Piperazinyl quinolines as chemosensitizers to increase fluconazole susceptibility of Candida albicans clinical isolates

  • Bioorg Med Chem Lett. 2011 Sep 15;21(18):5502-5. doi: 10.1016/j.bmcl.2011.06.105.
Willmen Youngsaye  1 ,  Benjamin Vincent ,  Cathy L Hartland ,  Barbara J Morgan ,  Sara J Buhrlage ,  Stephen Johnston ,  Joshua A Bittker ,  Lawrence MacPherson ,  Sivaraman Dandapani ,  Michelle Palmer ,  Luke Whitesell ,  Susan Lindquist ,  Stuart L Schreiber ,  Benito Munoz
Affiliations
  • 1. Chemical Biology Platform and Probe Development Center, Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA.
PMID: 21802942 DOI: 10.1016/j.bmcl.2011.06.105
Abstract

The effectiveness of the potent Antifungal drug fluconazole is being compromised by the rise of drug-resistant Fungal pathogens. While inhibition of HSP90 or Calcineurin can reverse drug resistance in Candida, such inhibitors also impair the homologous human host protein and fungal-selective chemosensitizers remain rare. The MLPCN library was screened to identify compounds that selectively reverse fluconazole resistance in a Candida albicans clinical isolate, while having no Antifungal activity when administered as a single agent. A piperazinyl quinoline was identified as a new small-molecule probe (ML189) satisfying these criteria.