4.6 Article

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

期刊

PHARMACEUTICALS
卷 13, 期 8, 页码 -

出版社

MDPI
DOI: 10.3390/ph13080186

关键词

azoles; antifungal agents; indole; microwave irradiation; X-ray crystallography; Candidaspecies; docking; CYP51; selectivity; cytochromes P450

资金

  1. Yang Ji Chemical Company of South Korea

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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 againstCandida albicansand otherCandidaspecies. The enantiomers of the best anti-Candidacompound, 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 (-)-8genantiomer (Minimum inhibitory concentration (MIC) = IC80= 0.000256 mu g/mL onC. albicansCA98001) was found with theS-absolute configuration. In contrast the (+)-8genantiomer was found with theR-absolute configuration (MIC = 0.023 mu g/mL onC. albicansCA98001). By comparison, the MIC value for FLC was determined as 0.020 mu g/mL for the same clinical isolate. Additionally, molecular docking calculations and molecular dynamics simulations were carried out using a crystal structure ofCandida albicanslanosterol 14 alpha-demethylase (CaCYP51). The (-)-(S)-8genantiomer 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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