Premium
Design, Synthesis and Biological Activity of New Amides Derived from 3‐Benzhydryl and 3‐ sec ‐Butyl‐2,5‐dioxo‐pyrrolidin‐1‐yl‐acetic Acid
Author(s) -
Góra Małgorzata,
Czopek Anna,
Rapacz Anna,
Giza Agnieszka,
KoczurkiewiczAdamczyk Paulina,
Pękala Elżbieta,
Obniska Jolanta,
Kamiński Krzysztof
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202001007
Subject(s) - chemistry , anticonvulsant , ed50 , pyrrolidine , analgesic , in vivo , pharmacology , stereochemistry , acetic acid , biological activity , nociception , in vitro , epilepsy , receptor , biochemistry , medicine , microbiology and biotechnology , psychiatry , biology
The aim of this study was to design and synthesize two new series of pyrrolidine‐2,5‐dione‐acetamides with a benzhydryl or sec ‐butyl group at position 3 as potential anticonvulsants. Their anticonvulsant activity was evaluated in standard animal models of epilepsy: the maximal electroshock (MES), the 6 Hz, and the subcutaneous pentylenetetrazole ( sc PTZ) tests. The in vivo studies revealed the most potent anticonvulsant activity for 15 (3‐( sec ‐butyl)‐1‐(2‐(4‐(3‐trifluoromethylphenyl)piperazin‐1‐yl)‐2‐oxoethyl)pyrrolidine‐2,5‐dione), with ED 50 values of 80.38 mg/kg (MES) and 108.80 mg/kg (6 Hz). The plausible mechanism of action was assessed in in vitro binding assays, in which 15 interacted effectively with voltage‐gated sodium (site 2) and L‐type calcium channels at a concentration of 100 μM. Subsequently, the antinociceptive activity of compounds 7 and 15 was observed in the hot plate test of acute pain. Moreover, compounds 7 , 11 and 15 demonstrated an analgesic effect in the formalin test of tonic pain. The hepatotoxic properties of the most effective compounds ( 7 , 11 and 15 ) in HepG2 cells were also investigated.