Design, synthesis and biological evaluation of novel human monoamine oxidase B inhibitors based on a fragment in an X-ray crystal structure
Design, synthesis and biological evaluation of novel human monoamine oxidase B inhibitors based on a fragment in an X-ray crystal structure
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基于X射线晶体结构片段的新型人单胺氧化酶B抑制剂的设计、合成和生物学评价
DOI：
10.1016/j.bmcl.2019.02.008
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发表时间：
2019-04-15
影响因子：
2.7
通讯作者：
Liao, Chenzhong
中科院分区：
文献类型：
--
作者：
Cheng, Kai;Li, Shiyu;Liao, Chenzhong
在这里，我们报告了我们开发基于isatin的可逆选择性hMAO-B抑制剂的努力，isatin是x射线晶体结构中的片段。设计了五种不同的支架，并合成了许多化合物。其中，化合物A3对hMAO-B具有非常高的效价和异构体选择性，其效价（IC50 = 3 nM）分别是标记药物selegiline和safinamide的11倍和13倍，选择性分别为23.64倍和6.8倍。然而，在hMAO-B结合位点的疏水环境中，将isatin的极性3- 1基团修饰为小的非极性疏水基团并没有带来hMAO-B抑制剂的改进，这可能会挑战我们对生物系统中分子相互作用和分子识别的理解。
Herein we report our efforts of developing reversible selective hMAO-B inhibitors based on isatin, a fragment in an X-ray crystal structure. Five different scaffolds were designed and many compounds were synthesized. Among them, compound A3 demonstrated very high potency and isoform selectivity against hMAO-B, 11 and 13 times more potent (IC50 = 3 nM) and 23.64 and 6.8 times more selective than the marked drugs, selegiline and safinamide. However, the endeavors to modify the polar 3-one group of isatin, that is in a hydrophobic environment in the binding site of hMAO-B, to small nonpolar hydrophobic groups did not bring about improved hMAO-B inhibitors, which may challenge our understanding of molecular interactions and molecular recognition in biological systems.