Structure–Activity Relationships for Itraconazole-Based Triazolone Analogues as Hedgehog Pathway Inhibitors

The Food and Drug Administration-approved
antifungal agent, itraconazole
(ITZ), has been increasingly studied for its novel biological properties.
In particular, ITZ inhibits the hedgehog (Hh) signaling pathway and
has the potential to serve as an anticancer chemotherapeutic against
several Hh-dependent malignancies. We have extended our studies on
ITZ analogues as Hh pathway inhibitors through the design, synthesis,
and evaluation of novel des-triazole ITZ analogues
that incorporate modifications to the triazolone/side chain region
of the scaffold. Our overall results suggest that the triazolone/side
chain region can be replaced with various functionalities (hydrazine
carboxamides and meta-substituted amides) resulting
in improved potency when compared to ITZ. Our studies also indicate
that the stereochemical orientation of the dioxolane ring is important
for both potent Hh pathway inhibition and compound stability. Finally,
our studies suggest that the ITZ scaffold can be successfully modified
in terms of functionality and stereochemistry to further improve its
anti-Hh potency and physicochemical properties.