Aytemir Mutlu Dilsiz, Septioğlu Ebubekir, Caliş Unsal
Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ankara, Turkey.
Arzneimittelforschung. 2010;60(1):22-9. doi: 10.1055/s-0031-1296244.
A series of new 3-hydroxy-6-hydroxymethyl-2-substituted 4H-pyran-4-one derivatives were synthesized as potential anticonvulsant compounds. Mannich compounds were prepared by the reaction of appropriate substituted piperazine derivatives with kojic acid and formaline. The structure of the synthesized compounds was confirmed using the elementary analysis results and spectroscopic techniques such as IR, 1H-NMR and ESI-MS. Anticonvulsant activities of the synthesized compounds 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 according to procedures of the Antiepileptic Drug Development (ADD) program. According to the activity studies, 2-[4-(4-chlorophenyl)piperazin-1-ylmethyl]-3-hydroxy-6-hydroxymethyl-4H-pyran-4-one (compound 11) against MES seizures and 3-hydroxy-6-hydroxymethyl-2-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]-4H-pyran-4-one (compound 7) against scMet seizures were determined to be the most active compounds at all doses without neurotoxicity.
合成了一系列新型的3-羟基-6-羟甲基-2-取代-4H-吡喃-4-酮衍生物作为潜在的抗惊厥化合物。通过适当的取代哌嗪衍生物与曲酸和甲醛反应制备曼尼希化合物。利用元素分析结果以及红外光谱（IR）、氢核磁共振谱（1H-NMR）和电喷雾电离质谱（ESI-MS）等光谱技术对合成化合物的结构进行了确证。通过最大电休克（MES）和皮下注射戊四氮（scMet）诱发惊厥试验检测合成化合物的抗惊厥活性。通过转棒毒性试验测定神经毒性。所有这些试验均按照抗癫痫药物开发（ADD）计划的程序进行。根据活性研究，2-[4-(4-氯苯基)哌嗪-1-基甲基]-3-羟基-6-羟甲基-4H-吡喃-4-酮（化合物11）对MES惊厥以及3-羟基-6-羟甲基-2-[4-(2-甲氧基苯基)哌嗪-1-基甲基]-4H-吡喃-4-酮（化合物7）对scMet惊厥在所有剂量下均被确定为活性最强的化合物，且无神经毒性。
