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

• Published in: Journal of medicinal chemistry 2019-09, Vol.62 (17), p.8249-8273
• Main Authors: Haranahalli, Krupanandan, Lazzarini, Cristina, Sun, Yi, Zambito, Julia, Pathiranage, Senuri, McCarthy, J. Brian, Mallamo, John, Del Poeta, Maurizio, Ojima, Iwao
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b01004

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.