Huang, Hsuan-ChunHsuan-ChunHuangChen, Tse-YuTse-YuChenYeh, Tsung-YuTsung-YuYehYu, Min-HsuanMin-HsuanYuWu, Sian-SiouSian-SiouWuLi, Guang-YiGuang-YiLiChen, Bo-YuBo-YuChenMIAO-HSIA LINLin, Ching-JungChing-JungLinHsu, Jui-LingJui-LingHsuJIH-HWA GUHCHAO-WU YU2025-11-042025-11-042025-10https://scholars.lib.ntu.edu.tw/handle/123456789/733368HDAC inhibitors, which have been proven to be effective for some cancers, have potential as treatments for Non-small cell lung cancer (NSCLC). Building on the core structure of the highly selective HDAC6 inhibitor J22352, we modified various zinc-binding groups of this inhibitor. The resulting compounds 1-8 were designed and synthesized to explore potential derivatives and assess their effects on NSCLC bioactivity. Notably, compounds 2, 7, and 8 selectively inhibited HDAC6, with IC values of 865.4, 145.0, and 11.9 nM, respectively. Additionally, a significant synergistic interaction was observed when benzamide 6 and ethyl hydrazine 7 were combined with the chemotherapy drug etoposide. The combination index of benzamide 6 (10 μM) with etoposide (10 μM) was 0.22, in contrast to 0.01 for ethyl hydrazine 7 (30 μM) with etoposide (10 μM). Encouragingly, ethyl hydrazine 7 also demonstrated superior bioavailability (149 %) after oral administration.enBenzamideEthyl hydrazineHistone deacetylase (HDAC)Non-hydroxamic acid histone deacetylase inhibitor (HDACi)[SDGs]SDG3journal article10.1016/j.bioorg.2025.10891740916300