6‑Substituted Triazolyl Benzoxaboroles as Selective Carbonic Anhydrase Inhibitors: <i>In Silico</i> Design, Synthesis, and X‑ray Crystallography

Benzoxaborole is currently a scaffold of great relevance in medicinal chemistry. In 2016, it was reported to be a new and valuable chemotype for designing carbonic anhydrase (CA) inhibitors. Herein, using an in silico design, we report the synthesis and characterization of substituted 6-(1H-1,2,3-triazol-1-yl)­benzoxaboroles. 6-Azidobenzoxaborole was described for the first time as a molecular platform to prepare libraries of inhibitors by a copper­(I)-catalyzed azide–alkyne cycloaddition via a click chemistry strategy. With inhibition constants below 30 nM, some derivatives, such as compound 20, showed efficacy as selective hCA VII and IX inhibitors. The design hypothesis was validated by crystallographic investigation on the hCA II/20 adduct, which provided explanations over the different inhibition behavior observed against the five evaluated hCA isoforms. Overall, this study identified 20 as a new promising lead compound to develop novel anticancer agents targeting the tumor-associated hCA IX but also potent neuropathic pain relievers targeting hCA VII.苯并氧硼杂环（benzoxaborole）目前是药物化学领域极具研究价值的核心骨架。2016年，已有研究将其报道为一类可用于设计碳酸酐酶（carbonic anhydrase, CA）抑制剂的新型高价值化学型。本文采用虚拟设计（in silico design）策略，报道了取代基修饰的6-(1H-1,2,3-三唑-1-基)苯并氧硼杂环的合成与表征工作。研究首次将6-叠氮基苯并氧硼杂环作为分子平台，通过点击化学（click chemistry）策略，经铜(I)催化的叠氮-炔环加成反应构建抑制剂化合物库。部分衍生物的抑制常数低于30 nM，其中化合物20表现出对人类碳酸酐酶（hCA）Ⅶ和Ⅸ亚型的选择性抑制活性。本研究通过对hCA Ⅱ/20复合物的晶体学分析验证了设计假说，并阐明了该类化合物对5种被测hCA亚型产生差异化抑制活性的机制。综上，本研究确定化合物20是一款极具开发前景的先导化合物，既可用于研发靶向肿瘤相关hCA Ⅸ的新型抗癌药物，也可用于开发靶向hCA Ⅶ的强效神经性疼痛治疗药物。