Small‐Molecule Inhibitors Targeting Sterol 14α‐Demethylase (CYP51): Synthesis, Molecular Modelling and Evaluation Against Candida albicans. (22nd June 2020)

• Record Type: Journal Article
• Authors: Binjubair, Faizah A.; Parker, Josie E.; Warrilow, Andrew G.; Puri, Kalika; Braidley, Peter J.; Tatar, Esra; Kelly, Steven L.; Kelly, Diane E.; Simons, Claire
• Is Part Of: ChemMedChem. Volume 15:Number 14(2020)
• Page Start: 1294
• Page End: 1309
• Publication Date: 2020-06-22
• Subjects: antifungal agents -- azoles -- Candida albicans -- CYP51 -- drug design -- molecular dynamics; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202000250
• Languages: English
• ISSNs: 1860-7179

Abstract

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‐(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, IC50 0.46 μM; 12 c K d 43±18 nM, IC50 0.33 μM, fluconazole K d 41±13 nM, IC50 0.31 μM, posaconazole K d 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 K d 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. Abstract : Two series of novel azole derivatives, short and long, have been designed, synthesised and investigated for CYP51 inhibitory activity, binding affinity and minimum inhibitory concentration against C. albicans strains. The short derivatives were more potent than the extended derivatives, but both displayed comparable enzyme binding and inhibition. Molecular modelling and biological and selectivity profiles provide useful SAR for further development.