磺胺类化合物是治疗多种疾病有前途的药物靶点——碳酸酐酶（CAs）潜在抑制剂之一。本文中，采用端基法设计了一系列含有1,2,3-三唑基团的苯磺酰胺类化合物作为人类α-CAs（hCAs）的抑制剂。设计方法将苯磺酰胺基团与一个肟基和一个结合锌的基团结合在1,2,3-三唑框架上构建。在合成的衍生物中，萘基（6m，KI为68.6 nM，SI为10.3）和甲基（6a，KI为56.3 nM，SI为11.7）衍生物（对hCA IX）以及丙基（6c，KI为95.6 nM，SI为2.7）和戊基（6d，KI为51.1 nM，SI为6.6）衍生物（对hCA XII）表现出针对hCA I和II亚型的明显选择性。同时，衍生物6e对细胞质亚型hCA I（KI为47.8 nM）和肿瘤相关亚型hCA IX和XII（各自的KI为195.9和116.9 nM）显示出有效的抑制作用，与参考药物乙酰唑胺（AAZ，其KI分别为451.8、437.2和338.9 nM）相比有明显优势。衍生物6b对细胞质亚型hCA II的抑制效果（KI为33.2 nM）甚至比AAZ（KI为327.3 nM）更显著。但是，将亲脂性较强的大萘基换成三唑型苯磺酰胺衍生物（6a-n）会增强衍生物对hCA I和XII的抑制作用，并对hCA IX亚型的选择性产生影响。对合成衍生物的细胞毒性进行了评估，其中几种化合物表现出显著的抗增殖活性和最小的细胞毒性。在分子对接研究中，磺胺基团与锌离子相互作用并完美地适合于hCAs的活性位点。延长端基被发现参与了与相邻氨基酸的不同亲水性和疏水性相互作用，最终影响了衍生物的有效性和特异性。版权所有©2023 Elsevier B.V. 发布。

Sulfonamides are among the most promising potential inhibitors for carbonic anhydrases (CAs), which are pharmaceutically relevant targets for treating several disease conditions. Herein, a series of benzenesulfonamides bearing 1,2,3-triazole moiety as inhibitors of human (h) α-CAs (hCAs) were designed using the tail approach. The design method combines a benzenesulfonamide moiety with a tail of oxime and a zinc-binding group on a 1,2,3-triazole scaffold. Among the synthesized derivatives, the naphthyl (6m, KI of 68.6 nM, SI of 10.3), and methyl (6a, KI of 56.3 nM, SI of 11.7) derivatives (over hCA IX) and propyl (6c, KI of 95.6 nM, SI of 2.7), and pentyl (6d, KI of 51.1 nM, SI of 6.6) derivatives (over hCA XII) displayed a noticeable selectivity for isoforms hCA I and II, respectively. Meanwhile, derivative 6e displayed a potent inhibitory effect versus the cytosolic isoform hCA I (KI of 47.8 nM) and tumor-associated isoforms hCA IX and XII (KIs of 195.9 and 116.9 nM, respectively) compared with the reference drug acetazolamide (AAZ, KIs of 451.8, 437.2, and 338.9 nM, respectively). Derivative 6b showed higher potency (KI of 33.2 nM) than AAZ (KI of 327.3 nM) towards another cytosolic isoform hCA II. Nevertheless, substituting the lipophilic large naphthyl tail to the 1,2,3-triazole linked benzenesulfonamides (6a-n) raised inhibitory effect versus hCA I and XII and selectivity towards hCA I and II isoforms over hCA IX. Evaluation of the cytotoxic potential of the synthesized derivatives was conducted in L929, MCF-7, and Hep-3B cell lines. Several compounds in the series demonstrated significant antiproliferative activity and minimal cytotoxicity. In the molecular docking study, the sulfonamide moiety interacted with the zinc-ion and neatly fit into the hCAs active sites. The extension of the tail was found to participate in diverse hydrophilic and hydrophobic interactions with adjacent amino acids, ultimately influencing the effectiveness and specificity of the derivatives.Copyright © 2023. Published by Elsevier B.V.