It should be noted that both itraconazole and posaconazole, both effective antifungal agents, could also have a phenylenediamine incorporated into their structures, thus conferring dual anti-fungal/antiinflammatory properties on these therapeutics as well. We are currently investigating the properties of these modified anti-fungal agents further, with the hope of utilizing the phenylenediamine moiety as a simple modification for adding 5-LOX inhibitory potency to known therapeutics. The fact that ketoconazole is both an anti-fungal and antiinflammatory molecule is not a new phenomenon in the field of anti-fungal therapeutics. Previously, we determined that the common anti-fungal agent, chloroxine, was also a non-specific LOX inhibitor. This fact suggested that the inherent selection process for the search for anti-seborrheic dermatitis agents could be responsible for the dual nature of the anti-fungal/antiinflammatory therapeutics, such as chloroxine and ketoconazole. With this hypothesis in mind, the anti-fungal agent, ciclopirox, presented a structure that could be interpreted as a LOX inhibitor, with the N-hydroxyamide being a possible chelator. The current data indicate that the phenylenediamine chemotype reported herein is a potent Rapamycin inhibitor against 5-LOX, demonstrating OTX015 enzyme selectivity and cellular activity. The mechanism of action is consistent with reduction of the active site ferric ion, similar to that seen for zileuton, the only FDA approved LOX inhibitor. It is interesting to note that unlike zileuton, which chelates the iron through the N-hydroxyurea, the phenylenediamine chemotype lacks an obvious chelating moiety, thus differentiating it from zileuton. Structural modification around the phenylenediamine core was well tolerated, however, even relatively minor changes to the phenylenediamine moiety resulted in a loss of activity, presumably due to changes in its reduction potential. This attribute was utilized to modify the structure of ketoconazole to include the phenylenediamine moiety and produce a novel inhibitor, ketaminazole. This novel compound demonstrated an in vitro 40-fold increase in potency against 5-LOX relative to ketoconazole. However, in whole blood ketaminazole demonstrated only a 2-fold greater potency than ketoconazole. In addition, the overall potency of ketaminazole was reduced by approximately 10-fold relative to its in vitro potency. It is currently unclear how the cellular environment is lowering the potency of ketaminazole, but pharmacokinetic investigations are currently underway to probe this further. Ketaminazole had comparable potency against fungal CYP51 and improved selectivity against the human CYP51, relative to ketoconazole, which suggests a possible therapeutic advantage.