Synthesis, single crystal X-ray analysis, and antifungal profiling of certain new oximino ethers bearing imidazole nuclei

Article abstract of DOI:10.3390/molecules22111895

Fungal infections threaten human health, particularly in immune-compromised patients worldwide. Although there are a large number of antifungal agents available, the desired clinical attributes for the treatment of fungal infections have not yet been achieved. Azoles are the mainstay class of the clinically used antifungal agents. In the current study, the synthesis, spectroscopic characterization, and antifungal activity of certain new oximino ethers Va-n bearing imidazole nuclei are reported. The (E)-configuration of the imine double bond of the synthesized compounds Va-n has been confirmed via single crystal X-ray analysis of compound Vi as a representative example of this class of compounds. The molecular structure of compound Vi was crystallized in the monoclinic, P2₁/c, a = 18.7879(14) ?,β= 5.8944(4) ?, c = 16.7621(12) ?³,β= 93.063(3)β V = 1855.5(2) ?3, Z = 4. The in vitro antifungal activity of the synthesized compounds Va-n were evaluated using diameter of the inhibition zone (DIZ) and minimum inhibitory concentration (MIC) assays against different fungal strains. Compound Ve manifested anti-Candida albicans activity with an MIC value of 0.050 μmol/mL, being almost equipotent with the reference antifungal drug fluconazole (FLC),while compounds Vi and Vn are the most active congeners against Candida parapsilosis, being equipotent and about twenty-three times more potent than FLC with an MIC value of 0.002 μmol/mL. The results of the current report might support the development of new potent and safer antifungal azoles.

Full text of DOI:10.3390/molecules22111895

molecules
Article
Synthesis, Single Crystal X-ray Analysis, and
Antifungal Profiling of Certain New Oximino Ethers
Bearing Imidazole Nuclei
1
,
1
1,2 ID
Reem I. Al-Wabli *, Alwah R. Al-Ghamdi , Hazem A. Ghabbour
,
Mohamed H. Al-Agamy 3
,4
ID
and Mohamed I. Attia
1,5,
*
ID
1
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457,
Riyadh 11451, Saudi Arabia; toto24se@hotmail.com (A.R.A.-G.); ghabbourh@yahoo.com (H.A.G.)
Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451,
Saudi Arabia; malagamy@ksu.edu.sa
Microbiology and Immunology Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt
Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research
Division, National Research Centre (ID: 60014618), El Bohooth Street, Dokki, Giza 12622, Egypt
Correspondence: ralwabli@ksu.edu.sa (R.I.A.-W.); mattia@ksu.edu.sa (M.I.A.)
2
3
4
5
*
Received: 4 October 2017; Accepted: 31 October 2017; Published: 3 November 2017
Abstract: Fungal infections threaten human health, particularly in immune-compromised patients
worldwide. Although there are a large number of antifungal agents available, the desired clinical
attributes for the treatment of fungal infections have not yet been achieved. Azoles are the mainstay
class of the clinically used antifungal agents. In the current study, the synthesis, spectroscopic
characterization, and antifungal activity of certain new oximino ethers Va
–n bearing imidazole nuclei
are reported. The (E)-configuration of the imine double bond of the synthesized compounds Va
–
n
has been confirmed via single crystal X-ray analysis of compound Vi as a representative example of
this class of compounds. The molecular structure of compound Vi was crystallized in the monoclinic,
◦
3
P2 /c, a = 18.7879(14) Å, b = 5.8944(4) Å, c = 16.7621(12) Å,
β
= 93.063(3) , V = 1855.5(2) Å , Z = 4.
The in vitro antifungal activity of the synthesized compounds Va were evaluated using diameter of
the inhibition zone (DIZ) and minimum inhibitory concentration (MIC) assays against different fungal
strains. Compound Ve manifested anti-Candida albicans activity with an MIC value of 0.050 mol/mL,
1
–
n
µ
being almost equipotent with the reference antifungal drug fluconazole (FLC),while compounds
Vi and Vn are the most active congeners against Candida parapsilosis, being equipotent and about
twenty-three times more potent than FLC with an MIC value of 0.002 µmol/mL. The results of the
current report might support the development of new potent and safer antifungal azoles.
Keywords: imidazole; Mannich reaction; X-ray; antifungal agents; anti-Candida
1
. Introduction
Fungal infections are an ever-growing burden on the health of mankind. They sometimes cause
significant morbidity and mortality particularly in immune-compromised individuals, like those taking
anticancer chemotherapy, patients with AIDS, or those receiving organ transplants [ ]. Invasive
fungal infections, like invasive aspergillosis and candidiasis, threaten the human health of millions of
patients annually worldwide [ ]. The available antifungal drugs can be classified into five main categories
according to their mode of action: antimetabolites (e.g., 5-fluorocytosine) [ ], polyenes (e.g., nystatin
and amphotericin B) [ ], azoles (e.g., itraconazole, voriconazole and fluconazole) [ ], allylamines
e.g., naftifine and terbinafine) [6], and echinocandins (e.g., micafungin and caspofungin) [7].
1,2
3
4
5
5
(
Molecules 2017, 22, 1895; doi:10.3390/molecules22111895
www.mdpi.com/journal/molecules

Molecules 2017, 22, 1895
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Azoles bearing either imidazole or triazole moiety as a pharmacophoric portion constitute
the mainstay antifungal therapy due to their good safety profile and favorable bioavailability [ ].
