新型苯甲酰胺-2-氧代吲哚苯磺酰胺类碳酸酐酶抑制剂的合成、分子模拟及构效关系研究。

Synthesis, molecular modelling and QSAR study of new phenylacetamide-2-oxoindole benzensulfonamide conjugates as carbonic anhydrase inhibitors with antiproliferative activity.

机构信息

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.

Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Florence, Italy.

出版信息

J Enzyme Inhib Med Chem. 2022 Dec;37(1):701-717. doi: 10.1080/14756366.2022.2036137.

In continuation of our previous studies to optimise potent carbonic anhydrase inhibitors, two new series of isatin phenylacetamide based sulphonamides were synthesised and screened for their human (h) carbonic anhydrase (EC 4.2.1.1) inhibitory activities against four isoforms CA I, CA II, CA IX and CA XII. The indole-2,3-dione derivative showed the most effective inhibition profile against CAI and CA II (K = 45.10, 5.87 nM) compared to acetazolamide ( as standard inhibitor. Moreover, showed appreciable inhibition activity against the tumour-associated CA XII, similar to showing K of 7.91 and 5.70 nM, respectively. The analogs and showed good cytotoxicity effects, and revealed promising selectivity towards lung cell line A549. Molecular docking was carried out for and to predict their binding conformations and affinities towards the CA I, II, IX and XII isoforms.

继我们之前的研究优化强效碳酸酐酶抑制剂之后，我们合成了两个新的基于靛红苯乙酰胺的磺酰胺系列，并对其抑制人源（h）碳酸酐酶（EC 4.2.1.1）的活性进行了筛选，共针对四个同工酶 CA I、CA II、CA IX 和 CA XII。与乙酰唑胺（作为标准抑制剂）相比，吲哚-2,3-二酮衍生物对 CAI 和 CA II 的抑制作用最为有效（K = 45.10、5.87 nM）。此外，对肿瘤相关的 CA XII 也表现出相当的抑制活性，与对 CA XII 的 K 值分别为 7.91 和 5.70 nM。类似物和表现出良好的细胞毒性作用，对肺细胞系 A549 具有良好的选择性。对和进行了分子对接，以预测它们与 CA I、II、IX 和 XII 同工酶的结合构象和亲和力。