Design, Synthesis, and Docking Study of Pyrimidine–Triazine Hybrids for GABA Estimation in Animal Epilepsy Models

Abstract

A series of new pyrimidine-triazine hybrids (4a-t) was designed and synthesized, from which potent anticonvulsant agents were identified. Most of the compounds exhibited promising anticonvulsant activity against the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests, along with minimal motor impairment with higher safety compared to the standard drugs, phenytoin and carbamazepine. In the series, 5-(4-(4-fluorophenyl)-6-(4-hydroxyphenyl)-2-thioxo-5,6-dihydropyrimidin-1(2H)-yl)-1,2-dihydro-1,2,4-triazin-3(6H)-one (4o) and 5-(6-(4-hydroxy-3-methoxyphenyl)-4-(4-hydroxyphenyl)-2-thioxo-5,6-dihydropyrimidin-1(2H)-yl)-1,2-dihydro-1,2,4-triazin-3(6H)-one (4s) emerged as most potent anticonvulsant agents with median doses of 22.54 and 29.40 mg/kg (MES ED ), 285.02 and 293.42 mg/kg (scPTZ ED ), and 389.11 and 412.16 mg/kg (TD ), respectively. Docking studies were also performed for all synthesized compounds to get insight into the binding pattern toward the GABA receptor as a possible mechanism of their anticonvulsant action, and in silico ADME studies were carried out to predict the safety and stability of the molecules. The increased GABA level in the experimental animals in the neurochemical estimation assay confirmed their GABAergic modulating activity. The most potent compounds were also evaluated for their neurotoxic and hepatotoxic effects. Fortunately, they did not show any sign of neurotoxicity or hepatotoxicity, suggesting that they have a broad spectrum of anticonvulsant activity with a large safety margin. Together, this research suggested that 4o and 4s may serve as leads in the discovery and development of new anticonvulsant drugs.

An Overview of Coumarin as a Versatile and Readily Accessible Scaffold with Broad-Ranging Biological Activities

“…Epilepsy is a widespread neurological disorder, characterized by periodic and unpredictable attacks, involving seizures and/or transient behavioral changes. Its pathogenesis has not been completely clarified yet; it is known, however, that an impairment between excitatory and inhibitory neurotransmission is involved [175][176][177][178][179] Here, we report some recent advances in the use of coumarins as anticonvulsant compounds. Abd-Allah and collaborators recently studied the anticonvulsant activity of a series of coumarin derivatives, achieved by merging two or more pharmacophoric scaffolds in order to create new chemical entities with an improved biological activity [180].…”

“…Abd-Allah and collaborators recently studied the anticonvulsant activity of a series of coumarin derivatives, achieved by merging two or more pharmacophoric scaffolds in order to create new chemical entities with an improved biological activity [180]. The compounds here described possess all the necessary elements to exert anti-convulsant activity: a lipophilic aryl ring, a hydrogen-bonding domain and an electron-donor moiety [178,179,181,182]. All the compounds were initially screened (phase I) using two standard animal seizure models, subcutaneous pentylenetetrazole (scPTZ) and maximal electric shock (MES) seizure tests using ethosuximide as reference drug.…”

In Vivo Screening of Xanthones from Garcinia oligantha Identified Oliganthin H as a Novel Natural Inhibitor of Convulsions

“…Through molecular docking, we investigated the potential targeted site of oliganthin H toward the GABAA receptor (PDB ID-4COF). Results indicated that oliganthin H could virtually bind to the GABAA receptor, through hydrogen bonds with the binding sites shown in Figure A, with an affinity of −9.8 kcal/mol. In comparison, phenobarbital binds to the same receptor through hydrogen bonds with the binding sites shown in Figure B, with an affinity of −6.7 kcal/mol.…”

“…Prior to the calculation, the prepared three-dimensional coordinates of GABAA (PDB ID-4COF) were retrieved from the RCSB Protein Data Bank. 50 Then, this structure was imported to the AutoDock Tools suite for docking setup. In brief, Gasteiger partial charges were assigned to all atoms, and the nonpolar hydrogen atoms were merged with carbon atoms using the united atom representation, reducing the degrees of freedom.…”

Investigation of 1, 3, 4 Oxadiazole Derivative in PTZ-Induced Neurodegeneration: A Simulation and Molecular Approach

“…Pyrimidine-trizine newly synthesized compounds were recently researched for their potential in attenuating the seizures attacks by their GABA mimetic action. 32 This study was also designed in order to develop and add a new moiety having anti-epileptic activity mediated through GABA receptors.…”