New generation modified azole antifungals against multidrug-resistant Candida auris

Article

Chen, Y., Li, Y., Nahar, K.S., Hasan, Md. M., Marsh, C., Clifford, M., Aleku, G.A., Kelly, S.L., Lamb, D.C., Mpamhanga, C.D., Kounatidis, I., Shah, A., Hind, C.K., Sutton, J.M. and Rahman, K.M. 2025. New generation modified azole antifungals against multidrug-resistant Candida auris . Journal of Medicinal Chemistry. 68 (13), pp. 14054-14071. https://doi.org/10.1021/acs.jmedchem.5c01253
TypeArticle
TitleNew generation modified azole antifungals against multidrug-resistant Candida auris
AuthorsChen, Y., Li, Y., Nahar, K.S., Hasan, Md. M., Marsh, C., Clifford, M., Aleku, G.A., Kelly, S.L., Lamb, D.C., Mpamhanga, C.D., Kounatidis, I., Shah, A., Hind, C.K., Sutton, J.M. and Rahman, K.M.
Abstract

The rise of antifungal resistance and limited treatment options highlight the urgent need for new drug classes. Candida auris is a serious global health threat with few effective therapies. In this study, novel azole-based compounds were developed by modifying the azole core with cyclic heteroaliphatic linkers connecting aromatic and heteroaromatic rings. Several compounds showed potent activity against C. auris, including azole-resistant strains, with MICs ranging from 0.016 to 4 µg/mL. The compounds also demonstrated strong activity against C. albicans, Nakaseomyces glabratus, C. tropicalis, and C. parapsilosis, with MICs mostly below 1 µg/mL. Compounds 7, 18, and 21 were more potent than fluconazole. Compound 7 inhibited CYP51, eradicated C. auris biofilms, and showed better intracellular accumulation than fluconazole. In vivo studies in Galleria mellonella and Drosophila melanogaster confirmed efficacy at 5 mg/kg and no toxicity up to 50 mg/kg, supporting further development of this scaffold against multidrug-resistant C. auris infections.

KeywordsCandida auris; antifungals; fluconazole
Sustainable Development Goals3 Good health and well-being
Middlesex University ThemeHealth & Wellbeing
Research GroupAntimicrobial Resistance
PublisherAmerican Chemical Society
JournalJournal of Medicinal Chemistry
ISSN0022-2623
Electronic1520-4804
Publication dates
Online23 Jun 2025
Print10 Jul 2025
Publication process dates
Submitted06 May 2025
Accepted11 Jun 2025
Deposited16 Jun 2025
Output statusPublished
Publisher's version
License
File Access Level
Open
Copyright Statement

© 2025 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY 4.0 https://creativecommons.org/licenses/by/4.0/

Digital Object Identifier (DOI)https://doi.org/10.1021/acs.jmedchem.5c01253
PubMed ID40550788
PubMed Central ID12257509
Web of Science identifierWOS:001518419500001
LanguageEnglish
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