Design, Synthesis, and Biological Evaluation of Thiourea‐Based Colchicine Derivatives as Proteasome Inhibitors in Cancer Therapy

ABSTRACT Cancer is a multifactorial disease, and proteasomes are established targets for chemotherapy in cancer treatment. Several covalent inhibitors are currently available on the market or in clinical use; however, these drugs often have unfavorable pharmacodynamic profiles due to the presence of electrophilic warheads. This can lead to mutations and overexpression of the proteasome, resulting in drug resistance. In this study, thiourea‐based colchicine derivatives were designed, synthesized, and evaluated for their ability to inhibit the chymotrypsin‐like activity of the β5 subunit in the proteasome, using a Jurkat cell lysate enriched with proteasomes. The in vitro proteasome inhibition assay revealed that the thiourea‐based derivative CTU5, featuring a methoxy group at the para position, exhibited the highest activity, achieving 65.29% inhibition at 50 µM, compared to the well‐known covalent inhibitor MG132. Additionally, a molecular docking investigation was performed to explore potential binding interactions. Furthermore, the in silico absorption, distribution, metabolism, and excretion (ADME) parameters suggested that CTU5 may possess drug‐like properties and could be developed into an orally active pharmaceutical. Overall, these findings indicate that CTU5 has the potential to serve as a new scaffold and starting point for the development of novel, potent proteasome inhibitors in the future.