DOI:
10.1039/C1MD00103E
(Concise Article)
Med. Chem. Commun., 2011,
2, 1066-1072
Received
16th April 2011
, Accepted 15th August 2011
First published on 9th September 2011
Introduction
There is a tendency that the incidence of invasive and systemic fungal infections, such as invasive candidiasis, cryptococcosis and aspergillosis, has increased dramatically worldwide during the last decades.1 Furthermore, the mortality (per 100,000 population) associated with invasive mycosis increased by 3.4-fold from 1980 to 1997.2 It is mainly caused by the growing number of immunocompromised individuals due to AIDS, organ transplantation and chemotherapy.3Candida albicans (C. albicans), Cryptococcus neoformans (C. neoformans) and Aspergillus fumigatus (A. fumigatus) are the most frequent pathogens isolated from clinical practice.4 Moreover, various moulds and yeasts such as Mucor, Fusarium and Zygomucetes have also emerged as new opportunistic fungi threatening patients' life. Currently, clinically available drugs against these fungal infections contain four major types: azoles (e.g. COMPOUND LINKS
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Download mol file of compoundfluconazole and COMPOUND LINKS
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Download mol file of compounditraconazole),5,6 polyene macrolides (e.g. amphotericin B),7 allyamines (e.g. COMPOUND LINKS
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Download mol file of compoundterbinafine)8 and echinocandins (e.g. caspofungin and micafungin).9,10 They vary in chemical structures and modes of action in different biological pathways. Clinically, azoles, especially triazoles, are first-line agents in treating fungal infections due to their advantageous properties (e.g. broad antifungal spectrum, high activity, oral applicability and chemical stability). However, their extensive use has led to the occurrence of resistant strains which greatly limited the therapeutic options.11 Hence, there is an emergent demand for the discovery of new antifungal azoles. Now, newer triazoles (e.g. COMPOUND LINKS
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Download mol file of compoundvoriconazole and COMPOUND LINKS
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Download mol file of compoundposaconazole)12,13 have been marketed. Other COMPOUND LINKS
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Download mol file of compoundtriazole candidates (e.g. ravuconazole and albaconazole)14,15 are currently under development.
Antifungal azoles target the ergosterol biosynthesis pathway by inhibiting COMPOUND LINKS
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Download mol file of compoundlanosterol 14α-demethylase (CYP51) which removes the methyl group at position C-14 of precursor sterols and thus prevents the synthesis of COMPOUND LINKS
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Download mol file of compoundergosterol, a major component of fungal cell membrane.16 Podust et al. reported the crystal structure of a prokaryotic sterol CYP51 from Mycobacterium tuberculosis (MTCYP51).17 On the basis of the MTCYP51 structure, our group constructed three-dimensional (3D) models of CYP51 from C. albicans (CACYP51), C. neoformans (CNCYP51) and A. fumigatus (AFCYP51) using homology modeling methods18–20 and investigated the binding modes of azoles by flexible molecular docking20,21 and site-directed mutagenesis.22 Several key residues, such as Tyr118 and Ser378, were found to play an important role in COMPOUND LINKS
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Download mol file of compoundazole binding. All of these results facilitated the rational design of novel COMPOUND LINKS
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Download mol file of compoundazole and non-azole CYP51 inhibitors.21,23–28
Recently, we reported a series of potent antifungal azoles with substituted phenoxyalkyl C-3 side chains as well as their conformationally restricted derivatives.24–26,29 In an attempt to improve the antifungal activity, spectrum and drug-like properties, structure-based COMPOUND LINKS
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Download mol file of compoundlead fusion was used to design a new type of side chain containing 4-(benzyloxy)piperidin-1-yl group. As compared with the COMPOUND LINKS
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Download mol file of compoundlead structures, the synthesized azoles showed improved antifungal activity and broader spectrum.
