title: Investigation of aryl isonitrile compounds with potent, broad-spectrum antifungal activity.
abstract: Invasive fungal infections present a formidable global public health challenge due to the limited number of approved antifungal agents and the emergence of resistance to the frontline treatment options, such as fluconazole. Three fungal pathogens of significant concern are Candida, Cryptococcus, and Aspergillus given their propensity to cause opportunistic infections in immunocompromised individuals. New antifungal agents composed of unique chemical scaffolds are needed to address this public health challenge. The present study examines the structure-activity relationship of a set of aryl isonitrile compounds that possess broad-spectrum antifungal activity primarily against species of Candida and Cryptococcus. The most potent derivatives are capable of inhibiting growth of these key pathogens at concentrations as low as 0.5µM. Remarkably, the most active compounds exhibit an excellent safety profile and are non-toxic to mammalian cells even at concentrations up to 256µM. The present study lays the foundation for further investigation of aryl isonitrile compounds as a new class of antifungal agents.
authors.affiliation: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN 47907, USA.
authors.forename: Haroon
authors.initials: H
authors.lastname: Mohammad
authors.affiliation: Department of Chemistry and Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Kwaku
authors.initials: K
authors.lastname: Kyei-Baffour
authors.affiliation: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN 47907, USA.
authors.forename: Waleed
authors.initials: W
authors.lastname: Younis
authors.affiliation: Department of Chemistry and Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Dexter C
authors.initials: DC
authors.lastname: Davis
authors.affiliation: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN 47907, USA.
authors.forename: Hassan
authors.initials: H
authors.lastname: Eldesouky
authors.affiliation: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN 47907, USA; Purdue Institute for Drug Discovery and Institute for Inflammation, Immunology, and Infectious Diseases, West Lafayette, IN 47907, USA. Electronic address: mseleem@purdue.edu.
authors.forename: Mohamed N
authors.initials: MN
authors.lastname: Seleem
authors.affiliation: Department of Chemistry and Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA; Purdue Institute for Drug Discovery and Institute for Inflammation, Immunology, and Infectious Diseases, West Lafayette, IN 47907, USA. Electronic address: mjdai@purdue.edu.
authors.forename: Mingji
authors.initials: M
authors.lastname: Dai
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001230:Aspergillus / Q000187:drug effects*; D002175:Candida / Q000187:drug effects*; D003454:Cryptococcus / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D009570:Nitriles
keywords: Antifungal; Aspergillus; Candida; Cryptococcus; Isonitrile