Exploring long arm amide-linked side chains in the design of antifungal azole inhibitors of sterol 14α-demethylase (CYP51)

Alsulaimany, Marwa, Keniya, Mikhail V., Alanazi, Rehab S., Ruma, Yasmeen N., Hughes, Carwyn S., Jones, Arwyn T. ORCID: https://orcid.org/0000-0003-2781-8905, Tyndall, Joel D. A., Parker, Josie E., Monk, Brian C. and Simons, Claire ORCID: https://orcid.org/0000-0002-9487-1100 2025. Exploring long arm amide-linked side chains in the design of antifungal azole inhibitors of sterol 14α-demethylase (CYP51). Journal of Medicinal Chemistry 10.1021/acs.jmedchem.4c02922

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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.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Pharmacy Schools > Biosciences
Publisher:	American Chemical Society
ISSN:	0022-2623
Date of First Compliant Deposit:	7 May 2025
Date of Acceptance:	28 April 2025
Last Modified:	03 Jun 2025 09:33
URI:	https://orca.cardiff.ac.uk/id/eprint/178129

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