Exploring Quinazolinones as Anticonvulsants by Molecular Fragmentation Approach: Structural Optimization, Synthesis and Pharmacological Evaluation Studies
Vinod G. Ugale, Sanjay B. Bari, Saurabh C. Khadse, Pedavenkatagari Narayana Reddy, Chandrakant Bonde, Prashant Chaudhari
Abstract
Abstract In recent years, design and synthesis of anticonvulsants effective against multiple seizures has attracted much attention of medicinal chemists. In an attempt to find novel anticonvulsants, herein we have reported structurally optimized sixteen different substituted quinazolinones explored through molecular fragmentation approach. The anticonvulsant activity of synthesized compounds was assessed by using predictable seizure models in mice. Two most promising analogues 8 d (ED 50 = 35.1 mg/kg, MES, mice, i. p .; ED 50 = 41.5 mg/kg, sc PTZ test, mice, i. p .) and 8 l (ED 50 = 21.2 mg/kg, MES, mice, i. p .; ED 50 = 32.4 mg/kg, sc PTZ test, mice, i. p .) exhibited broad spectrum anticonvulsant action in preclinical models of seizures. Compound 8 l was also shown profound activity against pharmaco‐resistant limbic seizures produced in 6 Hz test. Most of the synthesized molecules exhibited moderate to high anticonvulsant activity in all seizure models with no symptoms of neurotoxicity and hepatotoxicity. We have also used in‐silico protocol for prediction of physiochemical and pharmacokinetic properties of synthesized quinazolinones. The promising anticonvulsant activity of synthesized analogues, ex‐vivo toxicity, in‐silico molecular docking, physiochemical and pharmacokinetic predictions make us to anticipate emergence of synthesized quinazolinones as valid leads for the treatment of convulsive disorder.