Results and discussion
Chemistry
The chemical synthesis of compounds 10a–i is outlined in Scheme 1. The synthetic procedure of COMPOUND LINKS
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Download mol file of compoundoxirane compound 4 was according to our reported protocol.21 The 4-(substituted benzyloxy)piperidin-1-yl side chains 9a–i were synthesized via four steps. First, COMPOUND LINKS
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Download mol file of compoundpiperidin-4-one hydrochloride 5 was treated with excess COMPOUND LINKS
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Download mol file of compounddi-tert-butyl dicarbonate in the presence of COMPOUND LINKS
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Download mol file of compoundN,N-diisopropylethylamine (DIEA) in COMPOUND LINKS
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Download mol file of compoundH2O (4
:
1) to give compound COMPOUND LINKS
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Download mol file of compound6. Subsequently, compound COMPOUND LINKS
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Download mol file of compound6 was reduced by COMPOUND LINKS
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Download mol file of compoundpotassium borohydride in COMPOUND LINKS
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Download mol file of compoundmethanol to afford COMPOUND LINKS
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Download mol file of compound4-hydroxypiperidine-1-carboxylate (compound COMPOUND LINKS
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Download mol file of compound7). Then, compound COMPOUND LINKS
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Download mol file of compound7 was reacted with various substituted COMPOUND LINKS
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Download mol file of compoundbenzyl bromide in the presence of COMPOUND LINKS
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Download mol file of compoundsodium hydride in COMPOUND LINKS
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Download mol file of compoundN,N-dimethylformamide to give compounds 8a–i. Finally, compounds 8a–i were treated with COMPOUND LINKS
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Download mol file of compoundtrifluoroacetic acid in COMPOUND LINKS
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Download mol file of compounddichloromethane at room temperature overnight to afford the side chains 9a–i. The target compounds 10a–i were obtained as racemates by treating epoxide 4 with side chains 9a–i in the presence of COMPOUND LINKS
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Download mol file of compoundtriethylamine in COMPOUND LINKS
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Download mol file of compoundethanol at 80 °C with moderate to high yields.
 |
| Scheme 1 Reagents and conditions: a) ClCH2COCl, AlCl3, COMPOUND LINKS
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Download mol file of compoundCH2Cl2, 40 °C, 3 h, 50%; b) COMPOUND LINKS
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Download mol file of compoundCH2Cl2, RT, 24 h, 70.0%; c) (CH3)3SOI, COMPOUND LINKS
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Download mol file of compoundtoluene, 60 °C, 3 h, 62.3%. d) Boc2O, DIEA, 1,4-dioxane-H2O, RT, 24 h, 80.2%; e) KBH4, COMPOUND LINKS
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Download mol file of compoundMeOH, 65 °C, 0.5 h, 100%; f) substituted COMPOUND LINKS
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Download mol file of compoundDMF, 0 °C∼RT, 24 h, 29.5%–41.7%; g) CF3COOH, COMPOUND LINKS
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Download mol file of compoundCH2Cl2, RT, 12 h, 90.1%; h) 4, COMPOUND LINKS
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Download mol file of compoundEtOH, reflux, 9 h, 28.0%–60.6%. | |
Design rationale
In our previous studies, we have designed a series of novel azoles with substituted phenoxyalkyl C-3 side chains (COMPOUND LINKS
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Download mol file of compoundlead structure 1, Fig. 1)25–27 and their conformationally restricted derivatives possessing benzylpiperidin-4-yl side chains (COMPOUND LINKS
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Download mol file of compoundlead structure 2, Fig. 1).29 The COMPOUND LINKS
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Download mol file of compoundlead series exhibited good antifungal activity against most of the tested pathogenic fungi, but their potency toward A. fumigatus was weak. Starting from the two COMPOUND LINKS
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Download mol file of compoundlead structures, we aimed to design new antifungal triazoles with improved antifungal activity, broader antifungal spectrum and proper physico-chemical properties. Herein, a new idea of design rationale called structure-based COMPOUND LINKS
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Download mol file of compoundlead fusion was used in the COMPOUND LINKS
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Download mol file of compoundlead optimization process (Fig. 1). The fundamental idea of structure-based COMPOUND LINKS
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Download mol file of compoundlead fusion is to take advantages of key interactions of different COMPOUND LINKS
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Download mol file of compoundlead structures with the receptor and merge them into a new structure that possesses improved binding affinity and drug-like properties. Before structure fusion, the binding mode of two COMPOUND LINKS
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Download mol file of compoundlead structures should be fully investigated.
Previous molecular modeling and structure–activity relationship (SAR) studies showed that COMPOUND LINKS
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Download mol file of compoundlead structure 1 interacted with CACYP51 through hydrophobic, van der Waals and COMPOUND LINKS
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Download mol file of compoundhydrogen-bonding interactions.24,25 In particular, the COMPOUND LINKS
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Download mol file of compoundhydrogen-bonding interaction between its side chain COMPOUND LINKS
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Download mol file of compoundoxygen atom with Ser378 of CACYP51 was important for the antifungal activity. COMPOUND LINKS
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Download mol file of compoundLead structure 2 was conformationally restricted and formed stronger hydrophobic interactions with CACYP51, but it lost COMPOUND LINKS
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Download mol file of compoundhydrogen interaction with Ser378.29 On the basis of their binding mode, the side chains of the two COMPOUND LINKS
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Download mol file of compoundlead structures were merged into a new chemotype, namely O-substituted COMPOUND LINKS
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Download mol file of compoundpiperidin-4-ol. The new side chain has several advantages: (1) The COMPOUND LINKS
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Download mol file of compoundpiperidin-4-ol group is conformationally restricted and the COMPOUND LINKS
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Download mol file of compoundoxygen atom can function as COMPOUND LINKS
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Download mol file of compoundhydrogen bond acceptor to interact with CACYP51; (2) The COMPOUND LINKS
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Download mol file of compoundpiperidin-4-ol group is one of the most frequent scaffolds in marketed oral drugs with good drug-like properties;30 (3) Benzyl substituted COMPOUND LINKS
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Download mol file of compoundpiperidin-4-ol side chains can form strong hydrophobic, van der Waals and COMPOUND LINKS
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Download mol file of compoundhydrogen-bonding interactions with CACYP51; (4) The designed molecules have decreased Log P values. By the method of Wang's group,31 the Log P value of compound COMPOUND LINKS
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Download mol file of compound10a, COMPOUND LINKS
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Download mol file of compoundlead structure 1 and COMPOUND LINKS
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Download mol file of compoundlead structure 2 turned out to be 2.74, 3.22 and 3.22, respectively. It means that the designed azoles may have improved COMPOUND LINKS
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Download mol file of compoundwater-solubility, suggesting their potential as orally active antifungal agents. The comparison of physicochemical properties of compound COMPOUND LINKS
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Download mol file of compoundazole antifungal agents indicates that the designed compound has good drug-like properties (Table 1 in the ESI†).
