Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Taç Sok. No:3 Yenimahalle, 06560, Ankara, Turkey.
Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy.
ChemMedChem. 2022 May 18;17(10):e202200056. doi: 10.1002/cmdc.202200056. Epub 2022 Mar 9.
We describe the synthesis of a series of thiadiazolyl-benzenesulfonamide derivatives carrying an aromatic tail linked by an amide linker (12-34), as human carbonic anhydrase (hCA) inhibitors. These thiadiazol derivatives were evaluated against four physiologically relevant CA isoforms (hCA I, II, IX, and XII), and demonstrated intriguing inhibitory activity against CA II with K values in the range of 2.4-31.6 nM. Besides hCA II, also hCA XII activity was potently inhibited by some of the derivatives (K =1.5-88.5 nM), producing dual inhibitors of both isoforms. Notably, compound 17 was the most potent dual CA II (K =3.1 nM) and XII (K =1.5 nM) inhibitor with a significant selectivity ratio over CA I and IX isoforms. In conclusion, although all compounds exhibited preferential activity towards hCA II, the nature of the substituents at the tail part of the main scaffold influenced the activity and selectivity toward other isoforms.
我们描述了一系列噻二唑基-苯磺酰胺衍生物的合成，这些衍生物带有通过酰胺键连接的芳基尾部（12-34），可用作人碳酸酐酶（hCA）抑制剂。这些噻二唑衍生物针对四种生理相关的 CA 同工酶（hCA I、II、IX 和 XII）进行了评估，对 CA II 表现出有趣的抑制活性，K 值范围为 2.4-31.6 nM。除了 hCA II，一些衍生物还能强烈抑制 hCA XII 活性（K =1.5-88.5 nM），产生两种同工酶的双重抑制剂。值得注意的是，化合物 17 是最有效的双重 CA II（K =3.1 nM）和 XII（K =1.5 nM）抑制剂，对 CA I 和 IX 同工酶具有显著的选择性比值。总之，尽管所有化合物对 hCA II 均表现出优先活性，但主支架尾部取代基的性质会影响对其他同工酶的活性和选择性。
