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Small‐Molecule Inhibitors Targeting Sterol 14α‐Demethylase (CYP51): Synthesis, Molecular Modelling and Evaluation Against Candida albicans
Author(s) -
Binjubair Faizah A.,
Parker Josie E.,
Warrilow Andrew G.,
Puri Kalika,
Braidley Peter J.,
Tatar Esra,
Kelly Steven L.,
Kelly Diane E.,
Simons Claire
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000250
Subject(s) - posaconazole , azole , fluconazole , candida albicans , corpus albicans , stereochemistry , minimum inhibitory concentration , chemistry , sterol , enzyme , microbiology and biotechnology , pharmacology , in vitro , biology , itraconazole , biochemistry , antifungal , cholesterol
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‐(1 H ‐imidazol‐1‐yl)propanamide ( 5 f ) <0.03 μg/mL, N ‐(4‐((4‐chlorophenyl)sulfonamido)benzyl)‐2‐phenyl‐3‐(1 H ‐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 K d 62±17 nM, IC 50 0.46 μM; 12 c K d 43±18 nM, IC 50 0.33 μM, fluconazole K d 41±13 nM, IC 50 0.31 μM, posaconazole K d 43±11 nM, IC 50 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 K d values, although posaconazole was more selective (615‐fold) than 12 c (461‐fold) based on IC 50 values. Based on inhibitory activity and selectivity profile, the extended series are the better of the two series for further development.