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

• Willmen Youngsaye,
• 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 and
• Benito Munoz

Beilstein J. Org. Chem. 2013, 9, 1501–1507, doi:10.3762/bjoc.9.171

• 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: antifungal; Candida albicans; chemosensitizer; fluconazole; Molecular Libraries

• begins to emerge. With the smallest cycloalkane replacement, the cyclopropyl derivative 24 is inactive whereas the larger cyclohexane of 25 yields an active chemosensitizer (IC50 = 2.3 μM). When alternative heteroaromatic rings (26–29) were prepared, none of the examined systems possess any significant

• chemosensitizer of CaCi-2 and CaCi-8, introducing more electron-withdrawing substituents, such as trifluoromethyl (33) and cyano (34) groups, results in complete inactivity (IC50 > 26 µM). The activity of p-tolyl 30 and p-anisoyl 31 indicates that the inefficacy of 33 and 34 cannot be solely attributed to steric