Jump to main content
US EPA
United States Environmental Protection Agency
Search
Search
Main menu
Environmental Topics
Laws & Regulations
About EPA
Health & Environmental Research Online (HERO)
Contact Us
Print
Feedback
Export to File
Search:
This record has one attached file:
Add More Files
Attach File(s):
Display Name for File*:
Save
Citation
Tags
HERO ID
2453304
Reference Type
Journal Article
Title
Design, synthesis and anticonvulsant properties of new N-Mannich bases derived from 3-phenylpyrrolidine-2,5-diones
Author(s)
Kaminski, K; Obniska, J; Chlebek, I; Wiklik, B; Rzepka, S
Year
2013
Is Peer Reviewed?
Yes
Journal
Bioorganic & Medicinal Chemistry
ISSN:
0968-0896
EISSN:
1464-3391
Volume
21
Issue
21
Page Numbers
6821-6830
Language
English
PMID
23993970
DOI
10.1016/j.bmc.2013.07.029
Web of Science Id
WOS:000325164500060
URL
http://dx.doi.org/10.1016/j.bmc.2013.07.029
Exit
Abstract
The synthesis and anticonvulsant properties of new N-Mannich bases of 3-phenyl- (9a-d), 3-(2-chlorophenyl)- (10a-d), 3-(3-chlorophenyl)- (11a-d) and 3-(4-chlorophenyl)-pyrrolidine-2,5-diones (12a-d) were described. The key synthetic strategies involve the formation of 3-substituted pyrrolidine-2,5-diones (5-8), and then aminoalkylation reaction (Mannich-type) with formaldehyde and corresponding secondary amines, which let to obtain the final compounds 9a-d, 10a-d, 11a-d and 12a-d in good yields. Initial anticonvulsant screening was performed in mice (ip) using the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizures tests. The most effective compounds in mice were tested after oral administration in rats. The acute neurological toxicity was determined applying the minimal motor impairment rotarod test. The in vivo results revealed that numerous compounds were effective especially in the MES test (model of human tonic-clonic seizures). The most active in the MES seizures in rats was 1-[(4-benzyl-1-piperidyl) methyl]-3-(2-chlorophenyl) pyrrolidine-2,5-dione (10c) which showed ED50 value of 37.64 mg/kg. It should be stressed that this molecule along with 9a, 9d and 10d showed protection in the psychomotor seizure test (6-Hz), which is known as an animal model of therapy-resistant epilepsy. Furthermore compounds 9a, 9d and 10d were also tested in the pilocarpine-induced status prevention (PISP) test to assess their potential effectiveness in status epilepticus. For the most promising molecule 9d an influence on human CYP3A4 isoform of P-450 cytochrome was studied in vitro. (C) 2013 Elsevier Ltd. All rights reserved.
Keywords
N-Mannich bases; 3-Phenylpyrrolidine-2,5-diones; Succinimides; Anticonvulsant activity; In vivo studies; In vitro studies; Epilepsy
Tags
IRIS
•
Formaldehyde [archived]
2014 LitSearch
Nervous system effects
WOS
Search Update
Retroactive RIS import
2014
HERO_Formaldehyde_Nervoussystemeffects_2014SearchUpdate_pid_31_uid_5738
HERO_Formaldehyde_Nervoussystemeffects_SearchUpdate_pid_31_uid_5738Screening091214
Home
Learn about HERO
Using HERO
Search HERO
Projects in HERO
Risk Assessment
Transparency & Integrity