The 26S proteasome regulates several biological activities, including cell cycle progression, cell growth, differentiation and proliferation. The proteasome's abnormal degradation of essential regulatory proteins disrupts these processes which results in uncontrolled cell cycle progression and reduced cell death. Ridaifen analogues were reported as non-peptide non-covalent inhibitors of human 20S proteasome catalytic subunits (T-L, CT-L, PGPH), they are effective against both multiple myeloma and solid tumors. Herein we report novel non-covalent non-peptide proteasome inhibitors bearing a triphenylethylene (TPE) backbone. Compounds were tested for their ability to inhibit the three different catalytic subunits of the 20S proteasome core in vitro. Two series were adopted in this work, with rigid and flexible skeletons. We examined the structural activity relationship of the novel analogues to optimize their proteasomal inhibition activity. Compounds were tested for their anti-proliferative effects in the National Cancer Institute (NCI) -60 cell lines. Compound I, a rigid analogue bearing a bis-dimethlyamino propoxy side chain on ring B and C and a para methoxy substituent on ring A, showed mean GI₅₀ = 1.65 µM on all 60 NCI cell lines, IC₅₀ CT-L activity = 0.36 µM and PGPH activity IC₅₀ = 0.48 µM. TPE based SERMs like Toremifene and Clomiphene were reported to inhibit viral entry of Ebola Virus (EBOV) and its replication. Compound VI showed ability to inhibit EBOV replication with EC₅₀ = 0.11 µM, SI = 33.