Synthesis of Altissimacoumarin D and Other Prenylated Coumarins and Their Ability to Reverse the Multidrug Resistance Phenotype in ICandida 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...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Journal of fungi (Basel) 2023-07, Vol.9 (7)
Hauptverfasser: Silva, Anna Claudia, de Moraes, Daniel Clemente, do Carmo, Denilson Costa, Gomes, Giselle Cristina Casaes, Ganesan, A, Lopes, Rosangela Sabbatini Capella, Ferreira-Pereira, Antonio, Lopes, Cláudio Cerqueira
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page
container_issue 7
container_start_page
container_title Journal of fungi (Basel)
container_volume 9
creator Silva, Anna Claudia
de Moraes, Daniel Clemente
do Carmo, Denilson Costa
Gomes, Giselle Cristina Casaes
Ganesan, A
Lopes, Rosangela Sabbatini Capella
Ferreira-Pereira, Antonio
Lopes, Cláudio Cerqueira
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. 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.
doi_str_mv 10.3390/jof9070758
format Article
fullrecord <record><control><sourceid>gale</sourceid><recordid>TN_cdi_gale_infotracmisc_A759154247</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A759154247</galeid><sourcerecordid>A759154247</sourcerecordid><originalsourceid>FETCH-LOGICAL-g677-4ce75ac3e0478b202f166057fb55b0bef0cc2c2bbba784666e7f422ab81e889e3</originalsourceid><addsrcrecordid>eNptTU1LwzAYDqLgmLv4CwKeu6Vp89FjqV8DZUN38DaS9M2W0abSdEL_iL_XoDvsIO_heXk-EbpNyTzLCrI4dLYggggmL9CEZqRIOJEfl2f_NZqFcCCEpEzyosgm6Pt99MMeggu4s7hsBheCa5Xpjq3qncf3WPkar6Klx-se_NioAWpcnfTwK2_24Hpcate4YcRDh9_gC_oAOMbw6zGW1v1xF9k4MyhvAK_34Lth_AQcN5ZVLHG1wqrRzigfFssbdGVVE2B2winaPD5squfkZfW0rMqXZMeFSHIDgimTAcmF1JRQm3JOmLCaMU00WGIMNVRrrYTMOecgbE6p0jIFKQvIpujur3anGtg6b7uhV6Z1wWxLwYqU5TQX0TX_xxWvhtaZzoN1kT8L_ADa5HqF</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Synthesis of Altissimacoumarin D and Other Prenylated Coumarins and Their Ability to Reverse the Multidrug Resistance Phenotype in ICandida albicans/I</title><source>DOAJ Directory of Open Access Journals</source><source>PubMed Central Open Access</source><source>PubMed (Medline)</source><source>MDPI - Multidisciplinary Digital Publishing Institute</source><source>EZB Electronic Journals Library</source><creator>Silva, Anna Claudia ; de Moraes, Daniel Clemente ; do Carmo, Denilson Costa ; Gomes, Giselle Cristina Casaes ; Ganesan, A ; Lopes, Rosangela Sabbatini Capella ; Ferreira-Pereira, Antonio ; Lopes, Cláudio Cerqueira</creator><creatorcontrib>Silva, Anna Claudia ; de Moraes, Daniel Clemente ; do Carmo, Denilson Costa ; Gomes, Giselle Cristina Casaes ; Ganesan, A ; Lopes, Rosangela Sabbatini Capella ; Ferreira-Pereira, Antonio ; Lopes, Cláudio Cerqueira</creatorcontrib><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. 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.</description><identifier>ISSN: 2309-608X</identifier><identifier>EISSN: 2309-608X</identifier><identifier>DOI: 10.3390/jof9070758</identifier><language>eng</language><publisher>MDPI AG</publisher><subject>Coumarins ; Drug resistance in microorganisms ; Fluconazole ; Genetic aspects ; Organic compounds ; Synthesis</subject><ispartof>Journal of fungi (Basel), 2023-07, Vol.9 (7)</ispartof><rights>COPYRIGHT 2023 MDPI AG</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,865,27929,27930</link.rule.ids></links><search><creatorcontrib>Silva, Anna Claudia</creatorcontrib><creatorcontrib>de Moraes, Daniel Clemente</creatorcontrib><creatorcontrib>do Carmo, Denilson Costa</creatorcontrib><creatorcontrib>Gomes, Giselle Cristina Casaes</creatorcontrib><creatorcontrib>Ganesan, A</creatorcontrib><creatorcontrib>Lopes, Rosangela Sabbatini Capella</creatorcontrib><creatorcontrib>Ferreira-Pereira, Antonio</creatorcontrib><creatorcontrib>Lopes, Cláudio Cerqueira</creatorcontrib><title>Synthesis of Altissimacoumarin D and Other Prenylated Coumarins and Their Ability to Reverse the Multidrug Resistance Phenotype in ICandida albicans/I</title><title>Journal of fungi (Basel)</title><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. 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.