Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United States.
Inorg Chem. 2022 May 16;61(19):7631-7641. doi: 10.1021/acs.inorgchem.2c00891. Epub 2022 May 4.
The use of metal-binding pharmacophores (MBPs) in fragment-based drug discovery has proven effective for targeted metalloenzyme drug development. However, MBPs can still suffer from pharmacokinetic liabilities. Bioisostere replacement is an effective strategy utilized by medicinal chemists to navigate these issues during the drug development process. The quinoline pharmacophore and its bioisosteres, such as quinazoline, are important building blocks in the design of new therapeutics. More relevant to metalloenzyme inhibition, 8-hydroxyquinoline (8-HQ) and its derivatives can serve as MBPs for metalloenzyme inhibition. In this report, 8-HQ isosteres are designed and the coordination chemistry of the resulting metal-binding isosteres (MBIs) is explored using a bioinorganic model complex. In addition, the physicochemical properties and metalloenzyme inhibition activity of these MBIs were investigated to establish drug-like profiles. This report provides a new group of 8-HQ-derived MBIs that can serve as novel scaffolds for metalloenzyme inhibitor development with tunable, and potentially improved, physicochemical properties.
金属结合药效团（MBPs）在基于片段的药物发现中的应用已被证明对靶向金属酶药物开发有效。然而，MBPs 仍然可能存在药代动力学缺陷。生物等排体替换是药物化学家在药物开发过程中用于解决这些问题的有效策略。喹啉药效团及其生物等排体，如喹唑啉，是设计新型治疗药物的重要构建块。更与金属酶抑制相关的是，8-羟基喹啉（8-HQ）及其衍生物可用作金属酶抑制的 MBPs。在本报告中，设计了 8-HQ 的等排体，并使用生物无机模型配合物探索了所得金属结合等排体（MBIs）的配位化学。此外，还研究了这些 MBIs 的物理化学性质和金属酶抑制活性，以建立类药特征。本报告提供了一组新的 8-HQ 衍生的 MBIs，它们可以作为具有可调谐和潜在改善的物理化学性质的金属酶抑制剂开发的新型支架。
