Structural Optimization and Structure–Activity Relationship of 1<i>H</i>-Pyrazole-4-carboxylic Acid Derivatives as DNA 6mA Demethylase ALKBH1 Inhibitors and Their Antigastric Cancer Activity

DNA <i>N</i>⁶-methyladenine (6mA) demethylase ALKBH1 plays an important role in various cellular processes. Dysregulation of ALKBH1 is associated with the development of some cancer types, including gastric cancer, implicating a potential therapeutic target. However, there is still a lack of potent ALKBH1 inhibitors. Herein, we report the discovery of a highly potent ALKBH1 inhibitor, 1<i>H</i>-pyrazole-4-carboxylic acid derivative <b>29</b>. The structure-activity relationship of this series of compounds was also discussed. Because of the poor cell membrane permeability of <b>29</b>, we prepared a prodrug of <b>29</b> (<b>29E</b>), which showed excellent cellular activities. In gastric cancer cell lines HGC27 and AGS, <b>29E</b> treatment significantly increased the abundance of 6mA, inhibited cell viability, and upregulated the AMP-activated protein kinase (AMPK) signaling pathway. In addition, the hydrolysis product <b>29</b> showed high exposure in mice after administration of <b>29E</b>. Collectively, this research provides a new potent ALKBH1 inhibitor, which could serve as a lead compound for subsequent drug development.