Antifungal Agents. 11. N-Substituted Derivatives of 1-[(Aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazole: Synthesis, Anti-Candida Activity, and QSAR Studies
1-[(Aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazoles were recently reported by our group as potent anti-Candida agents belonging to the antifungal azole class. In the present paper the synthesis, anti-Candida activities, and QSAR studies on a novel series of N-substituted 1-[(aryl)(4-aryl-1H-pyrrol...
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| Veröffentlicht in: | Journal of medicinal chemistry 2005-08, Vol.48 (16), p.5140-5153 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 48 |
| creator | Di Santo, Roberto Tafi, Andrea Costi, Roberta Botta, Maurizo Artico, Marino Corelli, Federico Forte, Michela Caporuscio, Fabiana Angiolella, Letizia Palamara, Anna Teresa |
| description | 1-[(Aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazoles were recently reported by our group as potent anti-Candida agents belonging to the antifungal azole class. In the present paper the synthesis, anti-Candida activities, and QSAR studies on a novel series of N-substituted 1-[(aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazole derivatives are reported. The newly synthesized azoles were tested against 12 strains of Candida albicans together with bifonazole, miconazole, itraconazole, fluconazole, and compounds 1a, 1b, 3a, 3b, and 3c used as reference drugs. In general, tested derivatives showed good antifungal activities, and the most potent compound was 1d (MIC90 = 0.032 μg/mL), which was from 4- to 250-fold more potent than reference drugs. Catalyst software was applied to develop a quantitative pharmacophore model to be used for the rational design of new antifungal azoles. Some key interactions, as well as excluded volumes, further to the coordination bond of azole antifungals with the demethylase enzyme, are highlighted. |
| doi_str_mv | 10.1021/jm048997u |
| format | Article |
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N-Substituted Derivatives of 1-[(Aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazole: Synthesis, Anti-Candida Activity, and QSAR Studies</title><source>MEDLINE</source><source>ACS Publications</source><creator>Di Santo, Roberto ; Tafi, Andrea ; Costi, Roberta ; Botta, Maurizo ; Artico, Marino ; Corelli, Federico ; Forte, Michela ; Caporuscio, Fabiana ; Angiolella, Letizia ; Palamara, Anna Teresa</creator><creatorcontrib>Di Santo, Roberto ; Tafi, Andrea ; Costi, Roberta ; Botta, Maurizo ; Artico, Marino ; Corelli, Federico ; Forte, Michela ; Caporuscio, Fabiana ; Angiolella, Letizia ; Palamara, Anna Teresa</creatorcontrib><description>1-[(Aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazoles were recently reported by our group as potent anti-Candida agents belonging to the antifungal azole class. In the present paper the synthesis, anti-Candida activities, and QSAR studies on a novel series of N-substituted 1-[(aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazole derivatives are reported. The newly synthesized azoles were tested against 12 strains of Candida albicans together with bifonazole, miconazole, itraconazole, fluconazole, and compounds 1a, 1b, 3a, 3b, and 3c used as reference drugs. In general, tested derivatives showed good antifungal activities, and the most potent compound was 1d (MIC90 = 0.032 μg/mL), which was from 4- to 250-fold more potent than reference drugs. Catalyst software was applied to develop a quantitative pharmacophore model to be used for the rational design of new antifungal azoles. Some key interactions, as well as excluded volumes, further to the coordination bond of azole antifungals with the demethylase enzyme, are highlighted.