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New thiopyrimidine-benzenesulfonamide conjugates as selective carbonic anhydrase II inhibitors: synthesis, in vitro biological evaluation, and molecular docking studies.
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2020-01-22 , DOI: 10.1016/j.bmc.2020.115329
Heba T Abdel-Mohsen 1 , Ahmed M El Kerdawy 2 , Mohamed A Omar 1 , Emanuela Berrino 3 , Ahmed S Abdelsamie 4 , Hoda I El Diwani 1 , Claudiu T Supuran 3
Affiliation  

In the present work, a new series of thiopyrimidine-benzenesulfonamide conjugates was designed, synthesized and tested as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. Our design strategy was based on the molecular hybridization of the benzenesulfonamide moiety as a zinc binding group (ZBG), an alkylated thiopyrimidine moiety as a spacer and (un)substituted phenyl moieties with various electronic and hydrophobic environments as a tail. The designed and synthesized compounds were evaluated against four human (h) CA isoforms hCA I, hCA II, hCA IX and hCA XII. Series 6 showed promising activity and selectivity toward the cytosolic isoforms hCA I and hCA II versus the membrane bound isoforms hCA IX and hCA XII. Compounds 6e and 6f showed Ki of 0.04 µM against hCA II with a selectivity of 15.8- to 980-fold towards hCA II over hCA I, hCA IX, hCA XII isoforms. Molecular docking in the hCA II active site attributed the promising inhibitory activity of series 6 to the interaction of their sulfonamide moiety with the active site Zn2+ ion as well as its hydrogen bonding with the key amino acids Thr199 and Thr200. Through hydrophobic interaction, the benzenesulfonamide and the thiopyrimidine moieties interact with the hydrophobic side chains of the amino acids Val121/Leu198 and Ile91/Phe131, respectively. These results indicated that the designed and synthesized series is an interesting scaffold that can be further optimized for the development of selective antiglaucoma drugs.

中文翻译:


作为选择性碳酸酐酶 II 抑制剂的新型硫代嘧啶-苯磺酰胺缀合物:合成、体外生物学评价和分子对接研究。



在目前的工作中,设计、合成了一系列新的硫代嘧啶-苯磺酰胺缀合物,并作为碳酸酐酶(CA、EC 4.2.1.1)抑制剂进行了测试。我们的设计策略基于苯磺酰胺部分作为锌结合基团(ZBG)、烷基化硫代嘧啶部分作为间隔基以及具有各种电子和疏水环境的(未)取代的苯基部分作为尾部的分子杂交。针对四种人 (h) CA 同工型 hCA I、hCA II、hCA IX 和 hCA XII 评估了设计和合成的化合物。系列 6 对胞质同工型 hCA I 和 hCA II 与膜结合同工型 hCA IX 和 hCA XII 表现出良好的活性和选择性。化合物 6e 和 6f 对 hCA II 的 Ki 值为 0.04 µM,对 hCA II 的选择性是 hCA I、hCA IX、hCA XII 同种型的 15.8 至 980 倍。 hCA II 活性位点的分子对接将系列 6 的有前景的抑制活性归因于其磺酰胺部分与活性位点 Zn2+ 离子的相互作用以及其与关键氨基酸 Thr199 和 Thr200 的氢键。通过疏水相互作用,苯磺酰胺和硫代嘧啶部分分别与氨基酸 Val121/Leu198 和 Ile91/Phe131 的疏水侧链相互作用。这些结果表明,设计和合成的系列是一个有趣的支架,可以进一步优化用于选择性抗青光眼药物的开发。
更新日期:2020-01-22
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