Discovery of highly potent antifungal triazoles by structure-based COMPOUND LINKS

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lead
fusion

Wenya Wang , Shengzheng Wang , Guoqiang Dong , Yang Liu , Zizhao Guo , Zhenyuan Miao , Jianzhong Yao , Wannian Zhang * and Chunquan Sheng *
Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China. E-mail: shengcq@hotmail.com.; Fax: (+86)21-81870243; Tel: (+86)21-81870243; zhangwnk@hotmail.com; Fax: (+86)21-81871239; Tel: (+86)21-81871239

Received 16th April 2011 , Accepted 15th August 2011

First published on 9th September 2011


Abstract

By means of structure-based COMPOUND LINKS

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lead
fusion, a series of novel drug-like azoles possessing 4-(benzyloxy)piperidin-1-yl side chains were rationally designed and synthesized. Flexible molecular docking studies indicated that the newly synthesized azoles took advantages of the key interactions between the two COMPOUND LINKS

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lead
structures and CACYP51. As a result, they revealed improved antifungal activity and broader spectrum. All the new azoles showed good to excellent in vitro antifungal activity against all of the tested pathogenic fungi (MIC80 range: 2.33–0.01 μM). Compounds COMPOUND LINKS

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10a
, COMPOUND LINKS

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10g
and COMPOUND LINKS

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10h
, the most active azoles toward Candida albicans (MIC80 = 0.01 μM) are 82 fold more potent than COMPOUND LINKS

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fluconazole
. In particular, all the compounds also showed good activity against Aspergillus fumigatus (MIC80 = 2.33–0.55 μM) that is not sensitive to COMPOUND LINKS

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fluconazole
.


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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fluconazole
and COMPOUND LINKS

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itraconazole
),5,6 polyene macrolides (e.g. amphotericin B),7 allyamines (e.g. COMPOUND LINKS

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terbinafine
)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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voriconazole
and COMPOUND LINKS

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posaconazole
)12,13 have been marketed. Other COMPOUND LINKS

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triazole
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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lanosterol
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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ergosterol
, 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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azole
binding. All of these results facilitated the rational design of novel COMPOUND LINKS

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azole
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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lead
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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lead
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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oxirane
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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piperidin-4-one hydrochloride
5 was treated with excess COMPOUND LINKS

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di-tert-butyl dicarbonate
in the presence of COMPOUND LINKS

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N,N-diisopropylethylamine
(DIEA) in COMPOUND LINKS

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1,4-dioxane
/COMPOUND LINKS

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H2O
(4[thin space (1/6-em)]:[thin space (1/6-em)]1) to give compound COMPOUND LINKS

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6
. Subsequently, compound COMPOUND LINKS

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6
was reduced by COMPOUND LINKS

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potassium borohydride
in COMPOUND LINKS

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methanol
to afford COMPOUND LINKS

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tert-butyl
COMPOUND LINKS

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4-hydroxypiperidine-1-carboxylate
(compound COMPOUND LINKS

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7
). Then, compound COMPOUND LINKS

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7
was reacted with various substituted COMPOUND LINKS

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benzyl bromide
in the presence of COMPOUND LINKS

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sodium hydride
in COMPOUND LINKS

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N,N-dimethylformamide
to give compounds 8a–i. Finally, compounds 8a–i were treated with COMPOUND LINKS

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trifluoroacetic acid
in COMPOUND LINKS

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dichloromethane
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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triethylamine
in COMPOUND LINKS

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ethanol
at 80 °C with moderate to high yields.