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm048997u</identifier><identifier>PMID: 16078834</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antifungal agents ; Antifungal Agents - chemical synthesis ; Antifungal Agents - chemistry ; Antifungal Agents - pharmacology ; Biological and medical sciences ; Candida albicans - drug effects ; Imidazoles - chemical synthesis ; Imidazoles - chemistry ; Imidazoles - pharmacology ; Medical sciences ; Microbial Sensitivity Tests ; Models, Molecular ; Pharmacology. Drug treatments ; Pyrroles - chemical synthesis ; Pyrroles - chemistry ; Pyrroles - pharmacology ; Quantitative Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2005-08, Vol.48 (16), p.5140-5153</ispartof><rights>Copyright © 2005 American Chemical Society</rights><rights>2005 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm048997u$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm048997u$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17021596$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16078834$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Di Santo, Roberto</creatorcontrib><creatorcontrib>Tafi, Andrea</creatorcontrib><creatorcontrib>Costi, Roberta</creatorcontrib><creatorcontrib>Botta, Maurizo</creatorcontrib><creatorcontrib>Artico, Marino</creatorcontrib><creatorcontrib>Corelli, Federico</creatorcontrib><creatorcontrib>Forte, Michela</creatorcontrib><creatorcontrib>Caporuscio, Fabiana</creatorcontrib><creatorcontrib>Angiolella, Letizia</creatorcontrib><creatorcontrib>Palamara, Anna Teresa</creatorcontrib><title>Antifungal Agents. 11. N-Substituted Derivatives of 1-[(Aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazole: Synthesis, Anti-Candida Activity, and QSAR Studies</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>1-[(Aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazoles were recently reported by our group as potent anti-Candida agents belonging to the antifungal azole class. In the present paper the synthesis, anti-Candida activities, and QSAR studies on a novel series of N-substituted 1-[(aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazole derivatives are reported. The newly synthesized azoles were tested against 12 strains of Candida albicans together with bifonazole, miconazole, itraconazole, fluconazole, and compounds 1a, 1b, 3a, 3b, and 3c used as reference drugs. In general, tested derivatives showed good antifungal activities, and the most potent compound was 1d (MIC90 = 0.032 μg/mL), which was from 4- to 250-fold more potent than reference drugs. Catalyst software was applied to develop a quantitative pharmacophore model to be used for the rational design of new antifungal azoles. Some key interactions, as well as excluded volumes, further to the coordination bond of azole antifungals with the demethylase enzyme, are highlighted.</description><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antifungal agents</subject><subject>Antifungal Agents - chemical synthesis</subject><subject>Antifungal Agents - chemistry</subject><subject>Antifungal Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Candida albicans - drug effects</subject><subject>Imidazoles - chemical synthesis</subject><subject>Imidazoles - chemistry</subject><subject>Imidazoles - pharmacology</subject><subject>Medical sciences</subject><subject>Microbial Sensitivity Tests</subject><subject>Models, Molecular</subject><subject>Pharmacology. Drug treatments</subject><subject>Pyrroles - chemical synthesis</subject><subject>Pyrroles - chemistry</subject><subject>Pyrroles - pharmacology</subject><subject>Quantitative Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkttu1DAQhi0EokvhghdAvgEVqV58SGyHu7DQFqlaDlkQEkKW4zittzkssVM1XPWWp-DdeBK86tJqLkb659M_0j8DwFOC5wRT8mrd4kRmmRjvgRlJKUaJxMl9MMOYUkQ5ZXvgkfdrjDEjlD0Ee4RjISVLZuBP3gVXj92ZbmB-Zrvg55CQOVyiYix9cGEMtoJv7eAudXCX1sO-hgR9P8iHqXl5kCAdOyInaDMNQ98ghqLc2nA-NT-2smtdpX_1jX399_o3LKYunFvv_CHc7kUL3VVxDnMTvV2YDmEU4Kci_wyLMFbO-sfgQa0bb5_s-j74cvRutThBpx-O3y_yU6QZFgHpmlVlaYTIhEm1LDnFlkrLU05KwgXHukqzmomqyojWtcS1obESK6Vm3Bi2D17c-G6G_udofVCt88Y2je5sP3rFZZKkWSYj-GwHjmVrK7UZXBszUP8jjcDzHaC90U096M44f8eJeLE045FDN5zzwV7dzvVwobhgIlWrj4Wi3-Ty62r5RqV3vtp4te7HoYt5KILV9gXU7Quwf3oboA0</recordid><startdate>20050811</startdate><enddate>20050811</enddate><creator>Di Santo, Roberto</creator><creator>Tafi, Andrea</creator><creator>Costi, Roberta</creator><creator>Botta, Maurizo</creator><creator>Artico, Marino</creator><creator>Corelli, Federico</creator><creator>Forte, Michela</creator><creator>Caporuscio, Fabiana</creator><creator>Angiolella, Letizia</creator><creator>Palamara, Anna Teresa</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20050811</creationdate><title>Antifungal Agents. 