Design, Synthesis, Molecular Docking, and Pharmacological Evaluation of 3H-Quinazolin-4-one Derivatives as Potential Antiepileptic Agents

Abstract

Epilepsy is a chronic neurological condition characterized by abnormal electrical activity within clusters of neurons in the brain. These irregular signals may remain confined to one region (focal epilepsy) or spread across both hemispheres (generalized epilepsy). The term epilepsy originates from the Greek word epilepsia, meaning “falling sickness,” and is often referred to as a seizure, ictus, or convulsion. Quinazoline derivatives have gained attention as promising scaffolds in the design of novel anticonvulsant and central nervous system (CNS) depressant agents. Their pharmacological potential is largely attributed to the presence of an aromatic or aliphatic group at the 2-position and a substituted aromatic ring at the 3-position of the quinazoline nucleus. Among the synthesized derivatives, compounds Zc, Zd, and Ze demonstrated notable antioxidant properties, with IC₅₀ values of 7.48, 4.85, and 10.28 µg/mL, respectively. These compounds also displayed strong binding affinities toward carbonic anhydrase II, suggesting a possible structure–activity relationship (SAR). In vivo evaluation using a PTZ-induced seizure model in mice revealed that the same compounds exhibiting strong antioxidant potential also showed marked anticonvulsant activity, effectively mitigating tonic-clonic seizures. Furthermore, results from enzyme inhibition assays and computational docking studies support their potential as lead candidates for future drug development. Overall, the 3H-quinazoline-4-one core emerges as a valuable structural framework for designing new therapeutics with significant CNS and anticonvulsant activities.