Design, Synthesis, and Biological Evaluation of Dual-Target COX-2/CYP51 Inhibitors for the Treatment of Fungal Infectious Diseases

The design of novel dual-target (COX-2/CYP51) inhibitors
was proposed
in the study, and three series of compounds were constructed though
the pathway of skeleton screening and combination; their molecular
structures were synthesized and evaluated. Most of the compounds exhibited
significant antifungal ability. Among them, potential compounds (10a-2, 16b-3) with excellent antifungal and anti-drug-resistant
fungal ability (MIC50, 0.125–2.0 μg/mL) were
selected for the subsequent mechanistic study. On the one hand, these
compounds could block the ergosterol biosynthesis pathway by inhibiting
CYP51 and influence the internal physiological function of fungal
cells, which included the increase of the ROS level, the anomaly of
ΔΨm, and the emergence of an apoptotic state.
On the other hand, these compounds also effectively showed COX-2 inhibition
ability, eliminated the inflammatory reaction of the infected region,
and activated the body’s immune function. In summary, this
study not only provided a novel antifungal drug design pathway but
also discovered excellent target compounds.