In order to verify our hypothesis, a representative derivative, compound COMPOUND LINKS
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Download mol file of compound10h, was docked into the active site of CACYP51 using the Affinity module within InsightII 2000 software package.32Fig. 2 shows that compound COMPOUND LINKS
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Download mol file of compound10h binds to the active site of CACYP51 with an extended conformation. The triazolyl ring of the compound coordinates with COMPOUND LINKS
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Download mol file of compoundiron of COMPOUND LINKS
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Download mol file of compoundheme group, while the difluorophenyl group interacts with Phe126, Met306 and Phe145 though hydrophobic interaction. The piperidyl group forms hydrophobic and van der Waals interactions with Ile379 and Val509. COMPOUND LINKS
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Download mol file of compoundHydrogen-bonding interaction was observed between the COMPOUND LINKS
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Download mol file of compoundoxygen atom attached to the piperidyl group and Ser378. It is worth noting that π–π stacking interaction was found between the terminal benzyl group and Tyr118 which further improved the affinity and specificity of the inhibitors. In addition, the terminal benzyl group binds to substrate access channel 2 (FG loop)21 through the hydrophobic and van der Waals interactions with Phe380, Phe228 and Leu121.
In vitro antifungal activity
In vitro antifungal activities of the synthesized compounds were shown in Table 1. All the synthesized compounds revealed good activity against seven common fungal pathogens. In particular, compound COMPOUND LINKS
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Download mol file of compound10a was more active than COMPOUND LINKS
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Download mol file of compoundlead structures 1 and 2. C. albicans has a worldwide distribution and is the most common cause of life-threatening fungal infections. All the compounds showed higher antifungal activity toward C. albicans (MIC80 range: 0.14–0.01 μM) than COMPOUND LINKS
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Download mol file of compoundfluconazole (MIC80 = 0.82 μM). Particularly, the MIC80 values of compounds COMPOUND LINKS
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Download mol file of compound10a, COMPOUND LINKS
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Download mol file of compound10g and COMPOUND LINKS
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Download mol file of compound10h were 0.01 μM, indicating that they were 82 fold more potent than COMPOUND LINKS
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Download mol file of compoundfluconazole. Moreover, these compounds also displayed excellent inhibitory activity against other Candida spp., such as C. tropicalis, C. parapsilosis and C. kefyr with their MIC80 values in the range of 0.56 to 0.01 μM. For the dermatophyte (i.e. T. rubrum), most compounds were superior to COMPOUND LINKS
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Download mol file of compoundfluconazole and their MIC80 values ranged from 0.15 μM to 0.03 μM. On the C. neoformans strain, most compounds showed higher antifungal activity than COMPOUND LINKS
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Download mol file of compoundfluconazole (MIC80 = 0.20 μM) with their MIC80 values on the level of 0.03 μM. A. fumigatus is the leading cause of mortality in patients infected with invasive fungal pathogens. Improving the activity of azoles against A. fumigatus is a challenging task. COMPOUND LINKS
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Download mol file of compoundFluconazole is almost inactive toward A. fumigatus, whereas the two COMPOUND LINKS
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Download mol file of compoundlead structures only reveal weak inhibitory activity. In contrast, all the designed compounds exhibit improved activity (MIC80 range: 2.33–0.55 μM). Among them, compound COMPOUND LINKS
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Download mol file of compound10f was the most active COMPOUND LINKS
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Download mol file of compoundazole with its MIC80 value of 0.55 μM. Among these azoles, compounds COMPOUND LINKS
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Download mol file of compound10a, COMPOUND LINKS
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Download mol file of compound10g and COMPOUND LINKS
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Download mol file of compound10h exhibited the highest in vitro antifungal activity with broad antifungal spectrum, which were good drug candidates for further evaluation.
