Small-Molecule Inhibitors Targeting Sterol 14α-Demethylase (CYP51): Synthesis,Molecular Modelling and Evaluation Against Candida albicans |
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Authors: | Faizah A Binjubair Dr Josie E Parker Dr Andrew G Warrilow Kalika Puri Peter J Braidley Dr Esra Tatar Prof Steven L Kelly Prof Diane E Kelly Dr Claire Simons |
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Affiliation: | 1. School of Pharmacy & Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB UK;2. Centre for Cytochrome P450 Biodiversity, Institute of Life Science, Swansea University, Swansea, SA2 8PP UK;3. School of Pharmacy & Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB UK
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Istanbul, Turkey |
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Abstract: | Fungal infections are a global issue affecting over 150 million people worldwide annually, with 750 000 of these caused by invasive Candida infections. Azole drugs are the frontline treatment against fungal infections; however, resistance to current azole antifungals in C. albicans poses a threat to public health. Two series of novel azole derivatives, short and extended derivatives, have been designed, synthesised and investigated for CYP51 inhibitory activity, binding affinity and minimum inhibitory concentration (MIC) against C. albicans strains. The short derivatives were more potent against the C. albicans strains (e. g., MIC 2-(4-chlorophenyl)-N-(2,4-dichlorobenzyl)-3-(1H-imidazol-1-yl)propanamide ( 5 f ) <0.03 μg/mL, N-(4-((4-chlorophenyl)sulfonamido)benzyl)-2-phenyl-3-(1H-1,2,4-triazol-1-yl)propanamide ( 12 c ), 1 μg/mL, fluconazole 0.125 μg/mL) but both displayed comparable enzyme binding and inhibition ( 5 f Kd 62±17 nM, IC50 0.46 μM; 12 c Kd 43±18 nM, IC50 0.33 μM, fluconazole Kd 41±13 nM, IC50 0.31 μM, posaconazole Kd 43±11 nM, IC50 0.2 μM). The short series had poor selectivity for CaCYP51 over the human homologue, whereas the selectivity of the extended series, for example, compound 12 c , was higher (21.5-fold) than posaconazole (4.7-fold) based on Kd values, although posaconazole was more selective (615-fold) than 12 c (461-fold) based on IC50 values. Based on inhibitory activity and selectivity profile, the extended series are the better of the two series for further development. |
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Keywords: | antifungal agents azoles Candida albicans CYP51 drug design molecular dynamics |
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