Novel fluconazole derivatives with promising antifungal activity
[Display omitted] The fungistatic nature and toxicity concern associated with the azole drugs currently on the market have resulted in an increased demand for new azole antifungal agents for which these problematic characteristics do not exist. The extensive use of azoles has resulted in fungal stra...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2018-02, Vol.26 (3), p.573-580 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | Thamban Chandrika, Nishad Shrestha, Sanjib K. Ngo, Huy X. Howard, Kaitlind C. Garneau-Tsodikova, Sylvie |
| description | [Display omitted]
The fungistatic nature and toxicity concern associated with the azole drugs currently on the market have resulted in an increased demand for new azole antifungal agents for which these problematic characteristics do not exist. The extensive use of azoles has resulted in fungal strains capable of resisting the action of these drugs. Herein, we report the synthesis and antifungal activity of novel fluconazole (FLC) analogues with alkyl-, aryl-, cycloalkyl-, and dialkyl-amino substituents. We evaluated their antifungal activity by MIC determination and time-kill assay as well as their safety profile by hemolytic activity against murine erythrocytes as well as cytotoxicity against mammalian cells. The best compounds from our study exhibited broad-spectrum activity against most of the fungal strains tested, with excellent MIC values against a number of clinical isolates. The most promising compounds were found to be less hemolytic than the least hemolytic FDA-approved azole antifungal agent voriconazole (VOR). Finally, we demonstrated that the synthetic alkyl-amino FLC analogues displayed chain-dependent fungal membrane disruption as well as inhibition of ergosterol biosynthesis as possible mechanisms of action. |
| doi_str_mv | 10.1016/j.bmc.2017.12.018 |
| format | Article |
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The fungistatic nature and toxicity concern associated with the azole drugs currently on the market have resulted in an increased demand for new azole antifungal agents for which these problematic characteristics do not exist. The extensive use of azoles has resulted in fungal strains capable of resisting the action of these drugs. Herein, we report the synthesis and antifungal activity of novel fluconazole (FLC) analogues with alkyl-, aryl-, cycloalkyl-, and dialkyl-amino substituents. We evaluated their antifungal activity by MIC determination and time-kill assay as well as their safety profile by hemolytic activity against murine erythrocytes as well as cytotoxicity against mammalian cells. The best compounds from our study exhibited broad-spectrum activity against most of the fungal strains tested, with excellent MIC values against a number of clinical isolates. The most promising compounds were found to be less hemolytic than the least hemolytic FDA-approved azole antifungal agent voriconazole (VOR). Finally, we demonstrated that the synthetic alkyl-amino FLC analogues displayed chain-dependent fungal membrane disruption as well as inhibition of ergosterol biosynthesis as possible mechanisms of action.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2017.12.018</identifier><identifier>PMID: 29279242</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Antifungal Agents - chemistry ; Antifungal Agents - pharmacology ; Antifungal Agents - toxicity ; Azoles ; Candida - drug effects ; Cell Line ; Cell Survival - drug effects ; Clinical isolates ; Cytotoxicity ; Drug Design ; Erythrocytes - cytology ; Erythrocytes - drug effects ; Erythrocytes - metabolism ; Fluconazole - chemistry ; Fluconazole - pharmacology ; Fluconazole - toxicity ; Fungi - drug effects ; Hemolysis ; Hemolysis - drug effects ; Mice ; Microbial Sensitivity Tests ; Structure-Activity Relationship ; Time-kill studies ; Voriconazole - pharmacology ; Voriconazole - toxicity</subject><ispartof>Bioorganic & medicinal chemistry, 2018-02, Vol.26 (3), p.573-580</ispartof><rights>2017 Elsevier Ltd</rights><rights>Copyright © 2017 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c451t-1c2a068c821246f407600d7237aaa443badc62cc6dae3e16c9affd96df3f46663</citedby><cites>FETCH-LOGICAL-c451t-1c2a068c821246f407600d7237aaa443badc62cc6dae3e16c9affd96df3f46663</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmc.2017.12.018$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,315,781,785,886,3551,27929,27930,46000</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29279242$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Thamban Chandrika, Nishad</creatorcontrib><creatorcontrib>Shrestha, Sanjib K.