Anticonvulsant Action of Thiopyrano[2,3‐ d ]thiazole Derivative Les‐3384 as a Promising Antiepileptic Agent (In Vivo and In Silico Studies)

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ABSTRACT A novel thiopyrano[2,3‐d]thiazole derivative Les‐3384 ( rel ‐N‐(4‐chlorophenyl)‐3‐[(5 aR , 11bR) ‐2‐oxo‐5a,11b‐dihydro‐2 H ,5 H ‐chromeno[4’,3’:4,5]thiopyrano[2,3‐ d ]thiazol‐3(6 H )‐yl]propanamide) was evaluated for its anticonvulsant action. Anticonvulsant activity in mice was assessed using seizure models induced by picrotoxin, thiosemicarbazide, strychnine, caffeine, camphor action, or maximal electroshock (MES). Les‐3384 was administered orally at 100 mg/kg. For comparison, valproate, carbamazepine, and inosine were applied as standard AEDs. Seizure parameters and lethality were recorded in treated animals. Significantly increased latency to seizure onset (insert time), reduced seizure frequency, severity, and lethality in animal models induced by picrotoxin, strychnine, caffeine, and MES. Its efficacy was comparable to the action of reference drugs or exceeded their effects. However, no protective effect of Les‐3384 was observed in thiosemicarbazide and camphor models. Molecular docking studies revealed high binding affinity of Les‐3384 to the GABA A ‐receptor, suggesting that GABAergic modulation is a possible mechanism of action. The high effectiveness of Les‐3384 in the models of strychnine‐induced and caffeine‐induced seizures is confirmed by the results of molecular modeling, which indicate the affinity of the studied compound toward glycine and adenosine receptors. The LD 50 of Les‐3384 for mice is 1208 mg/kg by intragastric administration. The compound's efficacy and safety profile support its further preclinical study as a potential antiepileptic agent with the polytropic mechanisms of action.

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