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

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 ED50), 285.02 and 293.42 mg/kg (scPTZ ED50), and 389.11 and 412.16 mg/kg (TD50), respectively. Docking studies were also performed for all synthesized compounds to get insight into the binding pattern toward the GABAA 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 no...
Source: Archiv der Pharmazie - Category: Drugs & Pharmacology Authors: Tags: Full Paper Source Type: research