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Solid-phase Synthesis of [4.4] Spirocyclic Oximes
Published on: February 6, 2019
作为潜在的中枢神经系统活性和胆酶向性治疗药物,新型二和二氧化物
Milena Mlakić1, Tena Čadež2, Goran Šinko2
1Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Trg Marka Marulića 19, HR-10000 Zagreb, Croatia.
合成了针对中枢神经系统 (CNS) 乙胆酶 (AChE) 和丁胆酶 (BChE) 的新氧化物. 一些化合物显示出作为中枢神经系统活性活性剂的潜力,用于有机 (OP) 中毒和神经退行性疾病的治疗方法.
科学领域:
- 药用化学 医学化学
- 神经科学是一个神经科学.
- 毒理学 毒理学 毒理学
背景情况:
- 有机 (OP) 化合物抑制乙胆酶 (AChE) 和丁胆酶 (BChE),这些酶对神经传输至关重要,导致胆危机.
- 现有的氧化物再激活剂很难穿过血脑屏障,限制了它们在治疗OP中毒中中枢神经系统 (CNS) 影响方面的有效性.
- 需要针对胆酶的新疗法,用于OP中毒和神经退行性疾病,如阿尔茨海默氏症和帕金森症.
研究的目的:
- 合成来自,烯和三醇的新型异环氧化物.
- 评估这些化合物作为OP神经毒剂抑制的ACHE和BCHE的抑制剂和活性剂.
- 探索它们作为中枢神经系统活性治疗药物的潜力,用于OP中毒和神经退行性疾病.
主要方法:
- 合成了63种乙烯衍生物,其中26种氧化物被选择用于生物评估.
- 在体外测试以确定ACHE和BCHE对沙林和环素的抑制和活性动力学.
- 在分析,分子对接,分子动力学模拟和ADMET属性预测.
主要成果:
- 大多数合成的氧化物都在微分子范围内强烈抑制了ACHE和BCHE,其中一些具有选择性.
- 四种异环衍生物有效地重新激活了循环沙林抑制的BChE (高达70%),其中一种化合物显示的疗效与HI-6相比.
- 在 silico 研究中,与结构特征相关联的动力学数据,证实了与环素抑制的 BChE 活性部位的相互作用.
结论:
- 新型异环氧体体显示出作为胆酶的抑制剂和活性剂的显著潜力.
- 特定的化合物显示出开发中枢神经系统活性反应剂的希望,用于有机中毒.
- 这些氧化物也可能作为神经退行性疾病的胆酶向治疗药物,需要进一步调查.
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