N,N'-diaryl-bishydrazones in a biphenyl platform: Broad spectrum antifungal agents

  • Eur J Med Chem. 2019 Feb 15:164:273-281. doi: 10.1016/j.ejmech.2018.12.042.
Nishad Thamban Chandrika  1 ,  Emily K Dennis  1 ,  Sanjib K Shrestha  1 ,  Huy X Ngo  1 ,  Keith D Green  1 ,  Stefan Kwiatkowski  2 ,  Agripina Gabriela Deaciuc  1 ,  Linda P Dwoskin  1 ,  David S Watt  3 ,  Sylvie Garneau-Tsodikova  4
Affiliations
  • 1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, 40536-0596, USA.
  • 2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, 40536-0596, USA; Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY, 40536-0596, USA.
  • 3. Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY, 40536-0596, USA; Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY, 40536-0509, USA; Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY, 40536-0093, USA. Electronic address: [email protected].
  • 4. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, 40536-0596, USA. Electronic address: [email protected].
PMID: 30597328 DOI: 10.1016/j.ejmech.2018.12.042
Abstract

N,N'-Diaryl-bishydrazones of [1,1'-biphenyl]-3,4'-dicarboxaldehyde, [1,1'-biphenyl]-4,4'-dicarboxaldehyde, and 4,4'-bisacetyl-1,1-biphenyl exhibited excellent Antifungal activity against a broad spectrum of filamentous and non-filamentous fungi. These N,N'-diaryl-bishydrazones displayed no Antibacterial activity in contrast to previously reported N,N'-diamidino-bishydrazones and N-amidino-N'-aryl-bishydrazones. The leading candidate, 4,4'-bis((E)-1-(2-(4-fluorophenyl)hydrazono)ethyl)-1,1'-biphenyl, displayed less hemolysis of murine red blood cells at concentrations at or below that of a control Antifungal agent (voriconazole), was fungistatic in a time-kill study, and possessed no mammalian cytotoxicity and no toxicity with respect to hERG inhibition.

Keywords
Aspergillus sp.; Candida albicans; Cytotoxicity; Hemolysis; Non-albicans Candida; hERG channel.