They target lanosterol 14 -demethylase (CYP51) enzyme, a member of the CYP51 class of cytochrome
P450 enzymes, leading to inhibition of the biosynthesis of ergosterol and accumulation of the toxic
methylated sterol, which ultimately results in fungi cell death [ ]. Even though azoles are currently
6
α
8
the most clinically prescribed antifungal agents, they suffer from some limitations. Inhibition of
cytochrome P450 enzymes by azoles leads to interference with the metabolism of other co-administered
medications [
development of resistance toward fungal therapy [
9
]. Moreover, azoles lack fungicidal activity against many fungi, which leads to the
]. Therefore, there is considerable interest
3
in developing new azole-bearing antifungal agents endowed with a wide antifungal spectrum,
high potency, diminished undesired drug–drug interactions, and reduced adverse effects.
Screening the literature revealed that oxiconazole (
1, Figure 1) and its inverted oxime analog
2
(
Figure 1) are well known antifungal agents bearing both imidazole and oxime functionalities [10
,11].
Moreover, most of the currently available azole-bearing antifungal agents feature a spacer of two
carbon atoms between the azole pharmacophore moiety and an aromatic nucleus, while insufficient
information is available about azole antifungals bearing a three-carbon bridge connecting azole and
aromatic moieties [12–14]. Accordingly, it was of our interest to synthesize the oximino ethers Va–g to be
evaluated as new antifungal agents bearing oxime and imidazole fragments with a three-carbon atom
bridge between the imidazole pharmacophore and the aromatic moiety. In addition, a 1,3-benzodioxole
scaffold was incorporated into a plethora of bioactive molecules including antimicrobials [15
Therefore, the phenyl ring in compounds Va was replaced by 1,3-benzodioxole moiety to afford the
respective compounds Vh to be assessed as new antifungal candidates. Moreover, the configuration
around the imine double bond of the title compounds Va was explored via single crystal X-ray
analysis of compound Vi as a representative example of this type of compounds.
–17].
–
g
–n
–
n
X
Cl
Cl
O
Cl
Cl
N
CH3
O
O
N
N
N
N
N
N
Ar
N
N
Cl
Cl
Cl
Cl
1
2
Va-n
Figure 1. Chemical structures of the antifungal agents 1 and 2 as well as the target compounds Va–n.
2
. Results and Discussion
2
.1. Chemistry
The target compounds Va
in Scheme 1. The synthesis was commenced by utilizing the commercially available acetophenones
Ia to perform Mannich reactions to give the respective Mannich bases IIa . Compounds IIa
were elaborated to the corresponding ketones IIIa which were subsequently transformed to the
oximes IVa . The target oximino ethers Va were obtained in 24–63.4% yields via etherification of
the pivotal oximes IVa using the appropriate benzyl bromide/chloride in the presence of sodium
hydride. The assigned chemical structures of the title compounds Va were confirmed via different
spectroscopic techniques (IR, H-NMR, C-NMR and mass spectrometry). The aromatic protons of
compounds Va appeared along with imidazole protons in the range of 6.75–8.39 ppm, while the
benzylic protons occurred in the range of 5.13–5.29 ppm. The benzodiaxole methylene protons of
compounds Vh manifested around 5.9 ppm. The aliphatic ethylene protons of compounds Va
–n and their intermediates were successfully achieved as illustrated
,b
,
b
,b
,
b
,b
–n
,
b
–n
1
13
–
n
–
n
–n

Molecules 2017, 22, 1895
3 of 12
were observed in the expected upfield region of 3.14–4.29 ppm. The 13C spectra of compounds Va
showed aromatic as well as imidazole carbons in the range of 106.2–162.6 ppm. Their benzylic carbons
occurred at 74.8–76.7 ppm, while the benzoldiaxole methylene carbons of compounds Vh were
observed around 101 ppm. Moreover, the aliphatic ethylene carbons of compounds Va exhibited
signals in the expected region of 28.9–44.3 ppm while the oximino carbons manifested signals around
55 ppm. The mass spectral data of the target compounds Va are consistent with their assigned
chemical structures. The (E)-configuration of the oximino double bond of the title compounds Va
–n
–
n
–
n
1
–n
–n
has been proved using single crystal X-ray analysis of compound Vi as a representative example of the
prepared compounds Va–n.
O
O
O
NOH
i
ii
iii
Ar
CH3
Ar
N(CH
3
)
2
.HCl
Ar
N
N
Ar
N
N
X
Ia,b
IIa,b
IIIa,b
IVa,b
iv
I-IV
Ar
a
O
N
O
b
Ar
N
N
O
Va-n
Compound No.
Va
Ar
X
Compound No.
Vh
Ar
X
H
H
Vb
Vc
Vd
Ve
Vf
4-Br
Vi
Vj
4-Br
4-Cl
4-F
4-Cl
4-F
Vk
Vl
4-CH
3
4-CH
3
4-CF
3
Vm
Vn
4-CF
3
Vg
3,5-Bis-(CF
3)
2
3,5-Bis-(CF
3)2
Scheme 1. Synthesis of the target compounds Va–n. Reagents and conditions: (i) HN(CH ) .HCl,
3 2
(
CH O) , conc. HCl, ethanol, reflux, 2 h; (ii) Imidazole, water, reflux, 5 h; (iii) H NOH.HCl, KOH,
n
2
2
◦
ethanol, reflux, 18 h; (iv) Appropriate benzyl chloride/bromide derivative, NaH, DMF, 80 C, 3 h.
