Systematic fungal infections caused by Candida albicans (C. albicans) are life threatening with mortality rates estimated to be between 46-75%. Triazoles, such as fluconazole, are the mainstay treatment for fungal infections, which inhibit ergosterol biosynthesis via inhibition of 14α-demethylase (CYP51). However, increasing incidence of resistance to azole antifungals resulting in reduced efficacy is a major concern. Therefore, the aim of this project was to design and generate novel azole inhibitors effective against both wild type and fluconazole resistant Candida strains. The inhibitors were designed using a computational approach to determine optimal fit and binding interactions in the active site. The most promising designed inhibitors were selected for synthesis with two series of novel azole derivatives, short (fluconazole-type) and extended (posaconazole-type) derivatives, prepared and investigated for CYP51 inhibitory activity, binding affinity and minimum inhibitory concentration (MIC) against C. albicans strains. Each compound was achieved in an efficient three step synthesis. A further variation of this series to introduce substitutions required an additional three steps to prepare appropriate starting reagents. All the final compounds and intermediates were subject to 1H and 13C NMR, elemental analysis, HPLC and mass spectroscopy to confirm purity. The short derivatives were more potent against the C. albicans strains (MIC 0.03 μg/mL) compared with the extended derivatives (MIC 1 μg/mL) while both series showed similar enzyme binding and inhibition (Kd low nM, IC50 submicormolar) and were comparable with the standards fluconazole and posaconazole. The short series had poor selectivity for CaCYP51 over the human homolog, while the selectivity of the extended series was higher (21.5-fold) than posaconazole (4.7-fold) based on Kd values, although posaconazole was more selective (615-fold) compared with the extended series (461-fold) based on IC50 values. Based on inhibitory activity and selectivity profile, the extended series are optimal of the two series for further development.

Small molecule inhibitors targeting sterol 14α-demethylase (CYP51): synthesis, molecular modeling and evaluation against Candida albicans

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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