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

Journal of Medicinal Chemistry
Krupanandan HaranahalliIwao Ojima

Abstract

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.

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Citations

Mar 18, 2020·Metabolites·Jiří HoušťVladimír Havlíček
Jul 17, 2020·Expert Review of Anti-infective Therapy·Caroline Mota Fernandes, Maurizio Del Poeta
Jul 1, 2020·Antimicrobial Agents and Chemotherapy·Cristina LazzariniMaurizio Del Poeta
Aug 23, 2020·Journal of Fungi·Kyle McEvoyMaurizio Del Poeta
Nov 25, 2020·Antimicrobial Agents and Chemotherapy·Caroline Mota FernandesMaurizio Del Poeta
Feb 18, 2021·Antimicrobial Agents and Chemotherapy·Jhon Jhamilton Artunduaga BonillaLeonardo Nimrichter
Oct 19, 2021·Journal of Medicinal Chemistry·Ji Won ChoiKi Duk Park

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