Globally ~300 million people are affected by serious fungal infections. Drawbacks of current anti-fungal drugs include drug-drug interactions, toxicity and narrow spectrum of activity. With the increase in incidence of fungal infections resistant to current drugs, there is a dire need for the development of new antifungal agents with novel mechanisms of action. In this context, fungal sphingolopids that are essential for their virulence in alkaline environment is a potential target for the development of new antifungal agents. Initial screening of a library of 49,120 compounds from ChemBridge against C. neoformans resulted in identification of two aromatic acyl hydrazones, BHBM and D0 with MFC of 4 µg/mL and 1.2 µg/mL respectively as hits. Results from in vitro and in vivo assays including the inhibition of GlcCer synthesis supported the fact that BHBM and D0 provide a good starting point for the discovery of new anti-fungal agents. Further screening resulted in three more hit compounds including D13, with MIC80 0.03 µg/mL. Based on these results, a new library of 192 aromatic acylhydrazides was synthesized and tested against C. neoformans resulting in 42 hits with MIC80 ≤1 µg/mL. Some of the hits displayed excellent in vitro killing activity against C. neoformans. Based on MIC80 and killing activity of the hits from the library, further SAR was carried out for identification of better leads. All the hit compounds consisted of a hydroxyl group at the ortho position of aromatic ring B, indicating its significance towards antifungal activity. The synthesis and biological activity of the hits, as well as further SAR of N-(aromatic acyl)-2-hydroxyarylhydrazones and will be presented.

SAR of novel anti-fungal agents targeting the synthesis of fungal GlcCer

255th National Meeting (2018)

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