Anticonvulsant activity of 1,2,4-triazine derivatives with pyridyl side chain: synthesis, biological, and computational study

作者：Irannejad Hamid^*; Nadri Hamid; Naderi Nima; Rezaeian Seyedeh Nesa; Zafari Neda; Foroumadi Alireza; Amini Mohsen; Khoobi Mehdi

来源：Medicinal Chemistry Research, 2015, 24(6): 2505-2513.

DOI：10.1007/s00044-014-1315-3

• Synthesis
• 1,2,4-Triazine
• Anticonvulsant
• 15-LOX
• Molecular docking

A series of 5,6-bisaryl-1,2,4-triazine-3-thiol-substituted derivatives were synthesized by condensation of 1,2-diketones and thiosemicarbazide under microwave irradiations and subsequent alkylation of thiol group by chloromethylpyridinium chloride. Evaluation of anticonvulsant activity of compounds was performed by maximal electroshock and pentylenetetrazole-induced seizures tests. In order to evaluate their neuroprotective potential, the ability of compounds to inhibit soybean 15-lipoxygenase was also assessed. Further molecular modeling and docking study on Na+ channel and GABA(A) receptor was performed to elucidate their mechanisms of action and necessary interactions in the active site. Compounds 2c and 2d with bis(4-bromophenyl) and pyridyl substituents showed highest protection up to 70 and 80 % in PTZ and MES-induced seizures, respectively, compared to the control group. Molecular docking study revealed their possible antiseizure mechanism of action through GABA(A) receptor, and in silico assessment of their BBB permeability indicated them as CNS active agents.

• 出版日期2015-6