2
.2. Crystal Structure of Compound Vi
The selected bond lengths and bond angles of compound Vi are listed in Table 1. The asymmetric
unit contains one independent molecule as shown in Figure 2. All the bond lengths and angles are

Molecules 2017, 22, 1895
4 of 12
within normal ranges [18]. In the crystal packing, Figure 3, molecules are linked via one intermolecular
hydrogen bond (Table 2).
◦
Table 1. Selected geometric parameters (Å, ).
Bond Lengths
Br1–C18
O1–C1
O1–C2
O2–C1
O2–C7
O3–N1
O3–C14
1.905(3)
1.432(5)
1.386(4)
1.428(5)
1.373(4)
1.410(4)
1.442(4)
N1–C8
N2–C10
N2–C11
N2–C13
N3–C11
N3–C12
1.290(4)
1.462(5)
1.337(5)
1.347(6)
1.313(6)
1.343(6)
Bond Angles
C1–O1–C2
C1–O2–C7
105.9(3)
105.9(3)
107.6(2)
111.8(3)
127.2(3)
126.8(3)
106.0(3)
104.8(4)
108.0(3)
127.9(3)
109.3(3)
O2–C7–C2
O2–C7–C6
N1–C8–C4
110.5(3)
128.4(3)
114.9(3)
123.1(3)
112.3(3)
112.3(4)
110.2(4)
106.7(4)
113.3(3)
119.4(2)
119.3(3)
N1–O3–C14
O3–N1–C8
C10–N2–C11
C10–N2–C13
C11–N2–C13
C11–N3–C12
O1–C1–O2
O1–C2–C3
N1–C8–C9
N2–C10–C9
N2–C11–N3
N3–C12–C13
N2–C13–C12
O3–C14–C15
Br1–C18–C17
Br1–C18–C19
O1–C2–C7
◦
Table 2. Hydrogen-bond geometry (Å, ).
D–H···A
C3–H3A···N3
D–H
H···A
2.5300
D···A
3.453(5)
D–H···A
169.00
0.9300
Symmetry codes: (i) –x − 2, −y, −z + 1.
Figure 2. ORTEP diagram of compound Vi. Displacement ellipsoids are plotted at the 40% probability
level for non-H atoms.

Molecules 2017, 22, 1895
5 of 12
Figure 3. Molecular packing of compound Vi.
2
.3. Antifungal Evaluation
The antifungal activity of the synthesized compounds Va
–n was determined against three Candida
species and Asperagillus niger using in vitro diameter of the inhibition zone (DIZ) and minimum
inhibitory concentration (MIC) assays; the results are presented in Table 3.
Table 3. Antifungal activity of the target oximino ethers Va
C. parapsilosis and A. niger.
–n against C. albicans, C. tropicalis,
Candida albicans
Candida tropicalis
Candida parapsilosis
Asperagillus niger
Compound
No.
DIZ ± SD
mm)
MIC
(µmol/mL)
DIZ ± SD
MIC
(µmol/mL)
DIZ ± SD
MIC
(µmol/mL)
DIZ ± SD
MIC
(µmol/mL)
(
(mm)
(mm)
(mm)
Va
Vb
Vc
Vd
Ve
Vf
Vg
Vh
Vi
Vj
Vk
Vl
Vm
18 ± 1.00
23 ± 0.63
22 ± 0.52
18 ± 1.12
19 ± 1.10
18 ± 0.95
21 ± 1.13
14 ± 0.50
15 ± 1.20
15 ± 0.30
15 ± 0.58
16 ± 1.00
15 ± 0.58
13 ± 0.40
18 ± 1.10
ND
0.209
0.083
0.094
0.198
0.050
0.686
0.073
0.183
0.149
0.167
0.174
0.176
0.153
0.527
0.051
ND
16 ± 1.16
18 ± 0.97
22 ± 0.63
15 ± 1.21
17 ± 1.14
18 ± 1.13
20 ± 0.91
10 ± 0.58
15 ± 0.30
14 ± 0.60
12 ± 0.58
13 ± 0.60
13 ± 0.40
15 ± 1.20
19 ± 1.00
ND
0.419
0.083
0.094
0.198
0.100
0.343
0.145
0.183
0.149
0.167
0.174
0.176
0.153
0.527
0.045
ND
20 ± 0.68
24 ± 0.45
23 ± 0.61
19 ± 0.85
20 ± 1.00
21 ± 0.43
22 ± 0.58
13 ± 0.60
14 ± 0.50
21 ± 1.00
13 ± 0.58
19 ± 1.00
23 ± 0.60
19 ± 0.58
19 ± 0.90
ND
0.105
0.042
0.047
0.049
0.050
0.043
0.036
0.003
0.002
0.010
0.044
0.006
0.019
0.002
0.047
ND
21 ± 1.14
22 ± 0.94
19 ± 0.75
12 ± 0.30
12 ± 0.41
22 ± 0.99
13 ± 0.64
20 ± 0.50
13 ± 1.53
16 ± 1.31
23 ± 0.50
12 ± 0.58
14 ± 1.00
11 ± 0.20
ND
0.105
0.083
0.047
0.198
0.201
0.172
0.290
0.733
0.299
0.667
0.697
0.705
0.307
>1.05
ND
Vn
Fluconazole
Ketokonazole
29 ± 0.60
0.02
Arithmetic mean
inhibitory concentration; ND: not determined.
