Discovery of novel dual-active 3-(4-(dimethylamino)phenyl)-7-aminoalcoxy-coumarin as potent and selective acetylcholinesterase inhibitor and antioxidant
Discovery of novel dual-active 3-(4-(dimethylamino)phenyl)-7-aminoalcoxy-coumarin as potent and selective acetylcholinesterase inhibitor and antioxidant
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DOI：
10.1080/14756366.2019.1571270
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发表时间：
2019-01-01
影响因子：
5.6
通讯作者：
Kummerle, Arthur Eugen
中科院分区：
文献类型：
--
作者：
de Souza, Gabriela Alves;da Silva, Soraia John;Kummerle, Arthur Eugen
设计了一系列3-取代-7-氨基烷氧基香豆素类化合物，并对其作为胆碱酯酶抑制剂和抗氧化剂进行了评价。所有化合物均有效抑制AChE，效力在纳摩尔范围内。3-（4-（二甲氨基）苯基）-7-氨基乙氧基-香豆素（6a）被认为是一个热门，显示出良好的AChE抑制效力（IC 50 = 20 nM）和选择性（IC 50 BuChE/AChE = 354），与参比药物多奈哌齐（IC 50 = 6 nM; IC 50 BuChE/AChE = 365）非常相似，还具有抗氧化特性、低细胞毒性和良好的预测ADMET特性。通过动力学和分子模拟评价，描述了这一系列化合物的作用模式（混合型）和SAR分析。[图形]
A series of 3-substituted-7-aminoalcoxy-coumarin was designed and evaluated as cholinesterase inhibitors and antioxidants. All compounds were effective in inhibiting AChE with potencies in the nanomolar range. The 3-(4-(dimethylamino)phenyl)-7-aminoethoxy-coumarin (6a) was considered a hit, showing good AChE inhibition potency (IC50 = 20 nM) and selectivity (IC50 BuChE/AChE = 354), quite similar to the reference drug donepezil (IC50 = 6 nM; IC50 BuChE/AChE = 365), also presenting antioxidant properties, low citotoxicity and good-predicted ADMET properties. The mode of action (mixed-type) and SAR analysis for this series of compounds were described by means of kinetic and molecular modeling evaluations.[GRAPHICS]