Molecular Docking and Anticonvulsant Activity of Newly Synthesized Quinazoline Derivatives.

Hatem A Abuelizz,Rabab El Dib,Mohamed Marzouk,Yousreya A Maklad,El-Hassane Anouar,Hanan N Attia,Rashad Al-Salahi

doi:10.3390/molecules22071094

Abstract

A new series of quinazoline-4(3H)-ones are evaluated for anticonvulsant activity. After intraperitoneal (ip) injection to albino mice at a dose of 100 mg/kg body weight, synthesized quinazolin-4(3H)-ones (1–24) were examined in the maximal electroshock (MES) induced seizures and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. The Rotarod method was applied to determine the neurotoxicity. Most of the compounds displayed anticonvulsant activity in the scPTZ screen at a dose range of 0.204–0.376 mmol/mL. Out of twenty-four, compounds 8, 13 and 19 proved to be the most active with a remarkable protection (100%) against PTZ induced convulsions and four times more potent activity than ethosuximide. The structure-activity relationship concluded valuable pharmacophoric information, which was confirmed by the molecular docking studies using the target enzyme human carbon anhydrase II (HCA II). The studied quinazoline analogues suggested that the butyl substitution at position 3 has a significant effect on preventing the spread of seizure discharge and on raising the seizure threshold. However, benzyl substitution at position 3 has shown a strong anticonvulsant activity but with less seizure prevention compared to the butyl substitution.

Highlights

Epilepsy is a ubiquitous disease characterized by chronic and recurrent seizures usually caused by brief and excessive electrical discharges in a group of brain cells [1,2,3]
Based on the aforementioned considerations, bearing in mind the inherited anticonvulsant potency of quinazoline nuclei together with the similarities between methaqualone, mecloqualone, the reported anticonvulsants and our synthesized derivatives (A) (Figure 1), we report the evaluation of a new synthesized quinazolines series (1–24) [23,24,25] for anticonvulsant effects to explore the influence of butyl and benzyl groups at position 3 of the quinazolines (4–16,22,24) and (16–21,23), respectively
The results revealed that most of the compounds displayed 17–100% anticonvulsant activity in the subcutaneous pentylenetetrazole (scPTZ) screen at a dose range of 0.204–0.376 mmol/kg

Summary

Introduction

Epilepsy is a ubiquitous disease characterized by chronic and recurrent seizures usually caused by brief and excessive electrical discharges in a group of brain cells [1,2,3]. A wide variety of modalities such as yoga, surgery and drugs have been used for arresting and controlling seizures. Various ketogenic diets have been suggested as useful therapy in pharmacoresistant epileptic patients. This includes classic ketogenic diet, low glycemic index treatment, medium chain triglyceride administration, and a modified Atkins diet [5]. Remedy is Molecules 2017, 22, 1094; doi:10.3390/molecules22071094 www.mdpi.com/journal/molecules a modified Atkins diet [5]. Drug therapy remains the mainstay in epilepsy treatment

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