Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ankara, Turkey.
Arch Pharm (Weinheim). 2010 Mar;343(3):173-81. doi: 10.1002/ardp.200900236.
A series of new 3-hydroxy-6-hydroxymethyl/methyl-2-substituted 4H-pyran-4-ones were synthesized and prepared by the reaction of kojic acid or allomaltol with piperidine derivatives and formaline as potential anticonvulsant compounds. The structure of the synthesized compounds was confirmed using the elemental analysis results and the spectroscopic techniques such as IR, 1H-NMR, and ESI-MS. Anticonvulsant activities were examined by maximal electroshock (MES) and subcutaneous Metrazol (scMet)-induced seizure tests. Neurotoxicity was determined by the rotorod toxicity test. All these tests were performed in accordance with the procedures of the Antiepileptic Drug Development (ADD) program. According to the activity studies and at all doses, 3-hydroxy-2-[(4-hydroxy-4-phenylpiperidin-1-yl)methyl]-6-methyl-4H-pyran-4-one (compound 1), 2-{[4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl]methyl}-3-hydroxy-6-methyl-4H-pyran-4-one (compound 6), 2-[(4-acetyl-4-phenylpiperidin-1-yl)methyl]-3-hydroxy-6-(hydroxymethyl)-4H-pyran-4-one (compound 11), and 2-{[4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl] methyl}-3-hydroxy-6-hydroxymethyl-4H-pyran-4-one (compound 12) were found to have anticonvulsant activity against MES-induced seizures at 4 h. Also, 2-{[4-(4-bromophenyl)-4-hydroxypiperidin-1-yl]methyl}-3-hydroxy-6-(hydroxymethyl)-4H-pyran-4-one (compound 8) was determined to be the most active compound against scMet-induced seizures at all doses at 0.5 and 4 h. In the rotorod neurotoxicity screening, all compounds showed no toxicity at all doses.
一系列新的 3-羟基-6-羟甲基/甲基-2-取代 4H-吡喃-4-酮通过 kojic 酸或 allo maltol 与哌啶衍生物和甲醛的反应合成并制备，作为潜在的抗惊厥化合物。合成化合物的结构通过元素分析结果和光谱技术如 IR、1H-NMR 和 ESI-MS 来确认。抗惊厥活性通过最大电休克（MES）和皮下 Metrazol（scMet）诱导的惊厥试验进行检查。神经毒性通过旋转棒毒性试验确定。所有这些测试均按照抗癫痫药物开发（ADD）程序的程序进行。根据活性研究和所有剂量，3-羟基-2-[(4-羟基-4-苯基哌啶-1-基)甲基]-6-甲基-4H-吡喃-4-酮（化合物 1），2-[[4-(4-氯苯基)-3,6-二氢吡啶-1(2H)-基]甲基]-3-羟基-6-甲基-4H-吡喃-4-酮（化合物 6），2-[(4-乙酰基-4-苯基哌啶-1-基)甲基]-3-羟基-6-(羟甲基)-4H-吡喃-4-酮（化合物 11）和 2-[[4-(4-氯苯基)-3,6-二氢吡啶-1(2H)-基]甲基]-3-羟基-6-羟甲基-4H-吡喃-4-酮（化合物 12）被发现具有抗惊厥活性，可在 4 小时时对抗 MES 诱导的惊厥。此外，在所有剂量下，2-[[4-(4-溴苯基)-4-羟基哌啶-1-基]甲基]-3-羟基-6-(羟甲基)-4H-吡喃-4-酮（化合物 8）在 0.5 和 4 小时时被确定为对抗 scMet 诱导的惊厥最有效的化合物。在旋转棒神经毒性筛选中，所有化合物在所有剂量下均无毒性。
