Synthesis and evaluation of anticonvulsant activities of 7‐phenyl‐4,5,6,7‐tetrahydrothieno[3,2‐ b ]pyridine derivatives,Archiv der Pharmazie

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Synthesis and evaluation of anticonvulsant activities of 7‐phenyl‐4,5,6,7‐tetrahydrothieno[3,2‐ b ]pyridine derivatives
Archiv der Pharmazie ( IF 4.3 ) Pub Date : 2019-07-31 , DOI: 10.1002/ardp.201900106
Shiben Wang ₁ , Hui Liu ₂ , Xuekun Wang ₁ , Kang Lei ₁ , Guangyong Li ₁ , Xiaojing Li ₁ , Lichao Wei ₁ , Zheshan Quan ₃

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A series of 7‐phenyl‐4,5,6,7‐tetrahydrothieno[3,2‐b]pyridine derivatives containing triazole and other heterocycle substituents (methyltriazole, tetrazole, and triazolone) is described. Two experimental methods, maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ), were used to evaluate the anticonvulsant activity of the target compounds. Moreover, the neurotoxicity (NT) was tested using the Rotarod test. 5‐(4‐Chlorophenyl)‐4,5‐dihydrothieno[2,3‐e][1,2,4]triazolo[4,3‐a]pyridine (6c) showed the best anticonvulsant activity. In the MES and PTZ experiments, the 50% effective dose (ED50) values of compound 6c were 9.5 and 20.5 mg/kg, respectively. From the therapeutic index (PI) values, 6c (MES and PTZ with PI values of 48.0 and 22.2, respectively) showed better safety than the clinical drugs carbamazepine (MES with PI value of 6.4) and ethosuximide (PTZ with PI value of 3.2). The biological activities of the compounds were verified by using molecular docking studies. Compound 6c showed significant interactions with residues at the benzodiazepine‐binding site on gamma‐aminobutyric acid A (GABAA) receptors. The results of in vivo GABA estimation and bicuculline‐induced seizures showed that 6c may have an effect on the GABA system. The physicochemical and pharmacokinetic properties of the target compounds were predicted.

中文翻译：

7-苯基-4,5,6,7-四氢噻吩并[3,2-b]吡啶衍生物抗惊厥活性的合成与评价

描述了一系列含有三唑和其他杂环取代基（甲基三唑、四唑和三唑酮）的 7-苯基-4,5,6,7-四氢噻吩并[3,2-b]吡啶衍生物。两种实验方法，最大电休克 (MES) 和皮下戊四唑 (scPTZ)，用于评估目标化合物的抗惊厥活性。此外，使用 Rotarod 测试测试了神经毒性 (NT)。5-(4-氯苯基)-4,5-二氢噻吩并[2,3-e][1,2,4]三唑并[4,3-a]吡啶(6c)显示出最好的抗惊厥活性。在 MES 和 PTZ 实验中，化合物 6c 的 50% 有效剂量 (ED50) 值分别为 9.5 和 20.5 mg/kg。从治疗指数（PI）值来看，6c（MES和PTZ的PI值分别为48.0和22.2）比临床药物卡马西平（MES，PI值为6）显示出更好的安全性。4）和乙琥胺（PI值为3.2的PTZ）。通过分子对接研究验证了化合物的生物活性。化合物 6c 与 γ-氨基丁酸 A (GABAA) 受体上苯二氮卓结合位点的残基显示出显着的相互作用。体内 GABA 估计和荷包牡丹碱诱导的癫痫发作的结果表明 6c 可能对 GABA 系统有影响。预测了目标化合物的理化和药代动力学特性。体内 GABA 估计和荷包牡丹碱诱导的癫痫发作的结果表明 6c 可能对 GABA 系统有影响。预测了目标化合物的理化和药代动力学特性。体内 GABA 估计和荷包牡丹碱诱导的癫痫发作的结果表明 6c 可能对 GABA 系统有影响。预测了目标化合物的理化和药代动力学特性。

更新日期：2019-07-31

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