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Design, Synthesis, and Docking Study of Pyrimidine–Triazine Hybrids for GABA Estimation in Animal Epilepsy Models
Author(s) -
Sahu Meeta,
Siddiqui Nadeem,
Naim Mohd. Javed,
Alam Ozair,
Yar Mohammad Shahar,
Sharma Vidushi,
Wakode Sharad
Publication year - 2017
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201700146
Subject(s) - anticonvulsant , chemistry , pharmacology , ed50 , pyrimidine , adme , neurotoxicity , phenytoin , docking (animal) , epilepsy , stereochemistry , carbamazepine , neurochemical , pharmacokinetics , toxicity , biochemistry , receptor , medicine , nursing , organic chemistry , psychiatry
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(2 H )‐yl)‐1,2‐dihydro‐1,2,4‐triazin‐3(6 H )‐one ( 4o ) and 5‐(6‐(4‐hydroxy‐3‐methoxyphenyl)‐4‐(4‐hydroxyphenyl)‐2‐thioxo‐5,6‐dihydropyrimidin‐1(2 H )‐yl)‐1,2‐dihydro‐1,2,4‐triazin‐3(6 H )‐one ( 4s ) emerged as most potent anticonvulsant agents with median doses of 22.54 and 29.40 mg/kg (MES ED 50 ), 285.02 and 293.42 mg/kg (scPTZ ED 50 ), and 389.11 and 412.16 mg/kg (TD 50 ), respectively. Docking studies were also performed for all synthesized compounds to get insight into the binding pattern toward the GABA A 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.