Pyrazole-Isoindoline-1,3-dione Hybrid: A Promising Scaffold for 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors
Pyrazole-Isoindoline-1,3-dione Hybrid: A Promising Scaffold for 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors
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吡唑-异吲哚啉-1,3-二酮杂化物：4-羟基苯丙酮酸双加氧酶抑制剂的有前景的支架
DOI：
10.1021/acs.jafc.9b04917
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发表时间：
2019-10-02
影响因子：
6.1
通讯作者：
Yang, Guang-Fu
中科院分区：
文献类型：
--
作者：
He, Bo;Dong, Jin;Yang, Guang-Fu
4-羟苯基丙酮酸双加氧酶（HPPD，EC 1.13.11.27）抑制剂的发现由于其作为除草剂用于杂草控制的巨大潜力而一直是活跃的研究领域。从已知的HPPD抑制剂的结合模式出发，通过2-苯甲酰乙烯-1-醇与异吲哚啉-1，3-二酮片段的杂交，设计并合成了一系列具有新型分子骨架的HPPD抑制剂。体外实验结果表明，新合成的化合物对重组拟南芥HPPD（AtHPPD）具有良好的抑制活性，其IC 50值为0.0039 μ M至1 μ M以上。最有希望的是，化合物4ae，2-苄基-5-（5-羟基-1，3-二甲基-1H-吡唑-4-羰基）异吲哚啉-1，3-二酮，显示出最高的AtHPPD抑制活性，Ki值为3.92 nM，使其比磺草唑（Ki = 44 nM）有效约10倍，并且比甲基磺草酮（Ki = 4.56 nM）略有效。此外，AtHPPD-4ae复合物的共晶结构在1.8埃的分辨率下成功解析。X射线衍射分析表明，2-苯甲酰基乙烯-1-醇的两个羰基与金属离子形成双齿螯合作用，而异吲哚啉-1，3-二酮部分与Phe 381和Phe 424形成明显的π-π堆积作用。此外，观察到水介导的氢键相互作用之间的Asn 282和4ae的吡唑环的氮原子。上述结果表明，吡唑-异吲哚啉-1，3-二酮杂合物是开发HPPD抑制剂的有前景的支架。
The discovery of 4-hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) inhibitors has been an active area of research due to their great potential as herbicides for weed control. Starting from the binding mode of known inhibitors of HPPD, a series of HPPD inhibitors with new molecular scaffolds were designed and synthesized by hybridizing 2-benzoylethen-1-ol and isoindoline-1,3-dione fragments. The results of the in vitro tests indicated that the newly synthesized compounds showed good HPPD inhibitory activity with IC50 values against the recombinant Arabidopsis thaliana HPPD (AtHPPD) ranging from 0.0039 mu M to over 1 mu M. Most promisingly, compound 4ae, 2-benzyl-5-(5-hydroxy-1,3-dimethyl-1H-pyrazole-4-carbonyl)isoindoline-1,3-dione, showed the highest AtHPPD inhibitory activity with a K-i value of 3.92 nM, making it approximately 10 times more potent than pyrasulfotole (K-i = 44 nM) and slightly more potent than mesotrione (K-i = 4.56 nM). In addition, the cocrystal structure of the AtHPPD-4ae complex was successfully resolved at a resolution of 1.8 angstrom. The X-ray diffraction analysis indicated that the two carbonyl groups of 2-benzoylethen-l-ol formed a bidentate chelating interaction with the metal ion, while the isoindoline-1,3-dione moiety formed pronounced pi-pi stacking interactions with Phe381 and Phe424. Moreover, water-mediated hydrogen bonding interactions were observed between Asn282 and the nitrogen atoms of the pyrazole ring of 4ae. The above results showed that the pyrazole-isoindoline-1,3-dione hybrid is a promising scaffold for developing HPPD inhibitors.