New spirooxindole-thiazolidine derivatives as antiseizure agents: Biological evaluation and computational studies

Background: Oxindoles and spirooxindoles are considered privileged scaffolds in medicinal chemistry due to their diverse biological activities, which include anticonvulsant, anticancer, and antimicrobial properties. Their distinctive structural characteristics render them appealing targets for synthetic modification and the development of innovative therapeutic agents. Notably, their significance in pharmaceutical drug discovery arises from their capacity to interact with various biological targets implicated in disease pathogenesis. Objective: To evaluate the effects of several new spirooxindole derivatives in animal models of epilepsy, specifically using intravenous pentylenetetrazole (PTZ)-induced epilepsy mouse models and maximal electroshock (MES) models. Methods: This research examined the anticonvulsant properties of spiroindole thiazolidine derivatives (A1-A8) through intraperitoneal administration of pentylenetetrazole (PTZ) and maximal electroshock (MES) seizure models in NMRI mice. The compounds were given via intraperitoneal injection, and the latency, occurrence, and duration of seizures were measured. To investigate interactions with the GABA-A receptor, molecular docking and dynamics simulations were carried out. Statistical analysis was performed using ANOVA, and the results were presented as means ± SEM. Results: Some spirooxindole derivatives exhibited anticonvulsant effects in animal models of epilepsy; however, this effect was not consistent across all models and compounds. Among the compounds evaluated, A6 and A8 emerged as the most effective anticonvulsants, demonstrating an elevation in seizure threshold at administered doses of 25, 50, and 100 mg/kg. Docking studies indicated that certain compounds may act as GABA-A agonists. Furthermore, a docking study revealed that compounds A4 and A6 exhibited lower binding energy as GABA-A agonists. Molecular dynamics (MD) simulations were also conducted, confirming that A6 exhibited excellent binding affinity for GABA aminotransferase. Conclusion: These findings suggest the potential of certain new spirooxindole derivatives as candidates for anticonvulsant drugs. However, further studies are required to validate these results and to explore their mechanisms of action.