3.3.3. Zmp1 Inhibitors

Although its role is not fully understood yet, Zmp1 is involved in mycobacterial pathogenicity as it inhibits the inflammasome and therefore prevents phagosome maturation (Figure 1) [117]. Zinc peptidases like Zmp1 are often inhibited by molecules with specific zinc binding groups (ZBG) like 8-hydroxyquinolines. 8-hydroxyquinolines are already in use as metal-interacting structures in pharmacological applications [118]. Based on this, Vickers et al. synthesized compounds consisting of an 8-hydroxyquinoline ring and a hydroxamate moiety and isosteric analogues of these. One 8-hydroxyquinoline-2-hydroxamate derivative showed a reduction in colony forming units (CFU) in infected J774 mouse macrophages while no extracellular, anti-mycobacterial activity was observed. Treatment of infected human monocyte-derived macrophages with this substance led to a decrease in bacterial burden in a dose-dependent matter. In in-vitro inhibition assays the compound inhibited Zmp1 with an IC50 of 0.011 μM [119].
