Abstract

We evaluated the hCA (CA, EC 4.2.1.1) inhibitory activity of novel 4-(2-(2-substituted-thio-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamides (compounds 2–20) towards the isoforms I, II, IX, and XII. hCA Isoforms were effectively inhibited by most of new compounds comparable to those of AAZ. Compounds 2 and 4 showed interestingly efficient and selective antitumor (hCA IX and hCA XII) inhibitor activities (K_Is; 40.7, 13.0, and 8.0, 10.8 nM, respectively). Compounds 4 and 5 showed selective hCA IX inhibitory activity over hCA I (SI; 95 and 24), hCA IX/hCA II (SI; 23 and 5.8) and selective hCA XII inhibitory activity over hCA I (SI; 70 and 44), hCA XII/hCA II, (SI; 17 and 10) respectively compared to AAZ. Compounds 12–17, and 19–20 showed selective inhibitory activity towards hCA IX over hCA I and hCA II, with selectivity ranges of 27–195 and 3.2–19, respectively, while compounds 12, 14–17, and 19 exhibited selective inhibition towards hCA XII over hCA I and hCA II, with selectivity ratios of 48–158 and 5.4–31 respectively, compared to AAZ. Molecular docking analysis was carried out to investigate the selective interactions among the most active derivatives, 17 and 20 and hCAs isoenzymes. Compounds 17 and 20, which are highly selective CA IX and XII inhibitors, exhibited excellent interaction within the putative binding site of both enzymes, comparable to the co-crystallized inhibitors.

• Highlights

• Quinazoline-linked ethylbenzenesulfonamides inhibiting CA were synthesised.

• The new molecules potently inhibited the hCA isoforms I, II, IV, and IX.

• Compounds 4 and 5 were found to be selective hCA IX/hCA I and hCA IX/hCA II inhibitors.

• Compounds 4 and 5 were found to be selective hCA XII/hCA I and hCA XII/hCA II inhibitors.

• Compounds 12–17, 19, and 20 were found to be selective hCA IX/hCA I and hCA IX/hCA II inhibitors.

• Compounds 12, 14–17, 19 were found to be selective hCA XII/hCA I and hCA XII/hCA II inhibitors.

• Graphical Abstract

• 

• Compounds 4 and 5 are selective hCA IX and XII inhibitors over hCA I (selectivity ratios of 95, 23, and 24, 5.8, respectively) and hCA II (selectivity ratios of 70, 17, and 44, 10 respectively). Compounds 12–17, and 19–20 are selective hCA IX inhibitors over hCA I (selectivity ratios of 27-195) and hCA II (selectivity ratios of 3.2-19). Compounds 12, 14–17 and 19 are also selective hCA XII inhibitors over hCA I (selectivity ratios of 48-158) and hCA II (selectivity ratios of 5.4-31).

摘要

我们评估了新型4-（2-（2-（2-取代-硫代-4-氧代喹唑啉-3（4H）-基）乙基）苯磺酰胺（化合物2-20）的hCA（CA，EC 4.2.1.1）抑制活性。异构体I，II，IX和XII。与AAZ相当的大多数新化合物均有效抑制了hCA亚型。化合物2和4显示出有趣的是有效的和选择性的抗肿瘤（HCA IX和HCA XII）抑制剂活性（K_我S; 40.7，13.0和8.0，10.8纳米，分别地）。化合物4和5显示出对hCA I（SI; 95和24），hCA IX / hCA II（SI; 23和5.8）的选择性hCA IX抑制活性和对hCA I（SI; 70和44），hCA XII / hCA的选择性hCA XII抑制活性II（SI; 17和10）分别与AAZ进行比较。化合物12-17和19-20表明朝向HCA IX超过HCA I和II HCA选择性抑制活性，具有分别27-195和3.2-19，选择性范围，而化合物12，14-17，和19显示出选择性抑制相对于hCA I和hCA II对hCA XII的选择性，与AAZ相比，选择性比分别为48–158和5.4–31。进行了分子对接分析以研究最活跃的衍生物17之间的选择性相互作用。和20和hCAs同工酶。与共结晶抑制剂相比，作为高选择性CA IX和XII抑制剂的化合物17和20在两种酶的假定结合位点内均表现出出色的相互作用。

• 强调

• 合成了抑制CA的喹唑啉连接的乙基苯磺酰胺。

• 新分子有效抑制了hCA亚型I，II，IV和IX。

• 发现化合物4和5是选择性hCA IX / hCA I和hCA IX / hCA II抑制剂。

• 发现化合物4和5为选择性hCA XII / hCA I和hCA XII / hCA II抑制剂。

• 化合物12 - 17，19，和20被认为是选择性的HCA IX / HCA I和HCA IX / HCA II抑制剂。

• 化合物12，14 - 17，19被发现是选择性HCA XII / HCA I和HCA XII / HCA II抑制剂。

• 图形概要

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• 化合物4和5是hCA I（选择性比分别为95、23和24、5.8）和hCA II（选择性比分别为70、17和44、10）的选择性hCA IX和XII抑制剂。与hCA I（选择性比为27-195）和hCA II（选择性比为3.2-19）相比，化合物12-17和19-20是选择性hCA IX抑制剂。化合物12，14-17和19也选择性HCA XII抑制剂在HCA I（的48-158选择性比率）和HCA II（的5.4-31选择性比率）。