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Discovery of New 1,1'-Biphenyl-4-sulfonamides as Selective Subnanomolar Human Carbonic Anhydrase II Inhibitors.
ACS Medicinal Chemistry Letters ( IF 4.2 ) Pub Date : 2019-11-11 , DOI: 10.1021/acsmedchemlett.9b00437
Giuseppe La Regina 1 , Michela Puxeddu 1 , Marianna Nalli 1 , Daniela Vullo 2 , Paola Gratteri 3 , Claudiu Trandafir Supuran 2 , Alessio Nocentini 2, 3 , Romano Silvestri 1
Affiliation  

We report here the synthesis and human carbonic anhydrases (CA, EC 4.2.1.1) inhibitory properties of a series of 4'-substituted 1,1'-biphenyl-4-sulfonamides incorporating a 2″- or 3″-amino- or carboxyphenyl unit. Most compounds showed significant variations in their inhibition profiles against CA II and IX when compared to previously reported analogs 12-18 bearing a 4″-amino or a 4″-carboxy group. In particular, compounds 1-11 showed considerable improvement of the CA II inhibitory efficacy with K I values in the subnanomolar range (K Is spanning between 0.57 and 31.0 nM), a drop of activity against CA IX (K Is in the range 92.0 to 555.7 nM) and were as potent as 12-18 toward CA I (K Is in the range 5.9-217.7 nM). Docking and molecular dynamics were used to gain insights on the inhibition profiles. The reported inhibition data show that 1-11 have potential as novel agents to treat ocular pathologies, such as glaucoma, because of the potent and selective targeting of CA II, which is the isoform most implicated in this disease.

中文翻译:

发现新的1,1'-联苯-4-磺酰胺作为亚纳摩尔型选择性人类碳酸酐酶II抑制剂。

我们在这里报告了一系列结合有2“-或3”-氨基-或羧基苯基的4'-取代的1,1'-联苯-4-磺酰胺的合成及人类碳酸酐酶(CA,EC 4.2.1.1)的抑制特性单元。与先前报道的带有4“-氨基或4”-羧基的类似物12-18相比,大多数化合物在其对CA II和IX的抑制作用中表现出显着的变化。尤其是,化合物1-11的KI值在亚纳摩尔范围内(K介于0.57至31.0 nM之间)显示出对CA II抑制功效的显着改善,对CA IX的活性下降(K在92.0至555.7范围内) nM),对CA I的效力高达12-18(K在5.9-217.7 nM范围内)。使用对接和分子动力学来获得关于抑制曲线的见解。
更新日期:2019-11-11
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