Nafimidone is known for its clinical antiepileptic effects and alcohol derivatives of nafimidone were reported be potent anticonvulsants. These compounds are structurally similar to miconazole, which is known to inhibit cholinesterases, protect neurons, and ameliorate cognitive decline. Herein, we aimed to reveal the potential of three nafimidone alcohol esters (5 g, 5i, and 5 k), which were previously reported for their anticonvulsant effects, against co-morbidities of epilepsy such as inflammatory and neuropathic pain, cognitive and behavioral deficits, and neuron death, and understand their roles in related pathways such as γ-butyric acid type A (GABA_A) receptor and cholinesterases using in vitro, in vivo and in silico methods. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test was used for cytotoxicity evaluation, hippocampal slice culture assay for neuroprotection, formalin test for acute and inflammatory pain, sciatic ligation for neuropathic pain, Morris water maze and open field locomotor tasks for cognitive and behavioral deficits, radioligand binding for GABA_A receptor affinity, spectrophotometric methods for cholinesterase inhibition in vitro, and molecular docking in silico. The compounds were non-toxic to fibroblast cells. 5 k was neuroprotective against kainic acid-induced neuron death. 5i reduced pain response of mice in both the acute and the inflammatory phases. 5i improved survival upon status epilepticus. The compounds showed no affinity to GABA_A receptor but inhibited acetylcholinesterase, 5 k also inhibited butyrylcholinesterase. The compounds were predicted to interact mainly with the peripheric anionic site of cholinesterase enzymes. The title compounds showed neuroprotective, analgesic, and cholinesterase inhibitory effects, thus they bear promise against certain co-morbidities of epilepsy with neurological insults.

中文翻译：

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萘米酮衍生物对抗癫痫共病的潜力：体外、体内和计算机研究

Nafimidone 以其临床抗癫痫作用而闻名，据报道，nafimidone 的醇衍生物是有效的抗惊厥药。这些化合物在结构上类似于咪康唑，已知后者可抑制胆碱酯酶、保护神经元并改善认知能力下降。在此，我们旨在揭示三种萘米酮醇酯（5 g、5i和5 k）的潜力，这些酯之前曾报道其具有抗惊厥作用，可对抗癫痫共病，如炎症和神经性疼痛、认知和行为缺陷和神经元死亡，并了解它们在相关途径中的作用，例如 γ-丁酸 A 型（GABA _A) 使用体外、体内和计算机方法的受体和胆碱酯酶。3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) 试验用于细胞毒性评估，海马切片培养试验用于神经保护，福尔马林试验用于急性和炎症性疼痛，坐骨结扎用于神经性疼痛，Morris 水迷宫和针对认知和行为缺陷的开放场运动任务，针对 GABA _A受体亲和力的放射性配体结合，体外胆碱酯酶抑制的分光光度法，以及计算机中的分子对接。这些化合物对成纤维细胞无毒。5 k对红藻氨酸诱导的神经元死亡具有神经保护作用。5i降低了小鼠在急性期和炎症期的疼痛反应。5i提高了癫痫持续状态的生存率。这些化合物对 GABA _A受体没有亲和力，但抑制乙酰胆碱酯酶，5 k还抑制丁酰胆碱酯酶。预计这些化合物主要与胆碱酯酶的外围阴离子位点相互作用。标题化合物显示出神经保护、镇痛和胆碱酯酶抑制作用，因此它们有望对抗某些伴有神经损伤的癫痫共病。