Structural Exploration of Quinazolin-4(3H)-ones as Anticonvulsants: Rational Design, Synthesis, Pharmacological...

Anticonvulsants effective against multiple seizures are of wide interest as antiepileptic drugs, especially if active against pharmaco-resistant seizures. Herein, we synthesized 16 different, rationally designed 2-((6,7-dimethoxy-4-oxo-2-phenylquinazolin-3(4H)-yl)amino)-N-(substituted phenyl)acetamides and screened for anticonvulsant activities through in vivo experiments. Compound 4d emerged as prototype with excellent anti-seizure action in mice against electroshock, chemically induced and pharmaco-resistant 6-Hz seizure models with no symptoms of neurotoxicity and hepatotoxicity (ED₅₀  = 23.5 mg/kg, MES, mice, i.p.; ED₅₀  = 32.6 mg/kg, scPTZ, mice, i.p.; ED₅₀  = 45.2 mg/kg, 6-Hz, mice, i.p.; TD₅₀  = 325.9 mg/kg, mice, i.p.). In addition, investigation of compound 4l in mice for its pharmacological profile proved it as safer anticonvulsant, devoid of the side effects such as motor dysfunction and hepatotoxicity of classical antiepileptic drugs (ED₅₀  = 26.1 mg/kg, MES, mice, i.p.; ED₅₀  = 79.4 mg/kg, scPTZ, mice, i.p.; TD₅₀  = 361.2 mg/kg, mice, i.p.). We also predicted physiochemical and pharmacokinetic properties of structurally optimized quinazolin-4(3H)-ones by a computational protocol. A combination of in vivo anticonvulsant profile, ex vivo toxicity, and in silico studies suggested that the synthesized compounds may be useful as broad-spectrum anti-seizure drug candidates with favorable pharmacokinetic parameters.