During the last decade, fungal infections have been considered an increasing threat to human health. Despite the increasing need for efficient antifungal treatments, therapeutic options are still limited. The close relation between fungal and mammalian cells imposes a challenge for the development of new anti-fungal drugs. Recently, fungal sphingolipids have emerged as a potential target for new antifungals, because their biosynthesis in fungi is structurally different than that in mammals. Besides, some fungal sphingolipids play an important role in the regulation of virulence in a variety of fungi. Based on our previous SAR study, BHBM and D2 were found to be highly effective in vitro and in vivo against several pathogenic fungi. These two aromatic acylhydrazones were able to target the synthesis of sphingolipids, affect fungal cell morphology, and exhibit strong antifungal activity in vitro and in vivo. These results clearly indicate that BHBM and D2 would provide a good starting point for the discovery of next-generation antifungal agents. As our systematic approach to drug discovery and development, a new library of heteroaromatic acylhydrazones was designed, synthesized, and evaluated for their activity against C. neoformans. Then, a number of these novel compounds were found to be more potent than BHBM/D2, and fangicidal with excellent in vitro killing activities. The chemisty, biological evaluations and SAR of these novel acylhydrazones will be presented.

SAR study of novel heterocyclic acylhydrazones as anti-fungal agents targeting the synthesis of fungal GlcCer

256th National Meeting (2018)

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