</creatorcontrib><creatorcontrib>Ngo, Huy X.</creatorcontrib><creatorcontrib>Howard, Kaitlind C.</creatorcontrib><creatorcontrib>Garneau-Tsodikova, Sylvie</creatorcontrib><title>Novel fluconazole derivatives with promising antifungal activity</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>[Display omitted]
The fungistatic nature and toxicity concern associated with the azole drugs currently on the market have resulted in an increased demand for new azole antifungal agents for which these problematic characteristics do not exist. The extensive use of azoles has resulted in fungal strains capable of resisting the action of these drugs. Herein, we report the synthesis and antifungal activity of novel fluconazole (FLC) analogues with alkyl-, aryl-, cycloalkyl-, and dialkyl-amino substituents. We evaluated their antifungal activity by MIC determination and time-kill assay as well as their safety profile by hemolytic activity against murine erythrocytes as well as cytotoxicity against mammalian cells. The best compounds from our study exhibited broad-spectrum activity against most of the fungal strains tested, with excellent MIC values against a number of clinical isolates. The most promising compounds were found to be less hemolytic than the least hemolytic FDA-approved azole antifungal agent voriconazole (VOR). Finally, we demonstrated that the synthetic alkyl-amino FLC analogues displayed chain-dependent fungal membrane disruption as well as inhibition of ergosterol biosynthesis as possible mechanisms of action.</description><subject>Animals</subject><subject>Antifungal Agents - chemistry</subject><subject>Antifungal Agents - pharmacology</subject><subject>Antifungal Agents - toxicity</subject><subject>Azoles</subject><subject>Candida - drug effects</subject><subject>Cell Line</subject><subject>Cell Survival - drug effects</subject><subject>Clinical isolates</subject><subject>Cytotoxicity</subject><subject>Drug Design</subject><subject>Erythrocytes - cytology</subject><subject>Erythrocytes - drug effects</subject><subject>Erythrocytes - metabolism</subject><subject>Fluconazole - chemistry</subject><subject>Fluconazole - pharmacology</subject><subject>Fluconazole - toxicity</subject><subject>Fungi - drug effects</subject><subject>Hemolysis</subject><subject>Hemolysis - drug effects</subject><subject>Mice</subject><subject>Microbial Sensitivity Tests</subject><subject>Structure-Activity Relationship</subject><subject>Time-kill studies</subject><subject>Voriconazole - pharmacology</subject><subject>Voriconazole - toxicity</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMFO3DAQhq2qqCy0D9BLlWMvCR7b68SqVBWhFiohuLRny2uPF6-y8WInQfD0GC1F9MJpDvPNPzMfIZ-BNkBBnmya1dY2jELbAGsodO_IAoQUNecK3pMFVbKraafkITnKeUMpZULBB3LIFGsVE2xBflzFGfvK95ONg3mIPVYOU5jNGGbM1V0Yb6pdituQw7CuzDAGPw1r01fGFiKM9x_JgTd9xk_P9Zj8_fXzz9lFfXl9_vvs9LK2YgljDZYZKjvbMWBCekFbSalrGW-NMULwlXFWMmulM8gRpFXGe6ek89wLKSU_Jt_3ubtptUVncRiT6fUuha1J9zqaoP_vDOFGr-Oslx3lfNmVgK_PASneTphHXZ6y2PdmwDhlDaoDupSK8YLCHrUp5pzQv6wBqp_M640u5vWTeQ1MF_Nl5svr-14m_qkuwLc9gMXSHDDpbAMOFl1IaEftYngj_hFI3JYq</recordid><startdate>20180201</startdate><enddate>20180201</enddate><creator>Thamban Chandrika, Nishad</creator><creator>Shrestha, Sanjib K.</creator><creator>Ngo, Huy X.</creator><creator>Howard, Kaitlind C.