Synthesis, Optimization, Antifungal Activity, Selectivity, and CYP51 Binding of New 2-Aryl-3-azolyl-1-indolyl-propan-2-ols
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 intermediat...
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Published in | Pharmaceuticals (Basel, Switzerland) Vol. 13; no. 8; p. 186 |
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Main Authors | , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Switzerland
MDPI AG
08.08.2020
MDPI |
Subjects | |
Online Access | Get full text |
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Summary: | 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-(1
-benzotriazol-1-yl)methyl-1
-indole and the final opening of oxiranes by imidazole or 1
-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
and other
species. The enantiomers of the best anti-
compound, 2-(2,4-dichlorophenyl)-3-(1
-indol-1-yl)-1-(1
-1,2,4-triazol-1-yl)-propan-2-ol (
), were analyzed by X-ray diffraction to determine their absolute configuration. The (-)-
enantiomer (Minimum inhibitory concentration (MIC) = IC
= 0.000256 µg/mL on
CA98001) was found with the
-absolute configuration. In contrast the (
)-
enantiomer was found with the
-absolute configuration (MIC = 0.023 µg/mL on
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
lanosterol 14α-demethylase (CaCYP51). The (-)-(
)-
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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1424-8247 1424-8247 |
DOI: | 10.3390/ph13080186 |