±
standard deviation; DIZ: diameter of the inhibition zone; SD: standard deviation; MIC: minimum

Molecules 2017, 22, 1895
6 of 12
2
.4. Structure–Activity Relationships
The current study reports the antifungal potential of certain imidazole-bearing compounds having
either an unsubstituted phenyl ring (compounds Va ) or a benzodioxole fragment (compounds
Vh ) representing the aromatic pharmacophore moieties. The title compounds Va feature
-aryl-3-iminopropyl moiety attached at N of the imidazole ring. It has been previously reported
–
g
–
n
–n
1
3
that the presence of chlorine atoms in the aromatic moiety of the antifungal agents contributes to
the enhancement of their antifungal activity [19]. Substitution of the phenyl moiety of the benzyl
fragment with halogen, methyl, or 3,5-bis-trifluoromethyl groups of compounds Va
their antifungal activity against the tested Candida species. Compound Ve bearing 4-methylbenzyl
moiety exhibited the best MIC value of 0.050 mol/mL, being nearly equipotent with the reference
fluconazole (FLC) towards Candida albicans, while compounds Vb (4-bromobenzyl derivative) and Vg
3,5-bis-trifluoromethyl benzyl derivative) manifested the best MIC values of 0.083 and 0.36 mol/mL
towards Candida tropicalis and Candida parapsilosis, respectively. The same anti-Candida profile
was mostly observed in the respective analogs Vh except towards Candida parapsilosis in which
–g enhanced
µ
(
µ
–
n
substitution with halogen or methyl did not improve the activity as compared with the unsubstituted
analog, compound Vh. Substitution with the trifluoromethyl group gave compound Vm improved
activity towards Candida albicans and Candida tropicalis with, an MIC value of 0.153
The highest sensitivity of Asperagillus niger was observed towards the 4-chlorobenzyl derivative
analog, compound Vc, with an MIC value of 0.047 mol/mL. In summary, compounds Vb Vc Ve and
Vi, or Vn are the most active congeners towards Candida tropicalis, Asperagillus niger, Candida albicans,
and Candida parapsilosis, respectively. It seems that the antifungal profile of compounds Va is better
than that of their respective benzodioxole analogs, compounds Vh . Therefore, it is believed that the
µmol/mL.
µ
,
,
–
g
–n
replacement of an unsubstituted phenyl pharmacophore with benzodioxole moiety is not favorable
towards the tested fungal strains.
3
. Experimental
3
.1. General
The melting points were measured using a Gallenkamp melting point device and are uncorrected.
The NMR samples of the synthesized compounds Va–n were dissolved in DMSO-d and the NMR
6
spectra were recorded using a Bruker NMR spectrometer (Bruker, Reinstetten, Germany) at 500 MHz
1
13
for H and 125.76 MHz for C at the Research Center, College of Pharmacy, King Saud University,
Saudi Arabia. Chemical shifts are expressed in -values (ppm) relative to TMS as an internal standard.
Elemental analyses were carried out at Microanalysis Laboratory, Cairo University, Cairo, Egypt and
the results agreed favorably with the proposed structures within 0.4% of the theoretical values.
δ
±
Mass spectra were recorded using Agilent Quadrupole 6120 LC/MS with ESI (Electrospray ionization)
source (Agilent Technologies, Palo Alto, CA, USA).
3
.2. Chemistry
3
.2.1. Synthesis of (1E)-1-(2H-1,3-benzodioxol-5-yl)-N-hydroxy-3-(1H-imidazol-1-yl)propan-1-imine (IV)
Compound IV and its intermediates were prepared as previously reported [20
,21]. Their spectral
data are consistent with the reported ones.
3
.2.2. Synthesis of the Oximino Ethers Va–n
Sodium hydride (1.5 mmol) was added to a solution of the oxime (IV, 1.0 mmol) in DMF (5 mL)
and the reaction mixture was stirred at room temperature for 10 min. Then, the appropriate benzyl
bromide/chloride (1.1 mmol) in DMF (5 mL) was added dropwise. The reaction mixture was stirred
◦
at room temperature for 30 min. then heated at 80 C for two hours. The reaction mixture was
concentrated under vacuum and the residue was poured into ice cold water and extracted with

Molecules 2017, 22, 1895
7 of 12
ethyl acetate (3
×
20 mL). The organic phases were combined and washed with water (2 × 15 mL),
dried (Na SO ), and evaporated under reduced pressure. The crude oximino ethers Va–n were purified
2
4
using column chromatography, and chloroform/methanol (18:1) was used as the solvent system.
(
1E)-N-(Benzyloxy)-3-(1H-imidazol-1-yl)-1-phenylpropan-1-imine (Va). Yield 52.9%; light brown viscous
−
ν (cm ) 3003, 2964, 1724 1673 (C=N), 1506, 1437, 1286, 700; H-NMR (CDCl ): δ (ppm)
3
1
1
oil; IR (KBr):
3
.16 (br. s., 2H, –CH2–CH –N), 4.12 (br. s., 2H, –CH –CH2–N), 5.25 (s, 2H, –CH –C H ), 6.77 (s, 1H,
2 2 2 6 5
–
7
7
N–C
H
=CH–N=), 6.94 (s, 1H, –N–CH=C
H
–N=), 7.27–7.31 (m, 5H, Ar–H), 7.33–7.38 (m, 5H, Ar–H),
13
.41 (s, 1H, –N–CH=N–); C-NMR (CDCl3): (ppm) 29.4 (– H –CH –N), 43.4 (–CH – H –N),
6.7 (–
δ
C
C
2 2
2
2
C
H –C H ), 118.8 (–N–
CH=CH–N=), 125.9, 128.1, 128.3, 128.4, 128.5, 128.6, 129.1, 129.5, 134.8
2
6
4
+
(Ar–CH, Ar–C, –N–CH=
CH–N=), 137.3 (–N–CH=N–), 154.9 (C=N); MS m/z (ESI): 306.2 [M + H] ,
+
3
07.1 [(M + 1) + H] .
