In vivo antiseizure activity of triazolyl oxazolidinone derivatives in rats

Seizure disorders are frequent and disabling neurological conditions of the brain that are currently managed mainly with medications. However, the clinically available drugs are fraught with side effects and in some cases ineffectiveness. Thus, there is the need to develop newer and safer anti-seizure medications, especially those based on novel pharmacophores. Here we tested the hypothesis that compounds derived from the oxazolidinone pharmacophore have antiseizure activity in vivo by inducing seizures chemically and electrically in male Sprague Dawley rats and testing their ability to prevent/inhibit these seizures.

Rats were pretreated with 100 mg/kg of each compound (PH066, PH139, PH162, PH166 and PH192) and seizures induced at various time points afterwards by electrical pulse (electrically-induced) and by IP administration of pentylenetetrazol (chemically-induced). Seizure scoring was done visually by two experienced researchers.

We report here that compound PH162 provided the best protection across all seizure models with the longest duration of action. The rank order of efficacy and duration for all tested compounds is as follows: PH162 > PH139 > PH166 ≈ PH066 > PH192.

We conclude that although all the tested compounds had some antiseizure activity, PH162 provided a broader based protection with likely more favorable pharmacokinetics. Thus, PH162 is recommended as the lead compound among this group of compounds tested that may be further optimized for even better kinetics and/or safety by slight chemical modification of the basic structure.