Proteasomes play an important role in protein degradation and regulation of many cellular pathways by maintaining protein balance. Inhibitors of proteasomes disrupt this balance affecting proteins that are key in malignancies and as such have found applications in the treatment of multiple myeloma and mantle cell lymphoma. However, resistance mechanisms have been reported for these proteasome inhibitors including mutations at the β5 site which necessitates the constant development of new inhibitors. In this work, we report the identification of a new class of proteasome inhibitors, polycyclic molecules bearing a naphthyl–azotricyclic-urea–phenyl scaffold, from screening of the ZINC library of natural products. The most potent of these compounds showed evidence of dose dependency through proteasome assays with IC₅₀ values in the low micromolar range, and kinetic analysis revealed competitive binding at the β5c site with an estimated inhibition constant, K_i, of 1.15 μM. Inhibition was also shown for the β5i site of the immunoproteasome at levels similar to those of the constitutive proteasome. Structure–activity relationship studies identified the naphthyl substituent to be crucial for activity and this was attributed to enhanced hydrophobic interactions within β5c. Further to this, halogen substitution within the naphthyl ring enhanced the activity and allowed for π–π interactions with Y169 in β5c and Y130 and F124 in β5i. The combined data highlight the importance of hydrophobic and halogen interactions in β5 binding and assist in the design of next generation inhibitors of proteasomes.