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doi:10.22028/D291-31953
Titel: | Synthesis, Optimization, Antifungal Activity, Selectivity, and CYP51 Binding of New 2-Aryl-3-azolyl-1-indolyl-propan-2-ols |
VerfasserIn: | Lebouvier, Nicolas Pagniez, Fabrice Na, Young Min Shi, Da Pinson, Patricia Marchivie, Mathieu Guillon, Jean Hakki, Tarek Bernhardt, Rita Yee, Sook Wah Simons, Claire Lézé, Marie-Pierre Hartmann, Rolf W. Mularoni, Angélique Le Baut, Guillaume Krimm, Isabelle Abagyan, Ruben Le Pape, Patrice Le Borgne, Marc |
Sprache: | Englisch |
Titel: | Pharmaceuticals |
Bandnummer: | 13 |
Heft: | 8 |
Verlag/Plattform: | MDPI |
Erscheinungsjahr: | 2020 |
Freie Schlagwörter: | azoles antifungal agents indole microwave irradiation X-ray crystallography Candida species docking CYP51 selectivity cytochromes P450 |
DDC-Sachgruppe: | 500 Naturwissenschaften 610 Medizin, Gesundheit |
Dokumenttyp: | Journalartikel / Zeitschriftenartikel |
Abstract: | A 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 by X-ray diffraction to determine their absolute configuration. The (−)-8g enantiomer (Minimum inhibitory concentration (MIC) = IC80 = 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. |
DOI der Erstveröffentlichung: | 10.3390/ph13080186 |
Link zu diesem Datensatz: | urn:nbn:de:bsz:291--ds-319532 hdl:20.500.11880/30421 http://dx.doi.org/10.22028/D291-31953 |
ISSN: | 1424-8247 |
Datum des Eintrags: | 25-Jan-2021 |
Fakultät: | NT - Naturwissenschaftlich- Technische Fakultät |
Fachrichtung: | NT - Biowissenschaften NT - Pharmazie |
Professur: | NT - Prof. Dr. Rolf W. Hartmann NT - Keiner Professur zugeordnet |
Sammlung: | SciDok - Der Wissenschaftsserver der Universität des Saarlandes |
Dateien zu diesem Datensatz:
Datei | Beschreibung | Größe | Format | |
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pharmaceuticals-13-00186-v2.pdf | 5,27 MB | Adobe PDF | Öffnen/Anzeigen |
Diese Ressource wurde unter folgender Copyright-Bestimmung veröffentlicht: Lizenz von Creative Commons