Recently, fungal infections have rapidly increased, spreading to &gt; 300 million people worldwide, resulting in need for different drugs in order to alleviate this growth. The major classes of antifungal agents are polyenes, azoles, and echinocandins. However, each type of drug has a complication ranging from toxicity to weak resistance to limited activity. Glucosylceramide (GlcCer) a fungal sphingolipid, advocates virulence in Cryptococcus neoformans (Cn) making it a novel target for the development of new antifungal agents. A library of around 50,000 compounds from ChemBridge were tested against Cn at neutral to alkaline pH, resulting in two acyl hydrazones, BHBM and D0 as hits with MIC80 4 µg/mL and 1.2 µg/mL respectively. Based on the structure of BHBM and D0, a new library of 200 compounds were synthesized and tested against Cn, which resulted in 42 hits with MIC80≤1 µg/mL. All the hit compounds bear a hydroxyl group at the ortho position of the aromatic ring B. Based on these results, 23 new N-(aromatic acyl)-2-hydroxyarylhydrazones were synthesized. The synthesis and biological activity of these new acyl hydrazones will be reported.

Synthesis of novel acyl hydrazones as inhibitors for fungal GlcCer synthesis

255th National Meeting (2018)

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