(
1E)-N-[(4-Bromobenzyl)oxy]-3-(1H-imidazol-1-yl)-1-phenylpropan-1-imine (Vb). Yield 43.4%; pale yellow
−
ν (cm ) 3003, 2924, 1720, 1672 (C=N), 1510, 1436, 1220, 785; H-NMR (CDCl ):
3
1
1
viscous oil; IR (KBr):
δ
(ppm) 3.34 (br. s., 2H, –CH2–CH –N), 4.29 (br. s., 2H, –CH –CH2–N), 5.24 (s, 2H, –CH2–C H ),
2 2 6 4
6
.94 (s, 1H, –N–CH=CH–N=), 7.11 (s, 1H, –N–CH=CH–N=), 7.37 (d, J = 7.5 Hz, 2H, Ar–H), 7.47–7.57
13
(
2
1
m, 5H, Ar–H), 7.62 (d, J = 7.4 Hz, 2H, Ar–H), 7.66 (s, 1H, –N–CH=N–); C-NMR (CDCl3):
9.2 (– H –CH –N), 43.7 (–CH – H –N), 75.8 (– H –C H ), 119.0 (–N– H=CH–N=), 122.1, 126.1,
27.7, 128.5, 128.7, 129.7, 130.1, 131.6, 134.5 (Ar–CH, Ar–C, –N–CH=
δ (ppm)
C
C
C
C
2
2
2
2
2
6
4
C
H–N=), 136.4 (–N–CH=N–), 155.0
+
+
+
(C=N); MS m/z (ESI): 384.1 [M + H] , 386.1 [(M + 2) + H] , 387.1 [(M + 3) + H] .
(
1E)-N-[(4-Chlorobenzyl)oxy]-3-(1H-imidazol-1-yl)-1-phenylpropan-1-imine (Vc). Yield 63.4%; light brown
−
ν (cm ) 3003, 2928, 1722, 1671 (C=N), 1511, 1437, 1224, 696; H-NMR (CDCl ):
3
1
1
viscous oil; IR (KBr):
δ
(ppm) 3.30 (br. s., 2H, –CH2–CH –N), 4.25 (br. s., 2H, –CH –CH2–N), 5.26 (s, 2H, –CH2–C H ),
2 2 6 4
6
–
.92 (s, 1H, –N–C
H
=CH–N=), 7.08 (s, 1H, –N–CH=C
(ppm) 29.2 (– H –CH –N), 43.4 (–CH –
CH=CH–N=), 125.9, 128.5, 128.6, 129.1, 129.6, 129.7, 133.8, 134.5, 135.9 (Ar–CH, Ar–C,
H
–N=), 7.44–7.52 (m, 9H, Ar–H), 7.55 (s, 1H,
N–CH=N–); 13C-NMR (CDCl3):
δ
C
C
H –N), 75.7 (– H –C H ),
C
2
2
2
2
2
6
4
118.8 (–N–
+
+
–
N–CH=
C
H–N=), 136.8 (–N–CH=N–), 155.0 (C=N); MS m/z (ESI): 340.1 [M + H] , 341.1 [(M + 1) + H] ,
+
3
42.1 [(M + 2) + H] .
(
1E)-N-[(4-Fluorobenzyl)oxy]-3-(1H-imidazol-1-yl)-1-phenylpropan-1-imine (Vd). Yield 59.9%; light
−
1
brown viscous oil; IR (KBr):
ν (cm ) 3003, 2924, 1720, 1670 (C=N), 1510, 1435, 1217, 765;
1
H-NMR (CDCl3):
δ (ppm) 3.29 (t, J = 6.6 Hz, 2H, –CH2–CH –N), 4.25 (t, J = 6.5 Hz, 2H,
2
–
7
CH –CH2–N), 5.27 (s, 2H, –CH2–C H ), 6.90 (s, 1H, –N–CH=CH–N=), 7.08 (s, 1H, –N–CH=CH–N=),
2
6
4
13
.15–7.22 (m, 2H, Ar–H), 7.45–7.56 (m, 8H, Ar–H, –N–CH=N–), C-NMR (CDCl3):
δ
(ppm) 29.2
0
(
–
C
H –CH –N), 43.5 (–CH – H –N), 75.9 (– H –C H ), 115.3 (d, J
C
C
0
0
= 21.1 Hz, C–3 and
2
2
2
2
2
6
4
C–3 , F&C–5 , F
0
C–5 ), 118.9 (–N–
C
H=CH–N=), 125.9, 128.7, 128.8, 129.6, 134.6 (Ar–CH, Ar–C, –N–CH=
C
H–N=), 130.3
0
= 2.8 Hz, C–1 ), 136.8 (–N–CH=N–), 154.9
C–1 , F
0
0
0
(
(
d, J
0
0
= 8.3 Hz, C–2 and C–6 ), 133.2 (d, J
C–2 , F&C–6 , F
0
+
+
C=N), 162.5 (d, J
0
= 246.9 Hz, C–4 ); MS m/z (ESI): 324.2 [M + H] , 325.2 [(M + 1) + H] .