Reagents and conditions: a) ClCH2COCl, AlCl3, CH2Cl2, 40 °C, 3 h, 50%; b) triazole, K2CO3, CH2Cl2, RT, 24 h, 70.0%; c) (CH3)3SOI, NaOH, toluene, 60 °C, 3 h, 62.3%. d) Boc2O, DIEA, 1,4-dioxane-H2O, RT, 24 h, 80.2%; e) KBH4, MeOH, 65 °C, 0.5 h, 100%; f) substituted benzyl bromide, NaH, DMF, 0 °C∼RT, 24 h, 29.5%–41.7%; g) CF3COOH, CH2Cl2, RT, 12 h, 90.1%; h) 4, Et3N, EtOH, reflux, 9 h, 28.0%–60.6%.
Scheme 1 Reagents and conditions: a) ClCH2COCl, AlCl3, COMPOUND LINKS

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CH2Cl2
, 40 °C, 3 h, 50%; b) COMPOUND LINKS

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triazole
, K2CO3, COMPOUND LINKS

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CH2Cl2
, RT, 24 h, 70.0%; c) (CH3)3SOI, COMPOUND LINKS

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NaOH
, COMPOUND LINKS

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toluene
, 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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MeOH
, 65 °C, 0.5 h, 100%; f) substituted COMPOUND LINKS

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benzyl bromide
, COMPOUND LINKS

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NaH
, COMPOUND LINKS

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DMF
, 0 °C∼RT, 24 h, 29.5%–41.7%; g) CF3COOH, COMPOUND LINKS

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CH2Cl2
, RT, 12 h, 90.1%; h) 4, COMPOUND LINKS

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Et3N
, COMPOUND LINKS

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EtOH
, 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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lead
structure 1, Fig. 1)25–27 and their conformationally restricted derivatives possessing benzylpiperidin-4-yl side chains (COMPOUND LINKS

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lead
structure 2, Fig. 1).29 The COMPOUND LINKS

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lead
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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lead
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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lead
fusion was used in the COMPOUND LINKS

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lead
optimization process (Fig. 1). The fundamental idea of structure-based COMPOUND LINKS

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lead
fusion is to take advantages of key interactions of different COMPOUND LINKS

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lead
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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lead
structures should be fully investigated.

Design rationale of the new azoles with 4-(benzyloxy)piperidin-1-yl side chains by structure-based lead fusion.
Fig. 1 Design rationale of the new azoles with 4-(benzyloxy)piperidin-1-yl side chains by structure-based COMPOUND LINKS

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lead
fusion.

Previous molecular modeling and structure–activity relationship (SAR) studies showed that COMPOUND LINKS

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lead
structure 1 interacted with CACYP51 through hydrophobic, van der Waals and COMPOUND LINKS

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hydrogen
-bonding interactions.24,25 In particular, the COMPOUND LINKS

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hydrogen
-bonding interaction between its side chain COMPOUND LINKS

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oxygen
atom with Ser378 of CACYP51 was important for the antifungal activity. COMPOUND LINKS

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Lead
structure 2 was conformationally restricted and formed stronger hydrophobic interactions with CACYP51, but it lost COMPOUND LINKS

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hydrogen
interaction with Ser378.29 On the basis of their binding mode, the side chains of the two COMPOUND LINKS

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lead
structures were merged into a new chemotype, namely O-substituted COMPOUND LINKS

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piperidin-4-ol
. The new side chain has several advantages: (1) The COMPOUND LINKS

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piperidin-4-ol
group is conformationally restricted and the COMPOUND LINKS

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oxygen
atom can function as COMPOUND LINKS

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hydrogen
bond acceptor to interact with CACYP51; (2) The COMPOUND LINKS

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piperidin-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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piperidin-4-ol
side chains can form strong hydrophobic, van der Waals and COMPOUND LINKS

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hydrogen
-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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10a
, COMPOUND LINKS

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lead
structure 1 and COMPOUND LINKS

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lead
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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water
-solubility, suggesting their potential as orally active antifungal agents. The comparison of physicochemical properties of compound COMPOUND LINKS

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10a
with COMPOUND LINKS

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azole
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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10h
, 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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10h
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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iron
of COMPOUND LINKS

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heme
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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Hydrogen
-bonding interaction was observed between the COMPOUND LINKS

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oxygen
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.


The docking conformation of compound 10h in the active site of CACYP51. Important residues interacting with the compound are shown.
Fig. 2 The docking conformation of compound COMPOUND LINKS

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10h
in the active site of CACYP51. Important residues interacting with the compound are shown.

