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Silva, Anna Claudia, de Moraes, Daniel Clemente, do Carmo, Denilson Costa, Gomes, Giselle Cristina Casaes, Ganesan, A. 
ORCID: https://orcid.org/0000-0003-4862-7999, Lopes, Rosangela Sabbatini Capella, Ferreira-Pereira, Antonio and Lopes, Cláudio Cerqueira
(2023)
Synthesis of altissimacoumarin D and other prenylated coumarins and their ability to reverse the multidrug resistance phenotype in Candida albicans.
Journal of Fungi, 9 (7).
ISSN 2309-608X
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Abstract
Azoles are the main antifungal agents employed in clinical practice to treat invasive candidiasis. Nonetheless, their efficacy is limited by fungal resistance mechanisms, mainly the overexpression of efflux pumps. Consequently, candidiasis has a worrisome death rate of 75%. One potential strategy to overcome efflux-mediated resistance is to inhibit this process. Ailanthus altissima is a Chinese tree that produces several active substances, including altissimacoumarin D. Due to the low yield of its extraction and the need to search for new drugs to treat candidiasis, this study aimed to synthesize altissimacoumarin D and its analogues, as well as evaluating their ability to reverse the resistance phenotype of Candida albicans. Coumarin isofraxidin was prepared via total synthesis through a solvent-free Knoevenagel condensation as the key step. Isofraxidin and other commercially available coumarins were alkylated with prenyl or geranyl groups to yield the natural product altissimacoumarin D and seven analogues. The antifungal activity of the coumarins and their ability to reverse the fungal resistance phenotype were assessed using microbroth methodologies. Toxicity was evaluated using erythrocytes and an in silico prediction. All compounds improved the antifungal activity of fluconazole by inhibiting efflux pumps, and ACS47 and ACS50 were the most active. None of the coumarins were toxic to erythrocytes. In silico predictions indicate that ACS47 and ACS50 may be safe for human use. ACS47 and ACS50 are promising candidates when used as adjuvants in the antifungal therapy against C. albicans-resistant strains.
| Item Type: | Article |
|---|---|
| Additional Information: | Data Availability Statement: Not applicable. Funding Information: This research was funded by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior–Brazil (CAPES)–Finance Code 001. |
| Uncontrolled Keywords: | altissimacoumarin d,candidaspp,coumarins,efflux transporters,isofraxidin,multidrug resistance,ecology, evolution, behavior and systematics,plant science,microbiology (medical) ,/dk/atira/pure/subjectarea/asjc/1100/1105 |
| Faculty \ School: | Faculty of Science > School of Chemistry, Pharmacy and Pharmacology |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 10 Jan 2025 01:00 |
| Last Modified: | 10 Jan 2025 01:00 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/98137 |
| DOI: | 10.3390/jof9070758 |
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