Table 1
In vitro antifungal activities of the compounds (MIC80, μM)a
Structure–activity relationships
On the basis of the in vitro antifungal activity assay, preliminary SARs of the synthesized compounds were obtained. Because all the synthesized compounds exhibited good antifungal activity, the SARs are not so obvious. In general, the introduction of various substituent groups on the terminal benzyl group did not show significant effect on improving the antifungal activity. When the terminal benzyl group was substituted, the antifungal activities against C. neoformans and A. fumigatus were maintained, while the activities against C. tropicalis and C. kefyr. were decreased. For the position of the substitutions on the terminal phenyl group, the 2-substitited and 3-substituted derivatives (e.g. compounds COMPOUND LINKS
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Download mol file of compound10g and COMPOUND LINKS
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Download mol file of compound10h) are more potent than 4-substituted derivatives. Compared to the compounds substituted by COMPOUND LINKS
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Download mol file of compoundmono-chlorine group (e.g. compounds COMPOUND LINKS
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Download mol file of compound10e), di-chloro substituted derivatives (e.g. compounds COMPOUND LINKS
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Download mol file of compound10d) exhibit lower inhibitory activity. When the halogen atom was replaced by a cyano group (e.g. compound COMPOUND LINKS
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Download mol file of compound10f), the antifungal activity against A. fumigatus was increased by 4 fold.
Conclusions
In the present investigation, we provide a new idea, namely structure-based COMPOUND LINKS
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Download mol file of compoundlead fusion, for COMPOUND LINKS
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Download mol file of compoundazole optimization. The 4-(benzyloxy)piperidin-1-yl side chain was designed by taking advantages of the COMPOUND LINKS
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Download mol file of compoundlead structures' key interactions with CACYP51. Flexible molecular docking studies revealed that the designed compounds showed improved binding affinity and interacted with CACYP51 mainly through COMPOUND LINKS
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Download mol file of compoundhydrogen bonding (Ser378), π–π stacking, hydrophobic and van der Waals interactions. As compared with the COMPOUND LINKS
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Download mol file of compoundlead compounds, the azoles reported here have several advantages: (1) They showed improved antifungal activity with MIC80 values against Candida spp. and C. neoformans in the range of 0.56–0.01 μM. Several compounds, such as COMPOUND LINKS
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Download mol file of compound10a, COMPOUND LINKS
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Download mol file of compound10h, are worth of in vivo antifungal efficacy testing and evaluating their potential as drug candidates. (2) The antifungal spectrum of the synthesized azoles is expanded. Particularly, they showed good activity toward A. fumigatus that was not sensitive to COMPOUND LINKS
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Download mol file of compoundfluconazole. (3) The designed azoles showed good drug-like properties. COMPOUND LINKS
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Download mol file of compoundPiperidin-4-ol is a drug-like scaffold and the compounds have suitable Log P values as orally active drugs. The results of present studies can support the hypothesis that structure-based COMPOUND LINKS
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Download mol file of compoundlead fusion could be developed into a useful approach in COMPOUND LINKS
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Experimental section
Chemistry
COMPOUND LINKS
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Download mol file of compoundtert-Butyl 4-oxopiperidine-1-carboxylate (COMPOUND LINKS
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COMPOUND LINKS
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Download mol file of compoundN,N-Diisopropylethylamine (32.31 g, 0.25 mol, 2.5 equiv) was added to a solution of COMPOUND LINKS
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Download mol file of compoundpiperidin-4-one hydrochloride 5 (13.5 g, 0.10 mol, 1.0 equiv) in 200 mL COMPOUND LINKS
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Download mol file of compounddi-tert-butyl dicarbonate (32.74 g, 0.15 mol, 1.5 equiv) was added dropwise to the reaction mixture over 1 h, and the resulting solution was stirred at room temperature for 24 h. Then the solvent was evaporated under reduced pressure, and the residue was poured into a 5% COMPOUND LINKS
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Download mol file of compounddichloromethane (100 mL × 3). The organic layer was separated, dried with anhydrous Na2SO4, and concentrated to give crude solid, which was recrystallized from COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 3.60 (t, 4H, J = 6.2 Hz, piperidin-2,6-CH2), 2.34 (t, 4H, J = 6.2 Hz, piperidin-3,5-CH2), 1.43 (s, 9H, C(CH3)3); MS (ESI) m/z: 200 [M + H]+.
