1. School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
2. Center for Brain Science, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Zhejiang Da Xue Xue Bao Yi Xue Ban. 2022 Aug 1;51(4):415-421. doi: 10.3724/zdxbyxb-2022-0174.
To design and synthesize long-chain substituted 2-[(4'-hydroxyethoxy) phenyl]-4,4,5,5-tetramethyl-2-imidazoline-1-oxyl 3-oxide (HPN) derivatives with enhanced anti-hypoxic activity.
HPN derivatives 1, 3, 5 containing lipophilic long chains were synthesized via the alkylation of HPN with 6-bromohexan-1-ol, ethyl 6-bromohexanoate or 6-bromohexane, respectively using acetonitrile as the solvent and K CO as the acid-binding agent at 60 ℃. Derivative 2 was synthesized via hydrolysis reactions of derivative 1 in the NaOH/CH OH/H O system. Using dichloromethane as the solvent and , '-diisopropylcarbodiimide as the dehydrating agent, HPN underwent esterification with hexanoic acid to obtain derivative 4. The structures of derivatives 1-5 were characterized by infrared spectroscopy, electron paramagnetic resonance and high resolution mass spectrometry. The purities of derivatives were detected by high performance liquid chromatography, and the lipid solubilities of derivatives were evaluated by calculating the oil-water partition coefficients (log ). Anti-hypoxia activities of HPN and its long-chain lipophilic derivatives 1-5 were evaluated using normobaric hypoxia test and acute decompression hypoxia test.
The structures of the derivatives were confirmed by infrared spectroscopy, electron paramagnetic resonance and high resolution mass spectroscopy. The yields of target derivatives were all above 92%, and the purities were all above 96%. The log values of derivatives 1-5 were 2.78, 2.00, 2.04, 2.88 and 3.10, which were higher than that of HPN (0.97). Derivatives 1-5 significantly prolonged the survival time of mice at the dose of 0.3 mmol/kg in normobaric hypoxic test and reduced the mortality rate of acute decompression hypoxic mice to 60%, 70%, 60%, 70% and 40%, respectively.
The synthesis of derivatives 1-5 is convenient, and the yield is high. The synthesized derivatives especially derivative 5 show anti-hypoxic activity similar to or better than HPN at lower doses.
设计并合成具有增强的抗缺氧活性的长链取代 2-[(4'-羟乙氧基)苯基]-4,4,5,5-四甲基-2-咪唑啉-1-氧-3-氧化物（HPN）衍生物。
采用乙腈作溶剂，K₂CO₃作酸结合剂，在 60℃下，用 6-溴己醇、乙基 6-溴己酸酯或 6-溴己烷分别对 HPN 进行烷基化反应，合成含亲脂性长链的 HPN 衍生物 1、3、5。衍生物 1 在 NaOH/CH₃OH/H₂O 体系中进行水解反应得到衍生物 2。以二氯甲烷为溶剂，用, '-二异丙基碳二亚胺作为脱水剂，HPN 与己酸进行酯化反应得到衍生物 4。通过红外光谱、电子顺磁共振和高分辨质谱对衍生物的结构进行了表征。采用高效液相色谱法检测衍生物的纯度，通过计算油水分配系数（log P）评估衍生物的脂溶性。采用常压缺氧试验和急性减压缺氧试验评价 HPN 及其长链疏水性衍生物 1-5 的抗缺氧活性。
通过红外光谱、电子顺磁共振和高分辨质谱确认了衍生物的结构。目标衍生物的产率均在 92%以上，纯度均在 96%以上。衍生物 1-5 的 log P 值分别为 2.78、2.00、2.04、2.88 和 3.10，均高于 HPN（0.97）。衍生物 1-5 在 0.3mmol/kg 剂量下可显著延长常压缺氧试验中小鼠的存活时间，使急性减压缺氧小鼠的死亡率分别降低至 60%、70%、60%、70%和 40%。
衍生物 1-5 的合成方法简便，收率高。与 HPN 相比，合成的衍生物特别是衍生物 5 在较低剂量下具有相似或更好的抗缺氧活性。
