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

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.

Roles for Structural Biology in the Discovery of Drugs and Agrochemicals Targeting Sterol 14α-Demethylases

“…In some cases, the research has been extended using molecular dynamics simulations. For example, Lebouvier et al [160] identified R and S enantiomers of 2-(2,4-dichloropenyl)-3-(1H-indol-1-yl)-propan-2-ol as antifungal and found the 100-fold more active S enantiomer gave MIC values from 0.2-167 ngm/mL for a range of Candida species. While docking studies and molecular dynamics simulations were used to justify the preferential binding of the S enantiomer, a failure to consider the likely presence of a water-mediated hydrogen bond network between CaCyp51 Y132 and the tertiary hydroxyl in the ligand, as shown with the crystals structures of CaCYP51 and ScCYP51 in complex with VT-1161 or ScCYP51 in complex with FLC and VCZ, was an important deficiency.…”

The In Vitro Potential of 1-(1H-indol-3-yl) Derivatives against Candida spp. and Aspergillus niger as Tyrosinase Inhibitors

“…and the fungus Aspergillus niger and could potentially be used for topical formulations. Recently, a series of 2-aryl-3-azolyl-1-indolyl-propan-2-ol was synthetized and tested against Candida albicans and other Candida species: results showed a good antifungal potential of the compounds, with MIC values ranging between 0.005 and 1.25 µg/mL against C. albicans CA98001 [24]. The antimicrobial activity of novel indole derivatives containing 1,2,4-triazole, 1,3,4-thiadiazole and carbothioamide was evaluated against bacterial strains, including Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Escherichia coli, Bacillus subtilis, and the yeasts Candida albicans and Candida krusei: all compounds showed antimicrobial activity, with MIC values of 3.125-50 µg/mL [25].…”

Investigation of Novel Quinoline–Thiazole Derivatives as Antimicrobial Agents: In Vitro and In Silico Approaches

“…All ligands were set to the physiological pH (pH = 7.4) at the protonation step. The proteins were prepared according to the previous studies. ,, …”

“…The proteins were prepared according to the previous studies. 34,62,67 The molecular dynamics simulations (MDS) were performed using the Maestro Desmond interface program. 74 All molecular dynamics simulations (MDS) for 100 ns were carried out to analyze the stability of the identified hits from the in vitro docking results.…”

“…Indeed, each antifungal imidazole analogue has previously been studied on P450, and they have been identified as potent ligands of the heme iron atom of P450s . Moreover, ravuconazole and its analogues (fosravuconazole and isavuconazole) include a thiazole ring as a secondary azole, and albaconazole includes quinazolin-4-one ring, and their action mechanism is mediated through P450 enzymes. , Hence, it was proven that the other azole rings [such as (benzo)-1,2,3-triazole, , 1,2,4-triazole, , 1,3,4-oxadiazole, and 1,3-thiazole] and non-azole nitrogen-rich rings may have also a good antifungal activity profile against invasive fungi. However, several side effects were reported, , probably caused by similarity to the human aromatase (HA) enzyme, and also they showed some drug–drug interactions .…”