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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10a
was more active than COMPOUND LINKS

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lead
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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fluconazole
(MIC80 = 0.82 μM). Particularly, the MIC80 values of compounds COMPOUND LINKS

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10a
, COMPOUND LINKS

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10g
and COMPOUND LINKS

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10h
were 0.01 μM, indicating that they were 82 fold more potent than COMPOUND LINKS

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fluconazole
. 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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fluconazole
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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fluconazole
(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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Fluconazole
is almost inactive toward A. fumigatus, whereas the two COMPOUND LINKS

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lead
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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10f
was the most active COMPOUND LINKS

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azole
with its MIC80 value of 0.55 μM. Among these azoles, compounds COMPOUND LINKS

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10a
, COMPOUND LINKS

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10g
and COMPOUND LINKS

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10h
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
Compd C. alb. C. neo. C. tro. C. par. C. kef. T. rub. A. fum.
a Abbreviations: C. alb. = Candida albicans; C. neo. = Cryptococcus neoformans; C. tro. =Candida tropicalis; C. par. = Candida parapsilosis; C. kef. = Candida kefyr; T. rub. = Trichophyton rubrum; A. fum. = Aspergillus fumigatus; FLZ = COMPOUND LINKS

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Fluconazole
.
COMPOUND LINKS

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10a
0.01 0.04 0.04 0.04 0.15 0.15 2.33
COMPOUND LINKS

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10b
0.03 0.03 0.14 0.03 0.54 0.14 2.16
COMPOUND LINKS

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10c
0.13 0.03 0.13 0.03 0.50 0.13 2.01
COMPOUND LINKS

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10d
0.13 0.03 0.13 0.03 0.50 0.03 2.01
COMPOUND LINKS

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10e
0.14 0.03 0.14 0.03 0.54 0.03 2.16
COMPOUND LINKS

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10f
0.03 0.03 0.14 0.01 0.55 0.03 0.55
COMPOUND LINKS

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10g
0.01 0.12 0.12 0.12 0.49 0.12 1.97
COMPOUND LINKS

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10h
0.01 0.03 0.03 0.03 0.56 0.14 2.24
COMPOUND LINKS

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10i
0.14 0.03 0.03 0.03 0.56 0.03 2.24
Lead 1 0.04 0.15 0.04 0.15 0.60 0.60 >153.68
Lead 2 0.57 2.26 2.26 0.57 2.26 2.26 144.95
FLZ 0.82 0.20 3.26 0.82 3.26 3.26 >208.97


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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10g
and COMPOUND LINKS

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10h
) are more potent than 4-substituted derivatives. Compared to the compounds substituted by COMPOUND LINKS

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mono-chlorine
group (e.g. compounds COMPOUND LINKS

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10b
and COMPOUND LINKS

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10e
), di-chloro substituted derivatives (e.g. compounds COMPOUND LINKS

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10c
and COMPOUND LINKS

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10d
) exhibit lower inhibitory activity. When the halogen atom was replaced by a cyano group (e.g. compound COMPOUND LINKS

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10f
), 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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lead
fusion, for COMPOUND LINKS

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azole
optimization. The 4-(benzyloxy)piperidin-1-yl side chain was designed by taking advantages of the COMPOUND LINKS

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lead
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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hydrogen
bonding (Ser378), π–π stacking, hydrophobic and van der Waals interactions. As compared with the COMPOUND LINKS

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lead
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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10a
, COMPOUND LINKS

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10f
, COMPOUND LINKS

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10g
and COMPOUND LINKS

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10h
, 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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fluconazole
. (3) The designed azoles showed good drug-like properties. COMPOUND LINKS

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Piperidin-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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lead
fusion could be developed into a useful approach in COMPOUND LINKS

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lead
optimization.

