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) <0.03â µg/mL, N-(4-((4-chlorophenyl)sulfonamido)benzyl)-2-phenyl-3-(1H-1,2,4-triazol-1-yl)propanamide (12 c), 1â µg/mL, fluconazole 0.125â µg/mL) but both displayed comparable enzyme binding and inhibition (5 f Kd 62±17â nM, IC50 0.46â µM; 12 c Kd 43±18â nM, IC50 0.33â µM, fluconazole Kd 41±13â nM, IC50 0.31â µM, posaconazole Kd 43±11â nM, IC50 0.2â 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.