Oxadiazon Derivatives Elicit Potent Intracellular Growth Inhibition against by Disrupting Heme Biosynthesis.

Infections of can cause severe and sometimes fatal diseases in immunocompromised individuals. The heme biosynthesis pathway is required for intracellular growth and pathogenesis, making it an appealing therapeutic target. We synthesized a small library of derivatives of the herbicide oxadiazon, a known inhibitor of the penultimate reaction within the heme biosynthesis pathway in plants, catalyzed by protoporphyrinogen oxidase (PPO). Seven of the 18 analogs exhibit potent intracellular growth inhibition of wild-type (IC = 1 to 2.4 μM). An assay of the compounds against PPO knockout and complementation strains confirmed the mode of action to be due to the potent inhibition of PPO. The most potent compounds have no detectable cytotoxicity against human foreskin fibroblast cells up to 100 μM. This study suggests that oxadiazon derivatives may represent a new molecular scaffold for the effective treatment of infections.