Experimental section

Chemistry

General methods. Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker 500 spectrometer with TMS as an internal standard and COMPOUND LINKS

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CDCl3
as solvent. Chemical shifts (δ values) and coupling constants (J values) are given in ppm and Hz, respectively. ESI mass spectra were performed on an API-3000 LC-MS spectrometer. High-resolution mass spectrometry measurements were performed on an Agilent 6538 UHD Accurate-Mass 2-TOF LCMS spectrometer under electrospray ionization (ESI) conditions. TLC analysis was carried out on COMPOUND LINKS

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silica
gel plates GF254 (Qindao Haiyang Chemical, China). COMPOUND LINKS

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Silica
gel column chromatography was performed with COMPOUND LINKS

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Silica
gel 60 G (Qindao Haiyang Chemical, China). Commercial solvents were used without any pretreatment.
COMPOUND LINKS

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tert-Butyl 4-oxopiperidine-1-carboxylate
(COMPOUND LINKS

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6
).
COMPOUND LINKS

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N,N-Diisopropylethylamine
(32.31 g, 0.25 mol, 2.5 equiv) was added to a solution of COMPOUND LINKS

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piperidin-4-one hydrochloride
5 (13.5 g, 0.10 mol, 1.0 equiv) in 200 mL COMPOUND LINKS

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1,4-dioxane
and COMPOUND LINKS

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H2O
(v/v, 4/1). Subsequently, COMPOUND LINKS

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di-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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citric acid
solution, then extracted with COMPOUND LINKS

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dichloromethane
(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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cyclohexane
to afford COMPOUND LINKS

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6
as white needle (15.96 g, 80.2%): mp 72 °C; 1H-NMR (500 MHz, COMPOUND LINKS

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CDCl3
): 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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tert-Butyl
COMPOUND LINKS

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4-hydroxypiperidine-1-carboxylate
(COMPOUND LINKS

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7
).
COMPOUND LINKS

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Potassium borohydride
(0.54 g, 0.010 mol, 1 equiv) was added to a solution of compound COMPOUND LINKS

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6
(2.99 g, 0.015 mol, 1.5 equiv) in COMPOUND LINKS

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methanol
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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ethyl acetate
, washed with COMPOUND LINKS

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H2O
(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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7
as white solid (2.01 g, 100%): Rf 0.36 (COMPOUND LINKS

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CH2Cl2
/COMPOUND LINKS

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MeOH
, 100[thin space (1/6-em)]:[thin space (1/6-em)]2); mp 68 °C; 1H-NMR (500 MHz, COMPOUND LINKS

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CDCl3
): 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.
COMPOUND LINKS

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tert-Butyl 4-(benzyloxy)piperidine-1-carboxylate
(COMPOUND LINKS

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8a
).
COMPOUND LINKS

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Sodium 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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7
(4.02 g, 0.020 mol, 1 equiv) in 80 mL dried COMPOUND LINKS

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DMF
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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benzyl bromide
(4.45 g, 0.026 mol, 1.3 equiv) in 20 mL dried COMPOUND LINKS

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DMF
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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ethyl acetate
, washed with COMPOUND LINKS

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H2O
(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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silica
gel column chromatography (COMPOUND LINKS

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hexane
:COMPOUND LINKS

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EtOAc
, 20[thin space (1/6-em)]:[thin space (1/6-em)]1, v/v) to give COMPOUND LINKS

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8a
as colorless oil (1.72 g, 29.5%): Rf 0.32 (COMPOUND LINKS

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hexane
/COMPOUND LINKS

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EtOAc
, 20[thin space (1/6-em)]:[thin space (1/6-em)]1); 1H-NMR (500 MHz, COMPOUND LINKS

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CDCl3
): 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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8a
.
COMPOUND LINKS

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4-(Benzyloxy)piperidine trifluoroacetate
(COMPOUND LINKS

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9a
).
COMPOUND LINKS

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Trifluoroacetic acid
(0.91 g, 2.0 mmol, 4 equiv) was added to a solution of COMPOUND LINKS

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8a
(0.58 g, 2.0 mmol, 1 equiv) in COMPOUND LINKS

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dichloromethane
(25 mL), and the resulting solution was stirred at room temperature for 12 h. Then the solution was evaporated to dryness under reduced pressure to give COMPOUND LINKS

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9a
as yellow oil (0.55 g, 90.1%). The product was used in the next step without any further purification. Compounds 9b–i were synthesized according to the same protocol described for COMPOUND LINKS

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9a
.
COMPOUND LINKS

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3-[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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10a
).
A solution of epoxide 4 (1.67 g, 0.005 mol), 7a (2.57 g, 0.006 mol), COMPOUND LINKS

