Dipartimento CHIBIOFARAM, Università degli Studi di Messina, Viale Palatucci, Polo Didattico SS. Annunziata, 98168 Messina, Italy.
Istituto di Biostrutture e Bioimmagini-CNR, Via Mezzocannone 16, 80134 Napoli, Italy.
Bioorg Med Chem. 2021 Aug 15;44:116279. doi: 10.1016/j.bmc.2021.116279. Epub 2021 Jun 17.
To tackle the challenge of isoform selectivity, we explored the entrance of the cavity for selected druggable human Carbonic Anhydrases (hCAs). Based on X-ray crystallographic studies on the 4-(4-(2-chlorobenzoyl)piperazine-1-carbonyl)benzenesulfonamide in complex with the brain expressed hCA VII (PDB code: 7NC4), a series of 4-(4(hetero)aroylpiperazine-1-carbonyl)benzene-1-sulfonamides has been developed. To evaluate their capability to fit the hCA VII catalytic cavity, the newer benzenesulfonamides were preliminary investigated by means of docking simulations. Then, this series of thirteen benzenesulfonamides was synthesized and tested against selected druggable hCAs. Among them, the 4-(4-(furan-2-carbonyl)piperazine-1-carbonyl)benzenesulfonamide showed remarkable affinity towards hCA VII (K: 4.3 nM) and good selectivity over the physiologically widespread hCA I when compared to Topiramate (TPM).
为了解决同工型选择性的难题，我们探索了选定的可药物治疗的人碳酸酐酶（hCA）的空腔入口。基于与脑表达的 hCA VII（PDB 代码：7NC4）形成复合物的 4-（4-（2-氯苯甲酰基）哌嗪-1-羰基）苯磺酰胺的 X 射线晶体学研究，已经开发了一系列 4-（4-（杂芳基）哌嗪-1-羰基）苯-1-磺酰胺。为了评估它们适应 hCA VII 催化腔的能力，通过对接模拟初步研究了较新的苯磺酰胺。然后，合成了这一系列的十三苯磺酰胺，并针对选定的可药物治疗的 hCA 进行了测试。其中，4-（4-（呋喃-2-羰基）哌嗪-1-羰基）苯磺酰胺对 hCA VII 表现出显著的亲和力（K：4.3 nM），与 Topiramate（TPM）相比，对广泛分布于生理上的 hCA I 具有良好的选择性。