11. N-Substituted Derivatives of 1-[(Aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazole: Synthesis, Anti-Candida Activity, and QSAR Studies</title><author>Di Santo, Roberto ; Tafi, Andrea ; Costi, Roberta ; Botta, Maurizo ; Artico, Marino ; Corelli, Federico ; Forte, Michela ; Caporuscio, Fabiana ; Angiolella, Letizia ; Palamara, Anna Teresa</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a307t-af3dbbc7797c5a8b620e28e6561b16760ad59f37dd91aaf80fc2c2c4e88a36cc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antifungal agents</topic><topic>Antifungal Agents - chemical synthesis</topic><topic>Antifungal Agents - chemistry</topic><topic>Antifungal Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Candida albicans - drug effects</topic><topic>Imidazoles - chemical synthesis</topic><topic>Imidazoles - chemistry</topic><topic>Imidazoles - pharmacology</topic><topic>Medical sciences</topic><topic>Microbial Sensitivity Tests</topic><topic>Models, Molecular</topic><topic>Pharmacology. Drug treatments</topic><topic>Pyrroles - chemical synthesis</topic><topic>Pyrroles - chemistry</topic><topic>Pyrroles - pharmacology</topic><topic>Quantitative Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Di Santo, Roberto</creatorcontrib><creatorcontrib>Tafi, Andrea</creatorcontrib><creatorcontrib>Costi, Roberta</creatorcontrib><creatorcontrib>Botta, Maurizo</creatorcontrib><creatorcontrib>Artico, Marino</creatorcontrib><creatorcontrib>Corelli, Federico</creatorcontrib><creatorcontrib>Forte, Michela</creatorcontrib><creatorcontrib>Caporuscio, Fabiana</creatorcontrib><creatorcontrib>Angiolella, Letizia</creatorcontrib><creatorcontrib>Palamara, Anna Teresa</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Di Santo, Roberto</au><au>Tafi, Andrea</au><au>Costi, Roberta</au><au>Botta, Maurizo</au><au>Artico, Marino</au><au>Corelli, Federico</au><au>Forte, Michela</au><au>Caporuscio, Fabiana</au><au>Angiolella, Letizia</au><au>Palamara, Anna Teresa</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Antifungal Agents. 11. N-Substituted Derivatives of 1-[(Aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazole: Synthesis, Anti-Candida Activity, and QSAR Studies</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2005-08-11</date><risdate>2005</risdate><volume>48</volume><issue>16</issue><spage>5140</spage><epage>5153</epage><pages>5140-5153</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>1-[(Aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazoles were recently reported by our group as potent anti-Candida agents belonging to the antifungal azole class. In the present paper the synthesis, anti-Candida activities, and QSAR studies on a novel series of N-substituted 1-[(aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazole derivatives are reported. The newly synthesized azoles were tested against 12 strains of Candida albicans together with bifonazole, miconazole, itraconazole, fluconazole, and compounds 1a, 1b, 3a, 3b, and 3c used as reference drugs. In general, tested derivatives showed good antifungal activities, and the most potent compound was 1d (MIC90 = 0.032 μg/mL), which was from 4- to 250-fold more potent than reference drugs. Catalyst software was applied to develop a quantitative pharmacophore model to be used for the rational design of new antifungal azoles. Some key interactions, as well as excluded volumes, further to the coordination bond of azole antifungals with the demethylase enzyme, are highlighted.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>16078834</pmid><doi>10.1021/jm048997u</doi><tpages>14</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2005-08, Vol.48 (16), p.5140-5153 |
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| language | eng |
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| subjects | Antibiotics. Antiinfectious agents. Antiparasitic agents Antifungal agents Antifungal Agents - chemical synthesis Antifungal Agents - chemistry Antifungal Agents - pharmacology Biological and medical sciences Candida albicans - drug effects Imidazoles - chemical synthesis Imidazoles - chemistry Imidazoles - pharmacology Medical sciences Microbial Sensitivity Tests Models, Molecular Pharmacology. Drug treatments Pyrroles - chemical synthesis Pyrroles - chemistry Pyrroles - pharmacology Quantitative Structure-Activity Relationship |
| title | Antifungal Agents. 11. N-Substituted Derivatives of 1-[(Aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazole: Synthesis, Anti-Candida Activity, and QSAR Studies |
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