COMPOUND LINKS
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Download mol file of compoundPotassium borohydride (0.54 g, 0.010 mol, 1 equiv) was added to a solution of compound COMPOUND LINKS
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Download mol file of compoundmethanol 30 mL. The reaction mixture was heated to reflux for 0.5 h. Then the solvent was evaporated under reduced pressure, and the residue was diluted with 100 mL COMPOUND LINKS
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Download mol file of compoundH2O (30 mL × 3). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give COMPOUND LINKS
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Download mol file of compound7 as white solid (2.01 g, 100%): Rf 0.36 (COMPOUND LINKS
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:
2); mp 68 °C; 1H-NMR (500 MHz, COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 3.60 (t, 4H, J = 6.2 Hz, piperidin-2,6-CH2), 3.31 (s, 1H, piperidin-4-CH), 2.34 (t, 4H, J = 6.2 Hz, piperidin-3,5-CH2), 1.43 (s, 9H, C(CH3)3); MS (ESI) m/z: 202 [M + H]+. The product was used in the next step without further purification.
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Download mol file of compoundtert-Butyl 4-(benzyloxy)piperidine-1-carboxylate (COMPOUND LINKS
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Download mol file of compoundSodium hydride (60% dispersion, 1.20 g, 0.030 mol, 1.5 equiv) was added to a solution of compound COMPOUND LINKS
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Download mol file of compoundDMF which was cooled in an ice bath to 0 °C. The reaction mixture was stirred at room temperature for 2 h, then cooled to 0 °C again, and a solution of COMPOUND LINKS
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Download mol file of compoundbenzyl bromide (4.45 g, 0.026 mol, 1.3 equiv) in 20 mL dried COMPOUND LINKS
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Download mol file of compoundDMF was added dropwise to the mixture. The resulting mixture was stirred at room temperature for 24 h and then diluted with 200 mL COMPOUND LINKS
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Download mol file of compoundethyl acetate, washed with COMPOUND LINKS
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Download mol file of compoundH2O (50 mL × 3). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by COMPOUND LINKS
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Download mol file of compoundEtOAc, 20
:
1, v/v) to give COMPOUND LINKS
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Download mol file of compound8a as colorless oil (1.72 g, 29.5%): Rf 0.32 (COMPOUND LINKS
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Download mol file of compoundEtOAc, 20
:
1); 1H-NMR (500 MHz, COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 7.25∼7.35 (m, 5H, Ar-H), 4.56 (s, 2H, CH2O), 3.75∼3.79 (m, 2H, piperidin-2-CH2), 3.31 (s, 1H, piperidin-4-CH), 3.07∼3.13 (m, 2H, piperidin-6-CH2), 1.83∼1.87 (t, 2H, piperidin-3-CH2), 1.56∼1.60 (t, 2H, piperidin-5-CH2), 1.45 (s, 9H, C(CH3)3); MS (ESI) m/z: 292 [M + H]+. Compounds 8b–i were synthesized according to the same protocol described for COMPOUND LINKS
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COMPOUND LINKS
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Download mol file of compound3-[4-(Benzyloxy)piperidin-1-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (COMPOUND LINKS
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A solution of epoxide 4 (1.67 g, 0.005 mol), 7a (2.57 g, 0.006 mol), COMPOUND LINKS
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Download mol file of compoundEtOH (30 mL) was heated to reflux for 9h. The solvent was evaporated under reduced pressure. The residue was purified by COMPOUND LINKS
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:
2, v/v) to give COMPOUND LINKS
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Download mol file of compound10a as pale yellow solid (0.60 g, 28.0%): Rf 0.28 (COMPOUND LINKS
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:
2); mp 89–90 °C; 1H-NMR (500 MHz, COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 8.15 (s, 1H, TriazoleC3-H), 7.77 (s, 1H, TriazoleC5-H), 6.77∼7.57 (m, 8H, Ar-H), 4.50 (s, 2H, C1-HaHb), 4.47 (s, 2H, OCH2), 3.36 (br, 1H, piperidin-4-CH), 3.04 (d, 1H, J = 12.5 Hz, C3-Ha), 2.65 (d, 1H, J = 13.1 Hz, C3-Hb), 2.47∼2.53 (m, 2H, piperidin-2-CH2), 2.13∼2.25 (m, 2H, piperidin-6-CH2), 1.77 (br, 2H, piperidin-3-CH2), 1.59 (br, 2H, piperidin-5-CH2); 13C-NMR (500 MHz, COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 162.71, 158.91, 150.98, 144.63, 138.69, 129.32, 128.34, 127.42, 126.38, 111.50, 104.19, 72.98, 71.72, 69.75, 62.19, 56.49, 52.50, 51.97, 31.19, 29.66 ppm; HRMS-ESI: m/z [M + H]+ calcd for C23H26F2N4O2: 429.2102, found: 429.2101. The target compounds 10b–i were synthesized according to the same protocol described for COMPOUND LINKS
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Download mol file of compound10a.
COMPOUND LINKS
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Download mol file of compound3-[4-(2-Chlorobenzyloxy)piperidin-1-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (COMPOUND LINKS
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Download mol file of compound10b).
