A Study Of Anticonvulsant Constitutents From "Liang Relationship" Traditional Chinese Pair Herbs Polygala Tenuifolia And Gastrodia Elata And The Synthesis And Pharmacological Evaluation Of The Derivatives

Epilepsy is a group of neurological disorders characterized by recurrent seizures.Traditional Chinese medicine?TCM?has a long history and been widely used in prevention and treatment of epilepsy in China,and multiple isolated constituents from TCM have been proved to be effective in treating epilepsy.In spired from the classical TCM prescription Ding Xian Wan,this study focuses on the“Liang Relationship”pair herb drugs Polygala tenuifolia and Gastrodia elata based on the studies of the excavating precursors from the anticonvulsant TCM compound library.Constituents from P.tenuifolia and G.elata were virtually screened for their potential gamma-aminobutyric acid aminotransferase?GABA-AT?inhibitory potency.Sebsequently,85 kinds of derivatives were designed according to Combination of Traditional Chinese Medicine Chemistry?CMTCC?and synthesized with the evaluation of their anticovulsant activity.The CTCMC stragety provides inpiration for the development of clinical epilepsy drugs,in addition,it is a novel strategy for the chemical modernization and the development of potential scaffolds from TCM.The dissertation was divided into three chapters among which the author contributed greatly in following contents:1.Investigations of“Liang Relationship”pair herb drugs P.tenuifolia and G.elata have been possessed,the information about chemical constituents isolated from P.tenuifolia and G.elata have been collected with the help of online databases including CM-Database@Taiwan,TCMSP and PubChem.Subsequently,the HipHop pharmacophore was established according to the training set reported by the published literatures providing the information about the GABA-AT inhibitory skeleton.A total of26 kinds of compounds from P.tenuifolia and G.elata were virtually screened by the pharmacophore for the possible GABA-AT inhibitors,and the result showed that glycolipids from P.tenuifolia and glycosides from G.elata were the promising GABA-AT inihibitors with novel skeleton.2.The chemical modification of the lead compounds 3,4,5-trimethoxycinnamic acid?TMCA?was performed,a metabolite of internal standard substance 3,6?-disinapoyl sucrose from P.tenuifolia,and p-hydroxybenzyl alcohol,a metabolite of internal standard substance gastrodin from G.elata with its analogue vanillyl alcohol.Adopting the strategy of CMTCC,this study synthesized ester,amide and peptide analogues in total for 85 kinds of derivatives with their identificated data presented.Representitive derivatives inspired from TCM including TMCA-geraniol ester?A8?,TMCA-menthol ester?A12?,TMCA-borneol ester?A13?,TMCA-hydroxy benzyl alcohol ester?A19?,TMCA-vanillol ester?A20?,TMCA-acegastrodine ester?A28?,TMCA-vanillylamide?B18?,TMCA-gabapentin-isopentene vanillyl ester?C8?and TMCA-pregabalin-isopentene vanillyl ester?C23?.3.All the synthesized derivatives were biologically evaluated for their anticonvulsant potential using two acute model of seizures induced in mice,the maximal electroshock?MES?and sc-pentylenetetrazole?sc-PTZ?models.Simultaneously,the motor impairment as a surrogate of acute neurotoxicity were assessed.The pharmacological tests gave several active compounds with protective index(PI=TD₅₀/ED₅₀)far more than the reference standard carbamazepine.Promising anticovulsant compounds including ester derivatives like TMCA-acegastrodine ester?A28?exhibited anticonvulsant effect with ED₅₀ value for19.5 mg/kg and PI value for 51.2,TMCA-isopentene vanillyl ester?A32?showed anticonvulsant effect with ED₅₀ value for 21.9 mg/kg and PI value for 31.9,and the peptide derivatve TMCA-pregabalin-isopentene vanillyl ester?C23?displayed anticonvulsant effect with ED₅₀ value for 29.8 mg/kg and PI value for 30.1.The molecular modeling experiments predicted good binding interactions of part of the obtained active molecules with the GABA-AT through the roles of interactions of H-bonds or nonbonding.