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

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

  • J Med Chem. 2025 Jun 12;68(11):10781-10799. doi: 10.1021/acs.jmedchem.4c02922.
Marwa Alsulaimany 1,  Mikhail V Keniya 2,  Rehab S Alanazi 1,  Yasmeen N Ruma 2,  Carwyn S Hughes 1,  Arwyn T Jones 1,  Joel D A Tyndall 3,  Josie E Parker 4,  Brian C Monk 2,  Claire Simons 1
Affiliations

Affiliations

  • 1 School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, U.K.
  • 2 Faculty of Dentistry, Sir John Walsh Research Institute, University of Otago, Dunedin 9016, New Zealand.
  • 3 School of Pharmacy, University of Otago, Dunedin 9054, New Zealand.
  • 4 School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, U.K.
PMID: 40403151 DOI: 10.1021/acs.jmedchem.4c02922
Abstract

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.

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