In the present study, a series of novel 2-(substituted benzylidene)-7-(4-chlorophenyl)-5-(furan-2-yl)-2H-thiazolo[3,2-a]pyrimidin-3(7H)-one derivatives (4a–i) were designed and synthesized to meet the structural requirements essential for antiepileptic activity. Antiepileptic screening was performed by maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizures tests and neurotoxicity was determined by the rotorod test. Among the synthesized compounds 4f, 4g and 4h were found active in both MES and scPTZ models. In the view of results the most active compounds carry fluoro > chloro > bromo substituent’s at the para position in the phenyl ring. The chemical structures of the synthesized compounds were confirmed by means of IR, 1H NMR, mass spectroscopy and elemental analysis.