Design, Synthesis, and Anticonvulsant Activity of New Hybrid Compounds Derived from 2‑(2,5-Dioxopyrrolidin-1-yl)propanamides and 2‑(2,5-Dioxopyrrolidin-1-yl)butanamides

The
library of 27 new 1-(4-phenylpiperazin-1-yl)- or 1-(morpholin-4-yl)-(2,5-dioxopyrrolidin-1-yl)­propanamides
and (2,5-dioxopyrrolidin-1-yl)­butanamides as potential new hybrid
anticonvulsant agents was synthesized. These hybrid molecules join
the chemical fragments of well-known antiepileptic drugs (AEDs) such
as ethosuximide, levetiracetam, and lacosamide. Compounds 5, 10, 11, and 24 displayed
the broad spectra of activity across the preclinical seizure models,
namely, the maximal electroshock (MES) test, the subcutaneous pentylenetetrazole
(scPTZ) test, and the six-hertz (6 Hz) model of pharmacoresistant
limbic seizures. The highest protection was demonstrated by 11 (ED50 MES = 88.4 mg/kg, ED50 scPTZ = 59.9 mg/kg, ED50 6 Hz = 21.0 mg/kg).
This molecule did not impair the motor coordination of animals in
the chimney test even at high doses (TD50 > 1500 mg/kg),
yielding superb protective indexes (PI MES > 16.97, PI PTZ >
25.04,
PI 6 Hz > 71.43). As a result, 11 displayed distinctly
better safety profile than clinically relevant AEDs ethosuximide,
lacosamide, or valproic acid.