Psoralen Derivatives as Inhibitors of <i>Mycobacterium tuberculosis</i> Proteasome

Protein degradation is a fundamental process in all living organisms. An important part of this system is a multisubunit, barrel-shaped protease complex called the proteasome. This enzyme is directly responsible for the proteolysis of ubiquitin- or pup-tagged proteins to smaller peptides. In this study, we present a series of 92 psoralen derivatives, of which 15 displayed inhibitory potency against the Mycobacterium tuberculosis proteasome in low micromolar concentrations. The best inhibitors, i.e., 8 , 11 , 13 and 15 , exhibited a mixed type of inhibition and overall good inhibitory potency in biochemical assays. N -(cyanomethyl)acetamide 8 ( K i = 5.6 µM) and carboxaldehyde-based derivative 15 ( K i = 14.9 µM) were shown to be reversible inhibitors of the enzyme. On the other hand, pyrrolidine-2,5-dione esters 11 and 13 irreversibly inhibited the enzyme with K i values of 4.2 µM and 1.1 µM, respectively. In addition, we showed that an established immunoproteasome inhibitor, PR-957 , is a noncompetitive irreversible inhibitor of the mycobacterial proteasome ( K i = 5.2 ± 1.9 µM, k inact / K i = 96 ± 41 M -1 ·s -1 ). These compounds represent interesting hit compounds for further optimization in the development of new drugs for the treatment of tuberculosis.