C–4 , F
(
1E)-3-(1H-Imidazol-1-yl)-N-[(4-methylbenzyl)oxy]-1-phenylpropan-1-imine (Ve). Yield 52.2%; light brown
−
ν (cm ) 3003, 2781, 1714, 1676 (C=N), 1512, 1220, 790; H-NMR (CDCl ):
3
1
1
viscous oil; IR (KBr):
δ
(ppm) 2.41 (s, 3H, CH ), 3.25 (br. s., 2H, –CH2–CH –N), 4.22 (br. s., 2H, –CH –CH2–N), 5.26
3 2 2
(
s, 1H, –CH2–C H ), 6.95 (s, 1H, –N–CH=C
H
–N=), 7.04 (s, 1H, –N–CH=CH–N=), 7.26 (d, J = 6.3 Hz,
6
4
2
H, Ar–H), 7.37 (d, J = 6.5 Hz, 2H, Ar–H), 7.41–7.51 (m, 5H, Ar–H), 7.64 (s, 1H, –N–CH=N–);
13
C-NMR (CDCl3):
18.9 (–N– H=CH–N=), 125.9, 127.3, 128.5, 128.6, 129.1, 129.5, 129.6, 134.3, 134.9 (Ar–CH, Ar–C,
H–N=), 137.9 (–N–CH=N–), 154.7 (C=N); MS m/z (ESI): 320.2 [M + H] , 321.2 [(M + 1) + H] .
δ (ppm) 21.2 (CH ), 29.4 (–CH –CH –N), 43.4 (–CH –CH –N), 76.6 (–CH –C H ),
3 2 2 2 2 2 6 4
1
–
C
+
+
N–CH=
C
(
1E)-3-(1H-Imidazol-1-yl)-1-phenyl-N-{[4-(trifluoromethyl)benzyl]oxy}propan-1-imine (Vf). Yield 43.3%;
−
1
light brown viscous oil; IR (KBr):
ν(cm ) 3003, 2975, 1717, 1676 (C=N), 1502, 1437, 1219, 790;
1
H-NMR (CDCl3):
δ
(ppm) 3.27 (br. s., 2H, –CH2–CH –N), 4.21 (br. s., 2H, –CH –CH2–N), 5.27
2
2
(
s, 1H, –CH2–C H ), 6.86 (s, 1H, –N–C
H
=CH–N=), 7.01 (s, 1H, –N–CH=C
H
–N=), 7.39–7.51 (m, 9H,
6
4

Molecules 2017, 22, 1895
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Ar–H), 7.65 (s, 1H, –N–CH=N–); 13C-NMR (CDCl3):
δ
(ppm) 29.2 (–
C
H –CH –N), 43.6 (–CH –
C
H –N),
2
2
2
2
7
5.7 (–
C
H –C H ), 119.0 (–N–
C
H=CH–N=), 125.4, 125.5, 126.1, 127.4, 128.3, 128.8, 129.0, 129.8, 134.4,
2
6
4
+
1
36.9, 141.6 (Ar–CH, Ar–C, –N–CH=
C
H–N=, –N–CH=N–), 155.4 (C=N); MS m/z (ESI): 374.2 [M + H] ,
+
3
75.1 [(M + 1) + H] .
(
1E)-N-{[3,5-Bis(trifluoromethyl)benzyl]oxy}-3-(1H-imidazol-1-yl)-1-phenylpropan-1-imine (Vg). Yield 28%;
1
light brown viscous oil; IR (KBr):
ν
(cm
−
) 3003, 2970, 1717,1673 (C=N), 1502, 1420, 1223, 702;
1
H-NMR (CDCl3):
δ
(ppm) 3.31 (br. s., 2H, –CH2–CH –N), 4.25 (br. s., 2H, –CH –CH2–N), 5.29
2
2
(
s, 1H, –CH2–C H ), 6.89 (s, 1H, –N–C
H
=CH–N=), 7.05 (s, 1H, –N–CH=C
H
–N=), 7.39–7.52 (m, 6H,
6
4
13
Ar–H, –N–CH=N–), 7.75–7.86 (m, 2H, Ar–H), 8.39 (s, 1H, Ar–H); C-NMR (CDCl3):
H –CH –N), 44.3 (–CH – H –N), 74.9 (– H –C H ), 119.4 (–N– H=CH–N=), 121.9, 122.5, 124.0,
26.2, 128.3, 128.9, 130.2, 131.7, 131.9, 136.6, 140.1 (Ar–CH, Ar–C, –N–CH= H–N=, –N–CH=N–), 155.8
δ (ppm) 28.9
(
–
C
C
C
C
2
2
2
2
2
6
4
1
C
+
+
(C=N); MS m/z (ESI): 442.1 [M + H] , 443.1 [(M + 1) + H] .
