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

Affiliation

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.

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