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Synthesis, Optimization, Antifungal Activity, Selectivity, and CYP51 Binding of New 2-Aryl-3-azolyl-1-indolyl-propan-2-ols

hal.structure.identifierUniversité de la Nouvelle-Calédonie [UNC]
hal.structure.identifierCibles et Médicaments des Infections et de l'Immunité [IICiMed]
dc.contributor.authorLEBOUVIER, Nicolas
hal.structure.identifierCibles et Médicaments des Infections et de l'Immunité [IICiMed]
dc.contributor.authorPAGNIEZ, Fabrice
hal.structure.identifierCibles et Médicaments des Infections et de l'Immunité [IICiMed]
dc.contributor.authorNA, Young
hal.structure.identifierSkaggs School of Pharmacy and Pharmaceutical Sciences [San Diego]
dc.contributor.authorSHI, Da
hal.structure.identifierCibles et Médicaments des Infections et de l'Immunité [IICiMed]
dc.contributor.authorPINSON, Patricia
hal.structure.identifierInstitut de Chimie de la Matière Condensée de Bordeaux [ICMCB]
dc.contributor.authorMARCHIVIE, Mathieu
hal.structure.identifierRégulations Naturelles et Artificielles [ARNA]
dc.contributor.authorGUILLON, Jean
hal.structure.identifierSaarland University [Saarbrücken]
dc.contributor.authorHAKKI, Tarek
hal.structure.identifierSaarland University [Saarbrücken]
dc.contributor.authorBERNHARDT, Rita
hal.structure.identifierCardiff University
dc.contributor.authorYEE, Sook
hal.structure.identifierCardiff University
dc.contributor.authorSIMONS, Claire
hal.structure.identifierCibles et Médicaments des Infections et de l'Immunité [IICiMed]
hal.structure.identifierSaarland University [Saarbrücken]
dc.contributor.authorLÉZÉ, Marie-Pierre
hal.structure.identifierSaarland University [Saarbrücken]
dc.contributor.authorHARTMANN, Rolf
hal.structure.identifierMolécules bioactives et chimie médicinale [B2MC]
dc.contributor.authorMULARONI, Angélique
hal.structure.identifierCibles et Médicaments des Infections et de l'Immunité [IICiMed]
dc.contributor.authorLE BAUT, Guillaume
hal.structure.identifierCentre de Recherche en Cancérologie de Lyon [UNICANCER/CRCL]
dc.contributor.authorKRIMM, Isabelle
hal.structure.identifierSkaggs School of Pharmacy and Pharmaceutical Sciences [San Diego]
dc.contributor.authorABAGYAN, Ruben
hal.structure.identifierCibles et Médicaments des Infections et de l'Immunité [IICiMed]
dc.contributor.authorLE PAPE, Patrice
hal.structure.identifierMolécules bioactives et chimie médicinale [B2MC]
hal.structure.identifierCibles et Médicaments des Infections et de l'Immunité [IICiMed]
dc.contributor.authorLE BORGNE, Marc
dc.date.issued2020
dc.identifier.issn1424-8247
dc.description.abstractEnA series of 2-aryl-3-azolyl-1-indolyl-propan-2-ols was designed as new analogs of fluconazole (FLC) by replacing one of its two triazole moieties by an indole scaffold. Two different chemical approaches were then developed. The first one, in seven steps, involved the synthesis of the key intermediate 1-(1H-benzotriazol-1-yl)methyl-1H-indole and the final opening of oxiranes by imidazole or 1H-1,2,4-triazole. The second route allowed access to the target compounds in only three steps, this time with the ring opening by indole and analogs. Twenty azole derivatives were tested against Candida albicans and other Candida species. The enantiomers of the best anti-Candida compound, 2-(2,4-dichlorophenyl)-3-(1H-indol-1-yl)-1-(1H-1,2,4-triazol-1-yl)-propan-2-ol (8g), were analyzed Pharmaceuticals 2020, 13, 186 2 of 32 by X-ray diffraction to determine their absolute configuration. The (−)-8g enantiomer (Minimum inhibitory concentration (MIC) = IC 80 = 0.000256 µg/mL on C. albicans CA98001) was found with the S-absolute configuration. In contrast the (+)-8g enantiomer was found with the R-absolute configuration (MIC = 0.023 µg/mL on C. albicans CA98001). By comparison, the MIC value for FLC was determined as 0.020 µg/mL for the same clinical isolate. Additionally, molecular docking calculations and molecular dynamics simulations were carried out using a crystal structure of Candida albicans lanosterol 14α-demethylase (CaCYP51). The (−)-(S)-8g enantiomer aligned with the positioning of posaconazole within both the heme and access channel binding sites, which was consistent with its biological results. All target compounds have been also studied against human fetal lung fibroblast (MRC-5) cells. Finally, the selectivity of four compounds on a panel of human P450-dependent enzymes (CYP19, CYP17, CYP26A1, CYP11B1, and CYP11B2) was investigated.
dc.language.isoen
dc.publisherMDPI
dc.subject.endocking
dc.subject.enCYP51
dc.subject.enselectivity
dc.subject.encytochromes P450
dc.subject.enazoles
dc.subject.enantifungal agents
dc.subject.enindole
dc.subject.enmicrowave irradiation
dc.subject.enX-ray crystallography
dc.subject.enCandida species
dc.title.enSynthesis, Optimization, Antifungal Activity, Selectivity, and CYP51 Binding of New 2-Aryl-3-azolyl-1-indolyl-propan-2-ols
dc.typeArticle de revue
dc.identifier.doi10.3390/ph13080186
dc.subject.halChimie/Chimie thérapeutique
bordeaux.journalPharmaceuticals
bordeaux.page186 (32 p.)
bordeaux.volume13
bordeaux.issue8
bordeaux.peerReviewedoui
hal.identifierhal-02913479
hal.version1
hal.popularnon
hal.audienceInternationale
hal.origin.linkhttps://hal.archives-ouvertes.fr//hal-02913479v1
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