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triethylamine
(3 mL) and COMPOUND LINKS

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EtOH
(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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silica
gel column chromatography (COMPOUND LINKS

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CH2Cl2
: COMPOUND LINKS

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MeOH
100[thin space (1/6-em)]:[thin space (1/6-em)]2, v/v) to give COMPOUND LINKS

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10a
as pale yellow solid (0.60 g, 28.0%): Rf 0.28 (COMPOUND LINKS

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CH2Cl2
/COMPOUND LINKS

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MeOH
, 100[thin space (1/6-em)]:[thin space (1/6-em)]2); mp 89–90 °C; 1H-NMR (500 MHz, COMPOUND LINKS

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CDCl3
): 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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CDCl3
): 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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10a
.
COMPOUND LINKS

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3-[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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10b
).
Pale yellow solid (1.20 g, 51.9%); Rf 0.26 (COMPOUND LINKS

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CH2Cl2
/COMPOUND LINKS

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MeOH
, 100[thin space (1/6-em)]:[thin space (1/6-em)]2); mp 76–77 °C; 1H-NMR (500 MHz, COMPOUND LINKS

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CDCl3
): 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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OH
), 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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CDCl3
): 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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3-[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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10c
).
Yellow oil (1.13 g, 45.6%); Rf 0.27 (COMPOUND LINKS

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CH2Cl2
/COMPOUND LINKS

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MeOH
, 100[thin space (1/6-em)]:[thin space (1/6-em)]2); 1H-NMR (500 MHz, COMPOUND LINKS

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CDCl3
): 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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OH
), 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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3-[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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10d
).
Pale yellow solid (1.13 g, 45.6%); Rf 0.27 (COMPOUND LINKS

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CH2Cl2
/COMPOUND LINKS

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MeOH
, 100[thin space (1/6-em)]:[thin space (1/6-em)]2); mp 77–78 °C; 1H-NMR (500 MHz, COMPOUND LINKS

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CDCl3
): 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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OH
), 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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CDCl3
): 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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3-[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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10e
).
Yellow oil (1.32 g, 57.1%); Rf 0.28 (COMPOUND LINKS

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CH2Cl2
/COMPOUND LINKS

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MeOH
, 100[thin space (1/6-em)]:[thin space (1/6-em)]2); 1H-NMR (500 MHz, COMPOUND LINKS

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CDCl3
): 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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3-[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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10f
).
Pale yellow solid (1.37 g, 60.6%); Rf 0.28 (COMPOUND LINKS

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CH2Cl2
/COMPOUND LINKS

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MeOH
, 100[thin space (1/6-em)]:[thin space (1/6-em)]2); mp 140–141 °C; 1H-NMR (500 MHz, COMPOUND LINKS

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CDCl3
): 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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CDCl3
): 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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3-[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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10g
).
Yellow oil (0.97 g, 38.3%); Rf 0.28 (COMPOUND LINKS

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CH2Cl2
/COMPOUND LINKS

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MeOH
, 100[thin space (1/6-em)]:[thin space (1/6-em)]2); 1H-NMR (500 MHz, COMPOUND LINKS

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CDCl3
): 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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OH
), 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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2-(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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10h
).
Pale yellow solid (0.79 g, 35.4%); Rf 0.27 (COMPOUND LINKS

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CH2Cl2
/COMPOUND LINKS

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MeOH
, 100[thin space (1/6-em)]:[thin space (1/6-em)]2); mp 77–78 °C; 1H-NMR (500 MHz, COMPOUND LINKS

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CDCl3
): 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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OH
), 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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2-(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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10i
).
Pale yellow solid (0.88 g, 39.5%); Rf 0.27 (COMPOUND LINKS

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CH2Cl2
/COMPOUND LINKS

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MeOH
, 100[thin space (1/6-em)]:[thin space (1/6-em)]2); mp 89–90 °C; 1H-NMR (500 MHz, COMPOUND LINKS

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CDCl3
): 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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OH
), 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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CDCl3
): 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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Fluconazole
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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DMSO
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

This journal is © The Royal Society of Chemistry 2011
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