SAR Studies on Aromatic Acylhydrazone-Based Inhibitors of Fungal Sphingolipid Synthesis as Next-Generation Antifungal Agents

Recently, the fungal
sphingolipid glucosylceramide (GlcCer) synthesis
has emerged as a highly promising new target for drug discovery of
next-generation antifungal agents, and we found two aromatic acylhydrazones
as effective inhibitors of GlcCer synthesis based on HTP screening.
In the present work, we have designed libraries of new aromatic acylhydrazones,
evaluated their antifungal activities (MIC80 and time-kill
profile) against C. neoformans, and performed an
extensive SAR study, which led to the identification of five promising
lead compounds, exhibiting excellent fungicidal activities with very
large selectivity index. Moreover, two compounds demonstrated broad
spectrum antifungal activity against six other clinically relevant
fungal strains. These five lead compounds were examined for their
synergism/cooperativity with five clinical drugs against seven fungal
strains, and very encouraging results were obtained; e.g., the combination
of all five lead compounds with voriconazole exhibited either synergistic
or additive effect to all seven fungal strains.