Synthesis, molecular modelling study of the methaqualone analogues as anti-convulsant agent with improved cognition activity and minimized neurotoxicity

In the current research, methaqualone derivatives were synthesized and assessed for their anti-convulsant activity. Among them, compounds 3, 4, 6, 7 and 11 exhibited significant anti-convulsant activities with ED50 values of 132.23 mg/kg, 120.34 mg/kg, 100.78 mg/kg, 145.89 mg/kg, and 148.46 mg/kg, respectively. The toxicity profiling (TD50) of these compounds (3, 4, 6, 7 and 11) demonstrated that these drugs caused only a minor neurological impairment. The PI scores of these compounds (3, 4, 6, 7 and 11) were higher than the reference drug (methaqualone PI: 1.99). The acetylcholinesterase enzyme level is significantly reduced in these compounds, indicating the enhancement of cognition activity. Pharmacophoric modelling and molecular docking studies against the human GABA-A receptor are in close agreement with each other. Molecular dynamic simulation of compound 6 indicates that it remains stable with the human GABA-A receptor for a 100 ns time span. (C) 2021 Elsevier B.V. All rights reserved.

Automated summary

In this research, methaqualone derivatives were synthesized and evaluated for their anti-convulsant activity. Compounds 3, 4, 6, 7, and 11 showed significant anti-convulsant activities with low toxicity. They exhibited reduced acetylcholinesterase levels and stable interaction with the human GABA-A receptor.