Design and synthesis of novel 6-aryl substituted 4-anilinequinazoline derivatives as potential PI3Kδ inhibitors
Design and synthesis of novel 6-aryl substituted 4-anilinequinazoline derivatives as potential PI3Kδ inhibitors
复制标题
作为潜在 PI3K δ 抑制剂的新型 6-芳基取代 4-苯胺喹唑啉衍生物的设计和合成
DOI：
10.1016/j.bmcl.2017.03.020
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发表时间：
2017-05-01
影响因子：
2.7
通讯作者：
Zhang, San-Qi
中科院分区：
文献类型：
--
作者：
Xin, Minhang;Hei, Yuan-Yuan;Zhang, San-Qi
本研究基于已有的化学结构，设计并合成了一系列新的6-芳基取代4-苯胺喹唑啉作为PI3K抑制剂。初步建立构效关系（SAR），化合物13h和13k对PI3K δ的抑制作用最强，IC50值分别为9.3 nM和9.7 nM。化合物13h对三种人B细胞系表现出相似的抗增殖特性。在13h与PI3K δ酶的对接过程中发现了三个关键的氢键相互作用。这些结果表明，化合物13h具有纳米摩尔PI3K δ抑制活性和独特的化学结构，值得进一步的结构优化。(C) 2017 Elsevier Ltd.版权所有。
In this study, a series of new 6-aryl substituted 4-anilinequinazolines was designed and synthesized as PI3K delta inhibitors based on our reported chemical structures. The preliminary structure-activity relationship (SAR) was established, and compounds 13h and 13k displayed most potent PI3K delta inhibitory activities with the IC50 values of 9.3 nM and 9.7 nM, respectively. Compound 13h demonstrated similar anti proliferative profiles to idelalisib against three human B cell lines. Three key hydrogen bonding interactions were found in the docking of 13h with PI3K delta enzyme. These results suggest that compound 13h possessed nanomolar PI3K delta inhibitory activity and distinctive chemical structure, deserving further structural optimization. (C) 2017 Elsevier Ltd. All rights reserved.