Synthesis of Altissimacoumarin D and Other Prenylated Coumarins and Their Ability to Reverse the Multidrug Resistance Phenotype in <i>Candida albicans</i>
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...
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| Format: | Article |
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MDPI AG
2023-07-01
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| Series: | Journal of Fungi |
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| Online Access: | https://www.mdpi.com/2309-608X/9/7/758 |
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| author | Anna Claudia Silva Daniel Clemente de Moraes Denilson Costa do Carmo Giselle Cristina Casaes Gomes A. Ganesan Rosangela Sabbatini Capella Lopes Antonio Ferreira-Pereira Cláudio Cerqueira Lopes |
| author_facet | Anna Claudia Silva Daniel Clemente de Moraes Denilson Costa do Carmo Giselle Cristina Casaes Gomes A. Ganesan Rosangela Sabbatini Capella Lopes Antonio Ferreira-Pereira Cláudio Cerqueira Lopes |
| author_sort | Anna Claudia Silva |
| collection | DOAJ |
| description | 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. <i>Ailanthus altissima</i> 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 <i>Candida albicans</i>. 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 <i>C. albicans</i>-resistant strains. |
| first_indexed | 2024-03-11T00:55:21Z |
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| institution | Directory Open Access Journal |
| issn | 2309-608X |
| language | English |
| last_indexed | 2024-03-11T00:55:21Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Journal of Fungi |
| spelling | doaj.art-05151d99e7604701ba422680f1e48a422023-11-18T20:02:01ZengMDPI AGJournal of Fungi2309-608X2023-07-019775810.3390/jof9070758Synthesis of Altissimacoumarin D and Other Prenylated Coumarins and Their Ability to Reverse the Multidrug Resistance Phenotype in <i>Candida albicans</i>Anna Claudia Silva0Daniel Clemente de Moraes1Denilson Costa do Carmo2Giselle Cristina Casaes Gomes3A. Ganesan4Rosangela Sabbatini Capella Lopes5Antonio Ferreira-Pereira6Cláudio Cerqueira Lopes7Departamento de Química Analítica, Instituto de Química, Universidade Federal do Rio de Janeiro, Centro de Tecnologia, Bloco A, 508, Rio de Janeiro 21949-900, BrazilDepartamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Centro de Ciências da Saúde, Bloco I, 44, Rio de Janeiro 21941-902, BrazilDepartamento de Química Analítica, Instituto de Química, Universidade Federal do Rio de Janeiro, Centro de Tecnologia, Bloco A, 508, Rio de Janeiro 21949-900, BrazilDepartamento de Química Analítica, Instituto de Química, Universidade Federal do Rio de Janeiro, Centro de Tecnologia, Bloco A, 508, Rio de Janeiro 21949-900, BrazilSchool of Pharmacy, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UKDepartamento de Química Analítica, Instituto de Química, Universidade Federal do Rio de Janeiro, Centro de Tecnologia, Bloco A, 508, Rio de Janeiro 21949-900, BrazilDepartamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Centro de Ciências da Saúde, Bloco I, 44, Rio de Janeiro 21941-902, BrazilDepartamento de Química Analítica, Instituto de Química, Universidade Federal do Rio de Janeiro, Centro de Tecnologia, Bloco A, 508, Rio de Janeiro 21949-900, BrazilAzoles 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. <i>Ailanthus altissima</i> 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 <i>Candida albicans</i>. 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 <i>C. albicans</i>-resistant strains.https://www.mdpi.com/2309-608X/9/7/758altissimacoumarin D<i>Candida</i> spp.coumarinsefflux transportersisofraxidinmultidrug resistance |
| spellingShingle | Anna Claudia Silva Daniel Clemente de Moraes Denilson Costa do Carmo Giselle Cristina Casaes Gomes A. Ganesan Rosangela Sabbatini Capella Lopes Antonio Ferreira-Pereira Cláudio Cerqueira Lopes Synthesis of Altissimacoumarin D and Other Prenylated Coumarins and Their Ability to Reverse the Multidrug Resistance Phenotype in <i>Candida albicans</i> Journal of Fungi altissimacoumarin D <i>Candida</i> spp. coumarins efflux transporters isofraxidin multidrug resistance |
| title | Synthesis of Altissimacoumarin D and Other Prenylated Coumarins and Their Ability to Reverse the Multidrug Resistance Phenotype in <i>Candida albicans</i> |
| title_full | Synthesis of Altissimacoumarin D and Other Prenylated Coumarins and Their Ability to Reverse the Multidrug Resistance Phenotype in <i>Candida albicans</i> |
| title_fullStr | Synthesis of Altissimacoumarin D and Other Prenylated Coumarins and Their Ability to Reverse the Multidrug Resistance Phenotype in <i>Candida albicans</i> |
| title_full_unstemmed | Synthesis of Altissimacoumarin D and Other Prenylated Coumarins and Their Ability to Reverse the Multidrug Resistance Phenotype in <i>Candida albicans</i> |
| title_short | Synthesis of Altissimacoumarin D and Other Prenylated Coumarins and Their Ability to Reverse the Multidrug Resistance Phenotype in <i>Candida albicans</i> |
| title_sort | synthesis of altissimacoumarin d and other prenylated coumarins and their ability to reverse the multidrug resistance phenotype in i candida albicans i |
| topic | altissimacoumarin D <i>Candida</i> spp. coumarins efflux transporters isofraxidin multidrug resistance |
| url | https://www.mdpi.com/2309-608X/9/7/758 |
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