(
1E)-1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)-N-(benzyloxy)propan-1-imine (Vh). Yield 61%; light
−
ν (cm ) 3030, 2927, 1670 (C=N), 1606, 1489, 1284, 700; H-NMR (CDCl ):
3
1
1
brownviscousoil; IR (KBr):
δ
(ppm) 3.17 (t, J = 7.0 Hz, 2H, –CH2–CH –N), 4.18 (t, J = 7.0 Hz, 2H, –CH –CH2–N), 5.22 (s, 2H,
2 2
–
C
H2–C H ), 5.99 (s, 2H, –O–CH –O–), 6.76 (d, J = 8.0 Hz, 1H, Ar–H), 6.82 (s, 1H, –N–C
H
=CH–N=), 6.86
6
5
2
(
(
(
dd, J = 1.5, 8.5 Hz, 1H, Ar–H), 7.01 (s, 1H, –N–CH=C
m, 5H, Ar–H), 7.50 (s, 1H, –N–CH=N–); 13C-NMR (CDCl3):
–CH2– H –N), 76.2 (– H –C H ), 101.4 (–O–CH –O–), 106.2, 108.2 (Ar–CH), 119.0 (–N–
H–N=), 7.09 (d, J = 1.0 Hz, 1H, Ar–H), 7.33–7.37
δ
(ppm) 29.4 (–
C
H –CH –N), 43.7
2
2
C
C
C
H=CH–N=),
2
2
6
4
2
1
1
20.3, 128.2, 128.4, 128.5,128.7, 129.0, 136.9 (Ar–CH, Ar–C, –N–CH=CH–N=), 137.5 (–N–CH=N–), 148.2,
48.3 (Ar–C), 154.3 (C=N); MS m/z (ESI): 350.1 [M + H] .
+
(
1E)-1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)-N-[(4-bromobenzyl)oxy]propan-1-imine (Vi). Yield 55%;
◦
−1
pale yellow solid, m.p. 80–82 C; IR (KBr):
ν (cm ) 3115, 2934, 1670 (C=N), 1506, 1489, 1232, 756;
1
H-NMR (CDCl3):
δ (ppm) 3.17 (t, J = 7.0 Hz, 2H, –CH2–CH –N), 4.17 (t, J = 7.0 Hz, 2H, –CH –CH2–N),
2 2
5
.13 (s, 2H, –CH2–C H ), 5.98 (s, 2H, –O–CH –O–), 6.76 (d, J = 8.0 Hz, 1H, Ar–H), 6.84 (s, 1H,
6
4
2
–
N–C
H=CH–N=), 6.88 (dd, J = 1.5, 8.0 Hz, 1H, Ar–H), 7.01 (s, 1H, –N–CH=CH–N=), 7.07 (d, J = 1.0 Hz,
1
H, Ar–H), 7.25 (d, J = 8.0 Hz, 2H, Ar–H), 7.50 (d, J = 8.5 Hz, 2H, Ar–H), 7.52 (s, 1H, –N–CH=N–);
1
3
C-NMR (CDCl3):
δ (ppm) 29.2 (–CH –CH –N), 43.7 (–CH –CH –N), 75.8 (–CH –C H ), 101.5
2 2 2 2 2 6 4
(
–O–CH –O–), 106.2, 108.2 (Ar–CH), 119.0 (–N–
CH=CH–N=), 120.4, 122.1, 128.7, 128.9, 130.1, 131.5,
2
1
36.5 (Ar–CH, Ar–C, –N–CH=
C
H–N=), 136.9 (–N–CH=N–), 148.2, 149.0 (Ar–C), 154.6 (C=N); MS m/z
+
+
+
(ESI): 428.1 [M + H] , 430.0 [(M + 2) + H] , 431.0[(M + 3) + H] .
(
1E)-1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)-N-[(4-chlorobenzyl)oxy]propan-1-imine (Vj). Yield 40%;
−
1
1
light brown viscous oil; IR (KBr):
ν (cm ) 3017, 2932, 1670 (C=N), 1506, 1491, 1280, 756; H-NMR
(CDCl3):
δ
(ppm) 3.16 (t, J = 7.0 Hz, 2H, –CH2–CH –N), 4.15 (t, J = 7.0 Hz, 2H, –CH –CH2–N),
2
2
5
.15 (s, 2H, –CH2–C H ), 5.98 (s, 2H, –O–CH –O–), 6.76 (d, J = 8.0 Hz, 1H, Ar–H), 6.84 (s, 1H,
6 4 2
–
1
N–C
H
=CH–N=), 6.86 (dd, J = 1.5, 8.0 Hz, 1H, Ar–H), 7.01 (s, 1H, –N–CH=C
H
–N=), 7.07 (d, J = 1.0 Hz,
13
H, Ar–H), 7.31–7.33 (m, 2H, Ar–H), 7.35 (d, J = 8.5 Hz, 2H, Ar–H), 7.43 (s, 1H, –N–CH=N–); C-NMR
(CDCl3):
δ
(ppm) 29.3 (–
C
H –CH –N), 43.6 (–CH –
C
H –N), 76.7 (–
2
C
H –C H ), 101.5 (–O–CH –O–),
2
2
2
2
6
4
2
106.2, 108.2 (Ar–CH), 118.9 (–N–CH=CH–N=), 120.4, 121.9, 128.7, 129.3, 129.7, 133.9, 136.5 (Ar–CH,
Ar–C, –N–CH=
C
H–N=), 136.9 (–N–CH=N–), 148.2, 149.0 (Ar–C), 154.6 (C=N); MS m/z (ESI): 384.1
+
+
+
[M + H] , 385.1 [(M + 1) + H] , 386.1 [(M + 2) + H] .