Pale yellow solid (1.20 g, 51.9%); Rf 0.26 (COMPOUND LINKS
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Download mol file of compoundCH2Cl2/COMPOUND LINKS
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Download mol file of compoundMeOH, 100
:
2); mp 76–77 °C; 1H-NMR (500 MHz, COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 8.15 (s, 1H, TriazoleC3-H), 7.80 (s, 1H, TriazoleC5-H), 6.79∼7.46 (m, 7H, Ar-H), 5.30 (s, 1H, COMPOUND LINKS
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Download mol file of compoundOH), 4.55 (s, 2H, OCH2), 4.50 (d, 2H, J = 14.5 Hz, C1-HaHb), 3.42 (br, 1H, piperidin-4-CH), 3.05 (d, 1H, J = 13.4 Hz, C3-Ha), 2.66 (d, 1H, J = 13.6 Hz, C3-Hb), 2.49∼2.55 (m, 2H, piperidin-2-CH2), 2.14∼2.28 (m, 2H, piperidin-6-CH2), 1.80 (br, 2H, piperidin-3-CH2), 1.62 (br, 2H, piperidin-5-CH2); 13C-NMR (500 MHz, COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 162.69, 158.90, 150.98, 144.61, 136.41, 132.62, 129.29, 129.14, 128.78, 128.48, 126.73, 126.36, 111.47, 104.18, 73.70, 71.73, 66.90, 62.19, 56.46, 52.45, 51.93, 31.20 ppm; HRMS-ESI: m/z [M + H]+ calcd for C23H25ClF2N4O2: 463.1712, found: 463.1715.
COMPOUND LINKS
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Download mol file of compound3-[4-(2,4-Dichlorobenzyloxy)piperidin-1-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (COMPOUND LINKS
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Download mol file of compound10c).
Yellow oil (1.13 g, 45.6%); Rf 0.27 (COMPOUND LINKS
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Download mol file of compoundCH2Cl2/COMPOUND LINKS
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Download mol file of compoundMeOH, 100
:
2); 1H-NMR (500 MHz, COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 8.15 (s, 1H, TriazoleC3-H), 7.78 (s, 1H, TriazoleC5-H), 6.77∼7.56 (m, 6H, Ar-H), 5.30 (s, 1H, COMPOUND LINKS
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Download mol file of compoundOH), 4.52 (d, 2H, J = 14.4 Hz, C1-HaHb), 4.49 (s, 2H, OCH2), 3.40 (br, 1H, piperidin-4-CH), 3.05 (d, 1H, J = 13.2 Hz, C3-Ha), 2.66 (d, 1H, J = 13.6 Hz, C3-Hb), 2.48∼2.54 (m, 2H, piperidin-2-CH2), 2.15∼2.26 (m, 2H, piperidin-6-CH2), 1.79 (br, 2H, piperidin-3-CH2), 1.60 (br, 2H, piperidin-5-CH2); HRMS-ESI: m/z [M + H]+ calcd for C23H24Cl2F2N4O2: 497.1323, found: 497.1320.
COMPOUND LINKS
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Download mol file of compound3-[4-(3,4-Dichlorobenzyloxy)piperidin-1-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (COMPOUND LINKS
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Download mol file of compound10d).
Pale yellow solid (1.13 g, 45.6%); Rf 0.27 (COMPOUND LINKS
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Download mol file of compoundCH2Cl2/COMPOUND LINKS
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Download mol file of compoundMeOH, 100
:
2); mp 77–78 °C; 1H-NMR (500 MHz, COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 8.15 (s, 1H, TriazoleC3-H), 7.78 (s, 1H, TriazoleC5-H), 6.77∼7.56 (m, 6H, Ar-H), 5.30 (s, 1H, COMPOUND LINKS
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Download mol file of compoundOH), 4.52 (d, 2H, J = 14.0 Hz, C1-HaHb), 4.49 (s, 2H, OCH2), 3.35 (br, 1H, piperidin-4-CH), 3.04 (d, 1H, J = 13.3 Hz, C3-Ha), 2.65 (d, 1H, J = 13.6 Hz, C3-Hb), 2.46∼2.53 (m, 2H, piperidin-2-CH2), 2.13∼2.25 (m, 2H, piperidin-6-CH2), 1.76 (br, 2H, piperidin-3-CH2), 1.56 (br, 2H, piperidin-5-CH2); 13C-NMR (500 MHz, COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 162.77, 158.91, 151.00, 144.62, 139.10, 132.03, 131.25, 130.29, 129.29, 129.10, 126.40, 111.50, 104.20, 73.59, 71.83, 68.36, 62.18, 56.42, 52.42, 51.89, 31.17 ppm; HRMS-ESI: m/z [M + H]+ calcd for C23H24Cl2F2N4O2: 497.1323, found: 497.1325.
