Discovery of Novel 5‐Arylidenethiazolidine‐2,4‐dione Derivatives as Antidepressant and Antiepileptic Agents With In Silico ADMET and Molecular Docking Studies

Depression being one of the most common psychiatric comorbidities in people with epilepsy. Based on the potent antidepressant and anticonvulsant activities of thiazolidinone moieties, we designed and synthesized a novel series of 5-arylidenethiazolidine-2,4-dione derivatives (11a-h) and (12a-h), and investigated their in vivo anticonvulsant activity using the pentylenetetrazol-induced model (PTZ), along with their antidepressant activity assessed by the forced swim test (FST) and tail suspension test (TST) in mice. The structures of the synthesized compounds were established through ¹H NMR, ¹³C NMR, and LC-MS analysis. The study revealed that compounds 11e, 12e, and 12g exhibited potent antidepressant activity, which reduces immobility time by approximately 50% at 20 mg/kg. In addition, compounds 11c, 11e, 11g, 12c, and 12g were identified as potent anticonvulsants, reducing post-convulsion effects such as duration of convulsion, jerking, and Straub's tail by more than 60% at 20 mg/kg. Furthermore, key ADMET features were calculated in silico for the most active molecules to determine their pharmacokinetic properties. Molecular docking and MD simulation confirms their binding interactions to target proteins. Based on these findings, the compounds 11c, 11e, 11g, 12c, 12e, and 12g are promising lead candidates for the development of more effective anticonvulsant and antidepressant agents.