</creator><creator>Garneau-Tsodikova, Sylvie</creator><general>Elsevier Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20180201</creationdate><title>Novel fluconazole derivatives with promising antifungal activity</title><author>Thamban Chandrika, Nishad ; Shrestha, Sanjib K. ; Ngo, Huy X. ; Howard, Kaitlind C. ; Garneau-Tsodikova, Sylvie</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c451t-1c2a068c821246f407600d7237aaa443badc62cc6dae3e16c9affd96df3f46663</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Antifungal Agents - chemistry</topic><topic>Antifungal Agents - pharmacology</topic><topic>Antifungal Agents - toxicity</topic><topic>Azoles</topic><topic>Candida - drug effects</topic><topic>Cell Line</topic><topic>Cell Survival - drug effects</topic><topic>Clinical isolates</topic><topic>Cytotoxicity</topic><topic>Drug Design</topic><topic>Erythrocytes - cytology</topic><topic>Erythrocytes - drug effects</topic><topic>Erythrocytes - metabolism</topic><topic>Fluconazole - chemistry</topic><topic>Fluconazole - pharmacology</topic><topic>Fluconazole - toxicity</topic><topic>Fungi - drug effects</topic><topic>Hemolysis</topic><topic>Hemolysis - drug effects</topic><topic>Mice</topic><topic>Microbial Sensitivity Tests</topic><topic>Structure-Activity Relationship</topic><topic>Time-kill studies</topic><topic>Voriconazole - pharmacology</topic><topic>Voriconazole - toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Thamban Chandrika, Nishad</creatorcontrib><creatorcontrib>Shrestha, Sanjib K.</creatorcontrib><creatorcontrib>Ngo, Huy X.</creatorcontrib><creatorcontrib>Howard, Kaitlind C.</creatorcontrib><creatorcontrib>Garneau-Tsodikova, Sylvie</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Thamban Chandrika, Nishad</au><au>Shrestha, Sanjib K.</au><au>Ngo, Huy X.</au><au>Howard, Kaitlind C.</au><au>Garneau-Tsodikova, Sylvie</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel fluconazole derivatives with promising antifungal activity</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2018-02-01</date><risdate>2018</risdate><volume>26</volume><issue>3</issue><spage>573</spage><epage>580</epage><pages>573-580</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>[Display omitted]
The fungistatic nature and toxicity concern associated with the azole drugs currently on the market have resulted in an increased demand for new azole antifungal agents for which these problematic characteristics do not exist. The extensive use of azoles has resulted in fungal strains capable of resisting the action of these drugs. Herein, we report the synthesis and antifungal activity of novel fluconazole (FLC) analogues with alkyl-, aryl-, cycloalkyl-, and dialkyl-amino substituents. We evaluated their antifungal activity by MIC determination and time-kill assay as well as their safety profile by hemolytic activity against murine erythrocytes as well as cytotoxicity against mammalian cells. The best compounds from our study exhibited broad-spectrum activity against most of the fungal strains tested, with excellent MIC values against a number of clinical isolates. The most promising compounds were found to be less hemolytic than the least hemolytic FDA-approved azole antifungal agent voriconazole (VOR). Finally, we demonstrated that the synthetic alkyl-amino FLC analogues displayed chain-dependent fungal membrane disruption as well as inhibition of ergosterol biosynthesis as possible mechanisms of action.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>29279242</pmid><doi>10.1016/j.bmc.2017.12.018</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antifungal Agents - chemistry Antifungal Agents - pharmacology Antifungal Agents - toxicity Azoles Candida - drug effects Cell Line Cell Survival - drug effects Clinical isolates Cytotoxicity Drug Design Erythrocytes - cytology Erythrocytes - drug effects Erythrocytes - metabolism Fluconazole - chemistry Fluconazole - pharmacology Fluconazole - toxicity Fungi - drug effects Hemolysis Hemolysis - drug effects Mice Microbial Sensitivity Tests Structure-Activity Relationship Time-kill studies Voriconazole - pharmacology Voriconazole - toxicity |
| title | Novel fluconazole derivatives with promising antifungal activity |
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