Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Jul 26:9:1501-7.
doi: 10.3762/bjoc.9.171. eCollection 2013.

ML212: A small-molecule probe for investigating fluconazole resistance mechanisms in Candida albicans

Willmen Youngsaye  1 , Cathy L Hartland, Barbara J Morgan, Amal Ting, Partha P Nag, Benjamin Vincent, Carrie A Mosher, Joshua A Bittker, Sivaraman Dandapani, Michelle Palmer, Luke Whitesell, Susan Lindquist, Stuart L Schreiber, Benito Munoz
Affiliations

ML212: A small-molecule probe for investigating fluconazole resistance mechanisms in Candida albicans

Willmen Youngsaye et al. Beilstein J Org Chem. .

Abstract

The National Institutes of Health Molecular Libraries and Probe Production Centers Network (NIH-MLPCN) screened >300,000 compounds to evaluate their ability to restore fluconazole susceptibility in resistant Candida albicans isolates. Additional counter screens were incorporated to remove substances inherently toxic to either mammalian or fungal cells. A substituted indazole possessing the desired bioactivity profile was selected for further development, and initial investigation of structure-activity relationships led to the discovery of ML212.

Keywords: Candida albicans; Molecular Libraries Probe Production Center Network (MLPCN); antifungal; chemosensitizer; fluconazole.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Assay pipeline for triaging hits. Individual assay cut-offs are given in italics.
Figure 2
Figure 2
Hit compounds selected for further optimization.
Scheme 1
Scheme 1
Preparation of substituted methyl 2-(1H-indazol-1-yl)acetates. Reagents and conditions: (a) Et3N, Boc2O, DMAP, tetrahydrofuran; (b) ArB(OH)2, Pd(PPh3)4, aqueous Na2CO3, 1,4-dioxane, 120 °C; (c) methyl bromoacetate, K2CO3, acetone, 60 °C; (d) alkylmagnesium bromide, Et2O, 0 °C; (e) Dess–Martin periodinane, CH2Cl2; (f) hydrazine hydrate, 175 °C.
See this image and copyright information in PMC

References

    1. Martínez J L. Future Med Chem. 2012;4:347–359. doi: 10.4155/fmc.12.2. - DOI - PubMed
    1. Hawkey P M, Jones A M. J Antimicrob Chemother. 2009;64(Suppl 1):i3–i10. doi: 10.1093/jac/dkp256. - DOI - PubMed
    1. Gould I M. Int J Antimicrob Agents. 2008;32(Suppl 1):S2–S9. doi: 10.1016/j.ijantimicag.2008.06.016. - DOI - PubMed
    1. Vandeputte P, Ferrari S, Coste A T. Int J Microbiol. 2012:No. 713687. doi: 10.1155/2012/713687. - DOI - PMC - PubMed
    1. Pfaller M A, Diekema D J. Clin Microbiol Rev. 2007;20:133–163. doi: 10.1128/CMR.00029-06. - DOI - PMC - PubMed