In recent years, considerable interest has been generated in designing new multi-targeted compounds as they have been proven to be advantageous in the treatment of multifactorial diseases and also have been proven to alleviate health conditions linked to drug resistance. Epilepsy, which is recognized as the most common neurological disorder, without any doubt, fulfills both the aforementioned criteria. Importantly, about one-third of the patients with epilepsy develop resistance to antiepileptic drugs (AEDs). Thus, the multifunctional AEDs such as the valproic acid belong to the most often used anticonvulsants, especially valuable in case of different epilepsy types and epileptic seizures with undefined etiology.

Therefore, according to the molecular hybridization method and to obtain new highly effective and broad-spectrum anticonvulsants, in the previous study we have developed hybrid molecules. These compounds were designed by applying the fragment-based approach, thus they overlap on the common structural framework fragments of three chemically and pharmacologically diversified ADEs. The hybridization process yielded substances with potent and broad-spectrum anticonvulsant activity in the most widely employed animal seizure models (MES, scPTZ, 6 Hz).

Considering beneficial anticonvulsant properties of the hybrids reported previously, in the current studies we have developed the new series of hybrid molecules based on the pyrrolidine-2,5-dione core fragment. These compounds revealed potent anticonvulsant activity in the MES, scPTZ, and 6 Hz (32 mA) seizure models as well as in the 6 Hz (44 mA) test, which is recognized as model of pharmacoresistant epilepsy.

The studies were supported by the Polish National Scientific Centre grant 2018/29/N/NZ7/01966