Novel Ridaifen analogs were designed and synthesized to target the proteasome. Structure-activity relationship studies revealed potent and selective inhibition of the CT-L and PGPH activities, offering promising scaffolds for anticancer drug development.

Ridaifen (RID) analogues are identified as nonpeptide, noncovalent inhibitors of the catalytic subunits of the human 20S proteasome. They demonstrated effectiveness against both multiple myeloma and solid tumors. Herein, the synthesis and biological evaluation of 20 novel RID analogs that exhibit inhibitory effects on the three catalytic subunits of the 20S proteasome are reported. All the compounds were tested on the National Cancer Institute (NCI) 60 cancerous cell lines. The compounds bear symmetric aminoalkoxy groups on rings B and C, different substituents on ring A, and the terminal side chain on the ethylene backbone was modified to methyl and cyclopentyl groups.Compound 43 was the most potent inhibitor for both CT-L and PGPH (IC₅₀ = 0.22, 0.05 μM), which is threefold more potent for CT-L and tenfold more potent on PGPH than RID-F. Most of the analogs showed pan activity toward different cancer cell lines, and compound 20 was more potent than tamoxifen. Compound 20 showed submicromolar IC₅₀ values for CT-L and PGPH activities, indicating that it mediates its cytotoxic activity via proteasomal inhibition. Selected compounds were tested against Ebolavirus, and compound 36 showed the highest antiviral activity, surpassing the EC₅₀ of the reference compound favipiravir.