N-substituted noscapine derivatives as new antiprotozoal agents: Synthesis, antiparasitic activity and molecular docking study
N-substituted noscapine derivatives as new antiprotozoal agents: Synthesis, antiparasitic activity and molecular docking study
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DOI：
10.1016/j.bioorg.2019.103116
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发表时间：
2019-10-01
影响因子：
5.1
通讯作者：
Al-Harrasi, Ahmed
中科院分区：
文献类型：
--
作者：
Harikandei, Kosar Babanezhad;Salehi, Peyman;Al-Harrasi, Ahmed
在氰离子存在下，N-去甲诺斯卡品的环醚与不同的醛通过三组分Strecker反应合成了新型N-取代诺斯卡品衍生物。此外，通过氰化物部分的氧化以良好的产率合成了相应的酰胺。并对产物进行了体外抗原虫活性研究。有趣的是，一些类似物确实显示出有希望的抗布氏锥虫罗得西亚锥虫的抗寄生虫活性，IC 50值在2.5和10.0 μ M之间，选择性指数（SI）在0.8至13.2之间。8个化合物显示出对恶性疟原虫K1株的活性，IC 50范围为1.7-6.4 μ M，对L 6大鼠成肌细胞系的SI值在2.8和10.5之间。对作为研究设想的作用机制的靶标的锥虫硫酮还原酶（TbTR，PDB ID：2 WOW）和UDP-半乳糖4'差向异构酶（TbUDPGE PDB：1GY 8）进行分子对接。化合物6 j（2）和6 b（2）显示出优异的对接分数，TbTR和TbUDPGE分别为-8.59和-8.86 kcal/mol。
Novel N-substituted noscapine derivatives were synthesized by a three-component Strecker reaction of cyclic ether of N-nornoscapine with varied aldehydes, in the presence of cyanide ion. Moreover, the corresponding amides were synthesized by the oxidation of cyanide moieties in good yields. The in vitro antiprotozoal activity of the products was also investigated. Interestingly, some analogues did put on display promising antiparasitic activity against Trypanosoma brucei rhodesiense with IC50 values between 2.5 and 10.0 mu M and selectivity index (SI) ranged from 0.8 to 13.2. Eight compounds exhibited activity against Plasmodium falciparum K1 strain with IC50 ranging 1.7-6.4 mu M, and SI values between 2.8 and 10.5 against L6 rat myoblast cell lines. Molecular docking was carried out on trypanothione reductase (TbTR, PDB ID: 2WOW) and UDP-galactose 4' epimerase (TbUDPGE PDB: 1GY8) as targets for studying the envisaged mechanism of action. Compounds 6j(2) and 6b(2) displayed excellent docking scores with -8.59 and -8.86 kcal/mol for TbTR and TbUDPGE, respectively.