Exploring Long Arm Amide-Linked Side Chains in the Design of Antifungal Azole Inhibitors of Sterol 14α-Demethylase (CYP51)

The rise in fungal
drug resistance has exacerbated the treatment
of invasive fungal infections, most commonly caused by Candida. This research describes the synthesis of
extended “long-arm” azole antifungals that were evaluated
against wild-type and resistant fungal species. Biphenyl derivative 22 was the most effective derivative, displaying potent inhibitory
activity against Saccharomyces, Candida, and Cryptococcus CYP51 enzymes, including in resistant strains, in comparison with
posaconazole. The X-ray crystal structure of S-22 complexed with S. cerevisiae CYP51 showed a hydrogen bond between the oxygen of the
trifluoromethoxy group of S-22 and the
His381 side chain of S. cerevisiae CYP51, which is postulated to contribute significantly
to its binding, and stabilization in the presence of the S. cerevisiae CYP51 Y140F/H, C. parapsilosis and C. auris CYP51 Y132F mutations and the C. auris K143R mutation. Computational studies and IC50 evaluation
of compound 22 vs C. albicans wild-type, Y132F, and Y132H/K143 mutant strains supported
MIC observations.