COMPOUND LINKS
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Download mol file of compound3-[4-(3-Chlorobenzyloxy)piperidin-1-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (COMPOUND LINKS
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Download mol file of compound10e).
Yellow oil (1.32 g, 57.1%); Rf 0.28 (COMPOUND LINKS
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Download mol file of compoundCH2Cl2/COMPOUND LINKS
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Download mol file of compoundMeOH, 100
:
2); 1H-NMR (500 MHz, COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 8.15 (s, 1H, TriazoleC3-H), 7.78 (s, 1H, TriazoleC5-H), 6.79∼7.56 (m, 7H, Ar-H), 4.50 (d, 2H, J = 14.2 Hz, C1-HaHb), 4.44 (s, 2H, OCH2), 3.36 (br, 1H, piperidin-4-CH), 3.04 (d, 1H, J = 13.5 Hz, C3-Ha), 2.65 (d, 1H, J = 13.5 Hz, C3-Hb), 2.47∼2.54 (m, 2H, piperidin-2-CH2), 2.12∼2.27 (m, 2H, piperidin-6-CH2), 1.76 (br, 2H, piperidin-3-CH2), 1.54∼1.60 (m, 2H, piperidin-5-CH2); HRMS-ESI: m/z [M + H]+ calcd for C23H25ClF2N4O2: 463.1712, found: 463.1716.
COMPOUND LINKS
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Download mol file of compound3-[4-(4-Cyanobenzyloxy)piperidin-1-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (COMPOUND LINKS
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Download mol file of compound10f).
Pale yellow solid (1.37 g, 60.6%); Rf 0.28 (COMPOUND LINKS
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Download mol file of compoundCH2Cl2/COMPOUND LINKS
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Download mol file of compoundMeOH, 100
:
2); mp 140–141 °C; 1H-NMR (500 MHz, COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 8.14 (s, 1H, TriazoleC3-H), 7.78 (s, 1H, TriazoleC5-H), 6.79∼7.62 (m, 7H, Ar-H), 4.52 (s, 2H, OCH2), 4.50 (d, 2H, J = 14.2 Hz, C1-HaHb), 3.38 (br, 1H, piperidin-4-CH), 3.04 (d, 1H, J = 13.9 Hz, C3-Ha), 2.66 (d, 1H, J = 13.6 Hz, C3-Hb), 2.47∼2.54 (m, 2H, piperidin-2-CH2), 2.12∼2.27 (m, 2H, piperidin-6-CH2), 1.76 (br, 2H, piperidin-3-CH2), 1.54∼1.60 (m, 2H, piperidin-5-CH2); 13C-NMR (500 MHz, COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 162.65, 158.88, 150.94, 144.57, 144.31, 132.07, 129.26, 127.40, 126.32, 118.68, 111.35, 104.13, 73.81, 71.82, 68.77, 62.14, 56.35, 52.31, 51.81, 31.09 ppm; HRMS-ESI: m/z [M + H]+ calcd for C24H25F2N5O2: 454.2055, found: 454.2054.
COMPOUND LINKS
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Download mol file of compound3-[4-(3-Bromobenzyloxy)piperidin-1-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (COMPOUND LINKS
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Download mol file of compound10g).
Yellow oil (0.97 g, 38.3%); Rf 0.28 (COMPOUND LINKS
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Download mol file of compoundCH2Cl2/COMPOUND LINKS
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Download mol file of compoundMeOH, 100
:
2); 1H-NMR (500 MHz, COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 8.15 (s, 1H, TriazoleC3-H), 7.78 (s, 1H, TriazoleC5-H), 6.77∼7.56 (m, 7H, Ar-H), 5.30 (s, 1H, COMPOUND LINKS
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Download mol file of compoundOH), 4.50 (d, 2H, J = 14.2 Hz, C1-HaHb), 4.43 (s, 2H, OCH2), 3.35 (br, 1H, piperidin-4-CH), 3.04 (d, 1H, J = 13.6 Hz, C3-Ha), 2.66 (d, 1H, J = 13.6 Hz, C3-Hb), 2.47∼2.53 (m, 2H, piperidin-2-CH2), 2.14∼2.27 (m, 2H, piperidin-6-CH2), 1.76 (br, 2H, piperidin-3-CH2), 1.54∼1.59 (m, 2H, piperidin-5-CH2); HRMS-ESI: m/z [M + H]+ calcd for C23H25BrF2N4O2: 507.1207, found: 507.1210.
COMPOUND LINKS
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Download mol file of compound2-(2,4-Difluorophenyl)-3-[4-(2-fluorobenzyloxy)piperidin-1-yl]-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (COMPOUND LINKS
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Download mol file of compound10h).
