The discovery of novel antifungal phenylpyridines derivatives based on CYP53 binding model

Benzoates as toxic intermediate are naturally produced by fungal intracellular metabolism, and CYP53 can specific transform the substrates. In the study, we constructed the CYP53 homology model and analyzed the corresponding active region. At the same time, the molecular docking and the structure-based pharmacophore model (SBP) were performed to explore the bind mode of representative CYP53 inhibitors. On the basis, a series of phenylpyridines derivatives were designed as novel CYP53 inhibitors, and their molecular structures were synthesized and evaluated. Compared with the positive control groups, their antifungal activity showed the obvious upward trend. In particular, target compounds (13a, 15b) possessed the excellent biological activity against pathogenic fungi and drug-resistant fungi in vivo and in vitro. The preliminary action mechanism has confirmed that target compounds could inhibit CYP53 activity, and block the metabolism of toxic intermediates (Benzoates). This further induced the accumulation of reactive oxygen species (ROS) through the pattern of mitochondrial depolarization, which eventually caused fungal lysis and death. In summary, the study provided the reasonable computational models, and effectively guided the generation of novel CYP53 antifungal inhibitors.