Design, synthesis and anticonvulsant properties of new N-Mannich bases derived from 3-phenylpyrrolidine-2,5-diones

Kamiński, Krzysztof; Obniska, Jolanta; Chlebek, Iwona; Wiklik, Beata; Rzepka, Sabina

doi:10.1016/j.bmc.2013.07.029

Cited by 52 publications

(22 citation statements)

References 25 publications

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“…Moreover, a few candidates presented activity not only 0.5 h after administration, but also after 4 or 5 h, which is indicative of quick onset and long duration of anticonvulsant activity. Mannich bases 244 of 3-arylsuccinimides derived from other secondary aliphatic amines, such as morpholine, 4benzylpiperidine, 4-cyclohexylpiperazine, were generally effective in both screens [381,382]. Despite the large number of compounds evaluated in these studies, no consistent SARs could be established.…”

Section: Anticonvulsant Activitymentioning

confidence: 90%

“…Based on the significant number of candidates that have been synthesized, aminomethylated derivatives 244 of 3phenylsuccinimides ( Fig. 44) [382], generally showed protection in MES screen, but some of them were also effective in scPTZ screen. Moreover, a few candidates presented activity not only 0.5 h after administration, but also after 4 or 5 h, which is indicative of quick onset and long duration of anticonvulsant activity.…”

Section: Anticonvulsant Activitymentioning

confidence: 99%

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Mannich bases in medicinal chemistry and drug design

Roman¹

2015

European Journal of Medicinal Chemistry

274

110

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The biological activity of Mannich bases, a structurally heterogeneous class of chemical compounds that are generated from various substrates through the introduction of an aminomethyl function by means of the Mannich reaction, is surveyed, with emphasis on the relationship between structure and biological activity. The review covers extensively the literature reports that have disclosed Mannich bases as anticancer and cytotoxic agents, or compounds with potential antibacterial and antifungal activity in the last decade. The most relevant studies on the activity of Mannich bases as antimycobacterial agents, antimalarials, or antiviral candidates have been included as well. The review contains also a thorough coverage of anticonvulsant, anti-inflammatory, analgesic and antioxidant activities of Mannich bases. In addition, several minor biological activities of Mannich bases, such as their ability to regulate blood pressure or inhibit platelet aggregation, their antiparasitic and anti-ulcer effects, as well as their use as agents for the treatment of mental disorders have been presented. The review gives in the end a brief overview of the potential of Mannich bases as inhibitors of various enzymes or ligands for several receptors.

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Section: Anticonvulsant Activitymentioning

confidence: 90%

Section: Anticonvulsant Activitymentioning

confidence: 99%

Mannich bases in medicinal chemistry and drug design

Roman¹

2015

European Journal of Medicinal Chemistry

274

110

View full text Add to dashboard Cite

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“…In this series, pyrrolidine-2,5-dione ring is linked by two or three methylene carbon linkers with morpholine or 4-arylpiperazine fragment, which contains electron withdrawing fluorine and chlorine atoms or trifluoromethyl group. These 4-arylpiperazine fragments with electron withdrawing atoms or groups were chosen on the basis of structures of the most active pyrrolidine-2,5-dione derivatives described previously [13][14][15]. Moreover, analogues of the aforementioned compounds, in which the methylene carbon linker was replaced with an acetamide fragment, were designed.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Anticonvulsant and Antinociceptive Activity of New Hybrid Compounds: Derivatives of 3-(3-Methylthiophen-2-yl)-pyrrolidine-2,5-dione

Góra

Czopek

Rapacz

et al. 2020

IJMS

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The present study aimed to design and synthesize a new series of hybrid compounds with pyrrolidine-2,5-dione and thiophene rings in the structure as potential anticonvulsant and antinociceptive agents. For this purpose, we obtained a series of new compounds and evaluated their anticonvulsant activity in animal models of epilepsy (maximal electroshock (MES), psychomotor (6 Hz), and subcutaneous pentylenetetrazole (scPTZ) seizure tests). To determine the mechanism of action of the most active anticonvulsant compounds (3, 4, 6, 9), their influence on the voltage-gated sodium and calcium channels as well as GABA transporter (GAT) was assessed. The most promising compound 3-(3-methylthiophen-2-yl)-1-(3-morpholinopropyl)pyrrolidine-2,5-dione hydrochloride (4) showed higher ED50 value than those of the reference drugs: valproic acid (VPA) and ethosuximide (ETX) (62.14 mg/kg vs. 252.7 mg/kg (VPA) in the MES test, and 75.59 mg/kg vs. 130.6 mg/kg (VPA) and 221.7 mg/kg (ETX) in the 6 Hz test, respectively). Moreover, in vitro studies of compound 4 showed moderate but balanced inhibition of the neuronal voltage-sensitive sodium (site 2) and L-type calcium channels. Additionally, the antinociceptive activity of the most active compounds (3, 4, 6, 9) was also evaluated in the hot plate test and writhing tests, and their hepatotoxic properties in HepG2 cells were also investigated. To determine the possible mechanism of the analgesic effect of compounds 3, 6, and 9, the affinity for the TRPV1 receptor was investigated.

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“…These molecules were more potent and also less neuron-toxicity than that of phenytoin which was used as reference antiepileptic drug. Although Kaminski et al, had reported several series pyrrolidine-2,5-diones (Table 7) used for anticonvulsant activity, none exhibited better than compound 153 [128][129][130][131][132]. Table 7.…”

Section: The Pyrrolidine-25-dione Functional Groupmentioning

confidence: 99%

Current Research on Antiepileptic Compounds

2015

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Epilepsy affects about 1% of the world's population. Due to the fact all antiepileptic drugs (AEDs) have some undesirable side effects and about 30% of epileptic patients are not seizure-free with the existing AEDs, there is still an urgent need for the development of more effective and safer AEDs. Based on our research work on antiepileptic compounds and other references in recent years, this review covers the reported work on antiepileptic compounds which are classified according to their structures. This review summarized 244 significant anticonvulsant compounds which are classified by functional groups according to the animal model data, although there are some limitations in the data. This review highlights the properties of new compounds endowed with promising antiepileptic properties, which may be proven to be more effective and selective, and possibly free of unwanted side effects. The reviewed compounds represent an interesting possibility to overcome refractory seizures and to reduce the percentage of patients with a poor response to drug therapy.

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Design, synthesis and anticonvulsant properties of new N-Mannich bases derived from 3-phenylpyrrolidine-2,5-diones

Cited by 52 publications

References 25 publications

Mannich bases in medicinal chemistry and drug design

Mannich bases in medicinal chemistry and drug design

Synthesis, Anticonvulsant and Antinociceptive Activity of New Hybrid Compounds: Derivatives of 3-(3-Methylthiophen-2-yl)-pyrrolidine-2,5-dione

Current Research on Antiepileptic Compounds

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