroatoms at R1 substituents in the 1,2,4‐triazole ring appears to be responsible for more pronounced selectivity of these compounds on the phosphatidylcholine stationary phase. Molecular dynamics simulations revealed the selective preferences of the phosphatidylcholine with respect to the compounds with either ether of sulfide moieties. Experimental and theoretical set‐ups resulted in corresponding outcomes.

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Design, synthesis, antibacterial evaluation, and computational studies of hybrid oxothiazolidin–1,2,4‐triazole scaffolds

Pathak

Novak

Shukla

et al. 2021

Archiv der Pharmazie

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Bacterial infections are a serious threat to human health due to the development of resistance against the presently used antibiotics. The problem of growing and widespread antibiotic resistance is only getting worse with the shortage of new classes of antibiotics, creating a substantial unmet medical need in the treatment of serious bacterial infections. Therefore, in the present work, we report 18 novel hybrid thiazolidine–1,2,4‐triazole derivatives as DNA gyrase inhibitors. The derivatives were synthesized by multistep organic synthesis and characterized by spectroscopic methods (1H and 13C nuclear magnetic resonance and mass spectroscopy). The derivatives were tested for DNA gyrase inhibition, and the result emphasized that the synthesized derivatives have a tendency to inhibit the function of DNA gyrase. Furthermore, the compounds were also tested for antibacterial activity against three Gram‐positive (Bacillus subtilis [NCIM 2063], Bacillus cereus [NCIM 2156], Staphylococcus aureus [NCIM 2079]) and two Gram‐negative (Escherichia coli [NCIM 2065], Proteus vulgaris [NCIM 2027]) bacteria. The derivatives showed a significant‐to‐moderate antibacterial activity with noticeable antibiofilm efficacy. Quantitative structure–activity relationship (QSAR), ADME (absorption, distribution, metabolism, elimination) calculation, molecular docking, radial distribution function, and 2D fingerprinting were also performed to elucidate fundamental structural fragments essential for their bioactivity. These studies suggest that the derivatives 10b and 10n have lead antibacterial properties with significant DNA gyrase inhibitory efficacy, and they can serve as a starting scaffold for the further development of new broad‐spectrum antibacterial agents.

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Development of the 1,2,4-triazole-based anticonvulsant drug candidates acting on the voltage-gated sodium channels. Insights from in-vivo, in-vitro, and in-silico studies

Cited by 60 publications

References 28 publications

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

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

Thermodynamic study of new antiepileptic compounds by combining chromatography on the phosphatidylcholine biomimetic stationary phase and differential scanning calorimetry

Design, synthesis, antibacterial evaluation, and computational studies of hybrid oxothiazolidin–1,2,4‐triazole scaffolds

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