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 . This research describes the synthesis of extended "long-arm" azole antifungals that were evaluated against wild-type and resistant fungal species. Biphenyl derivative was the most effective derivative, displaying potent inhibitory activity against , , and CYP51 enzymes, including in resistant strains, in comparison with posaconazole. The X-ray crystal structure of - complexed with CYP51 showed a hydrogen bond between the oxygen of the trifluoromethoxy group of and the His381 side chain of CYP51, which is postulated to contribute significantly to its binding, and stabilization in the presence of the CYP51 Y140F/H, and CYP51 Y132F mutations and the K143R mutation. Computational studies and IC evaluation of compound vs wild-type, Y132F, and Y132H/K143 mutant strains supported MIC observations.