Recent statistics suggest that, globally around 300 million people are affected by serious fungal infections. Drawbacks of current drugs range from narrow spectrum of activity to side effects such as toxicity and drug-drug interactions. Furthermore, recently there has been an increase in the occurrence of resistant strains of fungi to current drugs, thus emphasizing the need for new anti-fungal drugs that are not only effective but also safe. Previously, 2 aromatic acylhydrazones BHBM and D13 were identified by screening a commercial library from ChemBridge as inhibitors of synthesis of fungal sphingolipid GlcCer in C. neoformans in our collaborator Del Poeta’s lab.1 Based on the structures of BHBM and D13, a new library of ~300 aromatic acylhydrazones was synthesized for hit to lead identification in Ojima’s lab at ICB&DD, Stony Brook University.2 Extensive SAR studies that were carried out as a part of this collaboration, resulted in identification of several lead compounds that displayed excellent MIC80, in vitro killing activity and high selectivity indices against C. neoformans.3 Some of the lead compounds also displayed broad spectrum antifungal activities in vitro. One of the lead compounds SB-AF-1002, displayed excellent MIC80 of 0.06 µg/mL (48 h incubation) and was also found to be fungicidal at the same concentration. Additionally, SB-AF-1002 resulted in 100% survival of infected mice in an in vivo model of cryptococcosis. The SAR study and biological evaluation of the lead compounds will be presented.

Acylhydrazones as novel antifungal agents targeting the synthesis of fungal sphingolipids

ACS Fall 2020 Virtual Meeting

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