Synthesis, Anticonvulsant, Antinociceptive Activity and Preliminary Safety Evaluations of Novel Hybrid Imidazolidine-2,4-dione Derivatives with Morpholine Moiety

This study aimed to design new hybrid compounds with imidazolidin-2,4-dione and morpholine rings as broad spectrum anticonvulsants. To achieve this goal, all compounds were evaluated in animal seizure models, namely the maximal electroshock (MES), the subcutaneous pentylenetetrazole (scPTZ), and selected in the 6 Hz (32 mA) tests. The most promising compound, 5-isopropyl-3-(morpholinomethyl)-5-phenylimidazolidine-2,4-dione (19), demonstrated broader anticonvulsant activity than phenytoin or levetiracetam, with ED50 of 26.3 mg/kg (MES), 11.1 and 40.9 mg/kg (6 Hz, 32 and 44 mA, respectively). Compared to phenytoin, compound 19 was active in both MES and 6 Hz (32 and 44 mA) tests. It showed nearly 2-fold higher efficacy than levetiracetam in the 6 Hz (32 mA test), but unlike levetiracetam, it was also active in 6 Hz (44 mA) test. Moreover, compound 23 (3-(morpholinomethyl)-5,5-diphenylimidazolidine-2,4-dione), displayed similar anticonvulsant efficacy to phenytoin and slightly higher activity than levetiracetam in 6 Hz (32 mA) test. In vitro binding studies compound 23 weakly inhibited sodium and calcium channels, whereas compound 19 did not exhibit this effect. Importantly, both compounds 19 and 23 showed no cytotoxicity in HepG2 cells (MTT test). Unfortunately, these compounds didn't show antinociceptive activity in the oxaliplatin-induced neuropathic pain model.