title: Design, Synthesis, and Biological Evaluation of 6-(2-Amino-substituted phenyl)-4-(substituted phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Derivatives as Anticonvulsant Agents.
abstract: As per structural requirement essential for anticonvulsant activity, a series of new 6-(2-amino-substituted phenyl)-4-(substituted phenyl)-1,2,4-triazine-3,5-dione derivatives were designed and synthesized. All the synthesized title derivatives were assessed for in vivo anticonvulsant screening by the two most employed standard animal seizure models, maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ)-induced seizures, along with minimal motor impairment screening by rotarod test. Among all the synthesized compounds, the compound 4r showed excellent anticonvulsant activity with neither signs of neurotoxicity in the minimal motor impairment test nor signs of hepatotoxicity in the serum enzyme activity assay. The in silico studies of these title compounds were carried out for estimation of a pharmacophore pattern and the prediction of pharmacokinetic properties. To know the exact mechanism of our title compounds, a molecular docking study was carried out on the homology model of sodium ion (Na(+) ) channel and GABAA receptors. The results of the docking study as well as the in vitro study on both the receptors showed that our target compounds best act through the GABAA receptor rather than the Na(+) channel receptors. Additionally, GABA enzyme estimation was performed for further confirmation of the mechanism involved in its anticonvulsant activity. Conclusively, the compound 4r presents a novel scaffold in the search for safer and efficient anticonvulsants having neuroprotective as well as GABAergic effects.
authors.affiliation: Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Jamia Hamdard (Hamdard University), New Delhi, India.
authors.forename: Ahsan Ahmed
authors.initials: AA
authors.lastname: Khan
authors.affiliation: Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Jamia Hamdard (Hamdard University), New Delhi, India.
authors.forename: Nadeem
authors.initials: N
authors.lastname: Siddiqui
authors.affiliation: Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Jamia Hamdard (Hamdard University), New Delhi, India.
authors.forename: Md Jawaid
authors.initials: MJ
authors.lastname: Akhtar
authors.affiliation: Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Jamia Hamdard (Hamdard University), New Delhi, India.
authors.forename: Zulphikar
authors.initials: Z
authors.lastname: Ali
authors.affiliation: Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Jamia Hamdard (Hamdard University), New Delhi, India.
authors.forename: Mohammad Shahar
authors.initials: MS
authors.lastname: Yar
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D004597:Electroshock; D051379:Mice; D062105:Molecular Docking Simulation; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D010433:Pentylenetetrazole; D011963:Receptors, GABA-A / Q000737:chemistry; D012640:Seizures / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D015222:Sodium Channels / Q000737:chemistry; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C000613241:6-(2-amino-5-chlorophenyl)-4-(4-hydroxyphenyl)-1,2,4-triazine-3,5(2H,4H)-dione; D000927:Anticonvulsants; D018696:Neuroprotective Agents; D011963:Receptors, GABA-A; D015222:Sodium Channels; D014227:Triazines; D005680:gamma-Aminobutyric Acid; D010433:Pentylenetetrazole
keywords: 1,2,4-Triazine; Anticonvulsant; GABA; In silico study; Na+ channel; scPTZ