</description><subject>Coumarins</subject><subject>Drug resistance in microorganisms</subject><subject>Fluconazole</subject><subject>Genetic aspects</subject><subject>Organic compounds</subject><subject>Synthesis</subject><issn>2309-608X</issn><issn>2309-608X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid/><recordid>eNptTU1LwzAYDqLgmLv4CwKeu6Vp89FjqV8DZUN38DaS9M2W0abSdEL_iL_XoDvsIO_heXk-EbpNyTzLCrI4dLYggggmL9CEZqRIOJEfl2f_NZqFcCCEpEzyosgm6Pt99MMeggu4s7hsBheCa5Xpjq3qncf3WPkar6Klx-se_NioAWpcnfTwK2_24Hpcate4YcRDh9_gC_oAOMbw6zGW1v1xF9k4MyhvAK_34Lth_AQcN5ZVLHG1wqrRzigfFssbdGVVE2B2winaPD5squfkZfW0rMqXZMeFSHIDgimTAcmF1JRQm3JOmLCaMU00WGIMNVRrrYTMOecgbE6p0jIFKQvIpujur3anGtg6b7uhV6Z1wWxLwYqU5TQX0TX_xxWvhtaZzoN1kT8L_ADa5HqF</recordid><startdate>20230701</startdate><enddate>20230701</enddate><creator>Silva, Anna Claudia</creator><creator>de Moraes, Daniel Clemente</creator><creator>do Carmo, Denilson Costa</creator><creator>Gomes, Giselle Cristina Casaes</creator><creator>Ganesan, A</creator><creator>Lopes, Rosangela Sabbatini Capella</creator><creator>Ferreira-Pereira, Antonio</creator><creator>Lopes, Cláudio Cerqueira</creator><general>MDPI AG</general><scope/></search><sort><creationdate>20230701</creationdate><title>Synthesis of Altissimacoumarin D and Other Prenylated Coumarins and Their Ability to Reverse the Multidrug Resistance Phenotype in ICandida albicans/I</title><author>Silva, Anna Claudia ; de Moraes, Daniel Clemente ; do Carmo, Denilson Costa ; Gomes, Giselle Cristina Casaes ; Ganesan, A ; Lopes, Rosangela Sabbatini Capella ; Ferreira-Pereira, Antonio ; Lopes, Cláudio Cerqueira</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-g677-4ce75ac3e0478b202f166057fb55b0bef0cc2c2bbba784666e7f422ab81e889e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Coumarins</topic><topic>Drug resistance in microorganisms</topic><topic>Fluconazole</topic><topic>Genetic aspects</topic><topic>Organic compounds</topic><topic>Synthesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Silva, Anna Claudia</creatorcontrib><creatorcontrib>de Moraes, Daniel Clemente</creatorcontrib><creatorcontrib>do Carmo, Denilson Costa</creatorcontrib><creatorcontrib>Gomes, Giselle Cristina Casaes</creatorcontrib><creatorcontrib>Ganesan, A</creatorcontrib><creatorcontrib>Lopes, Rosangela Sabbatini Capella</creatorcontrib><creatorcontrib>Ferreira-Pereira, Antonio</creatorcontrib><creatorcontrib>Lopes, Cláudio Cerqueira</creatorcontrib><jtitle>Journal of fungi (Basel)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Silva, Anna Claudia</au><au>de Moraes, Daniel Clemente</au><au>do Carmo, Denilson Costa</au><au>Gomes, Giselle Cristina Casaes</au><au>Ganesan, A</au><au>Lopes, Rosangela Sabbatini Capella</au><au>Ferreira-Pereira, Antonio</au><au>Lopes, Cláudio Cerqueira</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis of Altissimacoumarin D and Other Prenylated Coumarins and Their Ability to Reverse the Multidrug Resistance Phenotype in ICandida albicans/I</atitle><jtitle>Journal of fungi (Basel)</jtitle><date>2023-07-01</date><risdate>2023</risdate><volume>9</volume><issue>7</issue><issn>2309-608X</issn><eissn>2309-608X</eissn><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.</abstract><pub>MDPI AG</pub><doi>10.3390/jof9070758</doi></addata></record>
fulltext fulltext
identifier ISSN: 2309-608X
ispartof Journal of fungi (Basel), 2023-07, Vol.9 (7)
issn 2309-608X
2309-608X
language eng
recordid cdi_gale_infotracmisc_A759154247
source DOAJ Directory of Open Access Journals; PubMed Central Open Access; PubMed (Medline); MDPI - Multidisciplinary Digital Publishing Institute; EZB Electronic Journals Library
subjects Coumarins
Drug resistance in microorganisms
Fluconazole
Genetic aspects
Organic compounds
Synthesis
title Synthesis of Altissimacoumarin D and Other Prenylated Coumarins and Their Ability to Reverse the Multidrug Resistance Phenotype in ICandida albicans/I
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-13T20%3A19%3A24IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Synthesis%20of%20Altissimacoumarin%20D%20and%20Other%20Prenylated%20Coumarins%20and%20Their%20Ability%20to%20Reverse%20the%20Multidrug%20Resistance%20Phenotype%20in%20ICandida%20albicans/I&rft.jtitle=Journal%20of%20fungi%20(Basel)&rft.au=Silva,%20Anna%20Claudia&rft.date=2023-07-01&rft.volume=9&rft.issue=7&rft.issn=2309-608X&rft.eissn=2309-608X&rft_id=info:doi/10.3390/jof9070758&rft_dat=%3Cgale%3EA759154247%3C/gale%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/&rft_galeid=A759154247&rfr_iscdi=true