Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial molecular chaperone and a homolog of the 90-kDa heat shock protein (Hsp90) family that supports normal cellular function. By alleviating cellular stress, TRAP1 promotes cancer cell survival and is consequently overexpressed in various cancers. TRAP1 functions as a homodimer, with each protomer comprising three domains: an N-terminal domain (NTD), a middle domain (MD), and a C-terminal domain (CTD). In our previous work, we developed DN401, a mitochondria-permeable compound that selectively inhibits the TRAP1 NTD and exerts anticancer activity. However, DN401 exhibited unfavorable ADME properties. To address this limitation, we synthesized a new series of derivatives by modifying the problematic functional groups and evaluated their biological activity.