Novel 1-Phenyl-3-hydroxy-4-pyridinone Derivatives as Multifunctional Agents for the Therapy of Alzheimer's Disease.
Novel 1-Phenyl-3-hydroxy-4-pyridinone Derivatives as Multifunctional Agents for the Therapy of Alzheimer's Disease.
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DOI：
10.1021/acschemneuro.5b00224
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发表时间：
2016-01
影响因子：
5
通讯作者：
R. Sheng;Li Tang;Liu-Ying Jiang;Lingjuan Hong;Ying Shi;N. Zhou;Yongzhou Hu
中科院分区：
文献类型：
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作者：
R. Sheng;Li Tang;Liu-Ying Jiang;Lingjuan Hong;Ying Shi;N. Zhou;Yongzhou Hu
设计并合成了一系列新型的1-苯基-3-羟基-4-吡啶酮类化合物，通过将去铁酮的3-羟基-4-吡啶酮部分引入H3受体拮抗剂的支架中，合成了一系列用于阿尔茨海默病(AD)治疗的多功能药物。这些新化合物大多具有设计的四重功能：H3受体拮抗、抑制Aβ聚集、金属离子螯合和清除自由基。特别是，最有希望的化合物5c在H3受体拮抗剂中表现出高选择性的纳米分子IC50值，有效地阻断A-2，2‘-azino-bis(3-ethyl-benzothiazoline-6-sulfonic(1-42)纤维的形成，良好的铜和铁的螯合性能，以及比Trolox更强的β(·+)清除活性。进一步的生物学评价表明，在微摩尔浓度下，其未表现出明显的细胞毒性和HERG钾通道抑制作用。此外，化合物5c在体内表现出良好的药代动力学性质和良好的血脑屏障(BBB)通透性。所有这些结果表明，化合物5c是治疗AD的一种潜在的多功能候选化合物。
A series of novel 1-phenyl-3-hydroxy-4-pyridinone derivatives were designed and synthesized as multifunctional agents for Alzheimer's disease (AD) therapy through incorporation of 3-hydroxy-4-pyridinone moiety from deferiprone into the scaffold of H3 receptor antagonists. Most of these new compounds displayed designed quadruple functions, H3 receptor antagonism, Aβ aggregation inhibition, metal ion chelation, and radical scavenging. Especially, the most promising compound 5c displayed nanomolar IC50 values in H3 receptor antagonism with high selectivity, efficient capability to interrupt the formation of Aβ(1-42) fibrils, good copper and iron chelating properties, and more potent 2,2'-azino-bis(3-ethyl-benzothiazoline-6-sulfonic acid) radical cation (ABTS(•+)) scavenging activity than Trolox. Further biological evaluation revealed that it did not show obvious cytotoxicity and hERG potassium channel inhibition at micromolar concentration. In addition, compound 5c demonstrated suitable pharmacokinetic properties and acceptable blood-brain barrier (BBB) permeability in vivo. All these results indicate that compound 5c is a potential multifunctional candidate for AD therapy.