Pale yellow solid (0.79 g, 35.4%); Rf 0.27 (COMPOUND LINKS
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Download mol file of compoundCH2Cl2/COMPOUND LINKS
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Download mol file of compoundMeOH, 100
:
2); mp 77–78 °C; 1H-NMR (500 MHz, COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 8.15 (s, 1H, TriazoleC3-H), 7.78 (s, 1H, TriazoleC5-H), 6.79∼7.56 (m, 7H, Ar–H), 5.30 (s, 1H, COMPOUND LINKS
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Download mol file of compoundOH), 4.53 (s, 2H, OCH2), 4.50 (d, 2H, J = 14.2 Hz, C1-HaHb), 3.39 (br, 1H, piperidin-4-CH), 3.04 (d, 1H, J = 13.7 Hz, C3-Ha), 2.65 (d, 1H, J = 13.6 Hz, C3-Hb), 2.54 (br, 2H, piperidin-2-CH2), 2.14∼2.26 (m, 2H, piperidin-6-CH2), 1.78 (br, 2H, piperidin-3-CH2), 1.55∼1.61 (m, 2H, piperidin-5-CH2); HRMS-ESI: m/z [M + H]+ calcd for C23H25F3N4O2: 447.2008, found: 447.2010.
COMPOUND LINKS
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Download mol file of compound2-(2,4-Difluorophenyl)-3-[4-(4-fluorobenzyloxy)piperidin-1-yl]-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (COMPOUND LINKS
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Download mol file of compound10i).
Pale yellow solid (0.88 g, 39.5%); Rf 0.27 (COMPOUND LINKS
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Download mol file of compoundCH2Cl2/COMPOUND LINKS
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Download mol file of compoundMeOH, 100
:
2); mp 89–90 °C; 1H-NMR (500 MHz, COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 8.15 (s, 1H, TriazoleC3-H), 7.78 (s, 1H, TriazoleC5-H), 6.79∼7.56 (m, 7H, Ar–H), 5.30 (s, 1H, COMPOUND LINKS
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Download mol file of compoundOH), 4.50 (d, 2H, J = 14.4 Hz, C1-HaHb), 4.42 (s, 2H, OCH2), 3.35 (br, 1H, piperidin-4-CH), 3.04 (d, 1H, J = 13.9 Hz, C3-Ha), 2.65 (d, 1H, J = 13.7 Hz, C3-Hb), 2.46∼2.53 (m, 2H, piperidin-2-CH2), 2.11∼2.27 (m, 2H, piperidin-6-CH2), 1.75 (br, 2H, piperidin-3-CH2), 1.55∼1.58 (m, 2H, piperidin-5-CH2); 13C-NMR (500 MHz, COMPOUND LINKS
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Download mol file of compoundCDCl3): δ 162.66, 162.21, 158.90, 150.98, 144.61, 134.44, 129.31, 129.02, 126.29, 115.15, 111.42, 104.17, 73.17, 71.79, 69.05, 62.20, 56.45, 52.49, 51.95, 31.16, 29.63 ppm; HRMS-ESI: m/z [M + H]+ calcd for C23H25F3N4O2: 447.2008, found: 447.2006.
In vitro antifungal activity assays
In vitro antifungal activity was measured by means of the minimum inhibitory concentration (MIC) using the serial dilution method in 96-well microtest plates. COMPOUND LINKS
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Download mol file of compoundFluconazole was used as the reference drug. Test fungal strains were obtained from the ATCC or were clinical isolates. The MIC determination was performed according to the National Committee for Clinical Laboratory Standards (NCCLS) recommendations with RPMI 1640 (Sigma) buffered with 0.165M MOPS (Sigma) as the test medium. The MIC value was defined as the lowest concentration of test compounds that resulted in a culture with turbidity less than or equal to 80% inhibition when compared with the growth of the control. Test compounds were dissolved in COMPOUND LINKS
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Download mol file of compoundDMSO serially diluted in growth medium. The yeasts were incubated at 35 °C and the dermatophytes at 28 °C. Growth MIC was determined at 24 h for Candida species, at 72 h for C. neoformans, and at 7 days for filamentous fungi.
Flexible docking analysis
The 3D structures of the designed azoles were built by the Builder module within InsightII 2000 software package. Then, the flexible ligand docking procedure in the Affinity module within InsightII was used to define the lowest energy position for the substrate using a Monte Carlo docking protocol. The detailed docking parameters were from our previous studies.21
Acknowledgements
This work was supported by the National Natural Science Foundation of China (Grant Nos. 30930107), Science and Technology Commission of Shanghai (Grant Nos. 10431902100), Shanghai Rising-Star Program (Grant Nos. 09QA1407000) and Shanghai Leading Academic Discipline Project (Project Nos. B906).
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Footnote |
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c1md00103e |
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This journal is © The Royal Society of Chemistry 2011 |
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