(
1E)-1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)-N-[(4-fluorobenzyl)oxy]propan-1-imine (Vk). Yield 32%;
−
1
1
light brown viscous oil; IR (KBr):
ν (cm ) 3018, 2962, 1604 (C=N), 1510, 1490, 1215, 759; H-NMR
(CDCl3):
δ
(ppm) 3.14 (t, J = 7.1 Hz, 2H, –CH2–CH –N), 4.14 (t, J = 7.0 Hz, 2H, –CH –CH2–N),
2
2
5
.14 (s, 2H, –CH2–C H ), 5.96 (s, 2H, –O–CH –O–), 6.75 (d, J = 8.1 Hz, 1H, Ar–H), 6.82 (s, 1H,
6 4 2
–
N–C
H
=CH–N=), 6.86 (dd, J = 2.0, 8.5 Hz, 1H, Ar–H), 6.99 (s, 1H, –N–CH=C
H
–N=), 7.04–7.07
13
(
(
m, 3H, Ar–H), 7.35–7.38 (m, 2H, Ar–H), 7.41 (s, 1H, –N–CH=N–); C-NMR (CDCl3):
–
δ (ppm) 29.3
C
H –CH –N), 43.6 (–CH – H –N), 75.9 (– H –C H ), 101.5 (–O–CH –O–), 106.2, 108.2 (Ar–CH),
2
C
C
2
2
2
2
6
4
2

Molecules 2017, 22, 1895
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0
0
1
15.4 (d, J
0
0
= 21.4 Hz, C–3 and C–5 ), 119.0 (–N–
C
H=CH–N=), 120.3, 128.9, 129.3, (Ar–CH,
C–3 , F&C–5 , F
0
0
Ar–C, –N–CH=
C
H–N=), 130.3 (d, J
0
0
= 8.2 Hz, C–2 and C–6 ), 133.3 (d, J
0
= 3.2 Hz,
C–2 , F&C–6 , F
C–1 , F
0
0
C–1 ), 136.9 (–N–CH=N–), 148.2, 149.0 (Ar–C), 154.5 (C=N), 162.6 (d, J
ESI): 368.1 [M + H] , 369.1 [(M + 1) + H] .
0
= 246.4 Hz, C–4 ); MS m/z
C–4 , F
+
+
(
(
1E)-1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)-N-[(4-methylbenzyl)oxy]propan-1-imine (Vl). Yield 24%;
−
1
1
light brown viscous oil; IR (KBr):
ν (cm ) 3669, 3115, 2953, 1614 (C=N), 1585, 1510, 1248, 754; H-NMR
(CDCl3):
δ (ppm) 2.39 (s, 3H, CH ), 3.15 (t, J = 7.0 Hz, 2H, –CH2–CH –N), 4.17 (t, J = 7.0 Hz, 2H,
3 2
–
CH –CH2–N), 5.18 (s, 2H, –CH2–C H ), 5.99 (s, 2H, –O–CH –O–), 6.77 (d, J = 8.0 Hz, 1H, Ar–H),
2
6
4
2
6
(
–
.83 (s, 1H, –N–C
d, J = 1.5 Hz, 1H, Ar–H), 7.22 (d, J = 7.5 Hz, 2H, Ar–H), 7.32 (d, J = 8.0 Hz, 2H, Ar–H), 7.46 (s, 1H,
N–CH=N–); 13C-NMR (CDCl3):
(ppm) 21.2 (CH ), 29.4 (– H –CH –N), 43.7 (–CH – H –N), 76.6
H –C H ), 101.4 (–O–CH –O–), 106.2, 108.2 (Ar–CH), 118.9 (–N–
H=CH–N=), 6.88 (dd, J = 1.5, 8.0 Hz, 1H, Ar–H), 7.01 (s, 1H, –N–CH=CH–N=), 7.09
δ
C
C
2 2
3
2
2
(–
C
CH=CH–N=), 120.4, 128.6, 128.9,
2
6
4
2
1
1
29.1, 129.2, 134.4, 136.9 (Ar–CH, Ar–C, –N–CH=
54.2 (C=N); MS m/z (ESI): 364.1 [M + H] .
CH–N=), 137.9 (–N–CH=N–), 148.1, 148.9 (Ar–C),
+
(
1E)-1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)-N-{[4-(trifluromethyl)benzyl]oxy}propan-1-imine (Vm).
◦
−1
ν (cm ) 3016, 2941, 1670 (C=N), 1506, 1448,
Yield 25%; light brown solid, m.p. 81–83 C; IR (KBr):
1
1
232, 756; H-NMR (CDCl ):
δ
(ppm) 3.23 (t, J = 7.0 Hz, 2H, –CH2–CH –N), 4.23 (t, J = 7.0 Hz, 2H,
3
2
–
CH –CH2–N), 5.24 (s, 2H, –CH2–C H ), 5.99 (s, 2H, –O–CH –O–), 6.78 (d, J = 8.1 Hz, 1H, Ar–H),
2
6
4
2
6
.86 (s, 1H, –N–CH=CH–N=), 6.91 (dd, J = 1.6, 8.1 Hz, 1H, Ar–H), 7.04 (s, 1H, –N–CH=CH–N=), 7.09
(
–
d, J = 1.4 Hz, 1H, Ar–H), 7.49 (d, J = 7.7 Hz, 2H, Ar–H), 7.65 (d, J = 7.9 Hz, 2H, Ar–H), 7.68 (s, 1H,
N–CH=N–); 13C-NMR (CDCl3):
δ
(ppm) 29.1 (– H –CH –N), 43.9 (–CH – H –N), 75.6 (– H –C H ),
C
C
C
2
2
2
2
2
6
4
1
1
01.5 (–O–CH –O–), 106.2, 108.3 (Ar–CH), 119.1 (–N–
C
H=CH–N=), 120.5, 123.0, 125.4, 125.5, 128.4,
2
28.5, 130.1, 136.8, 141.6 (Ar–CH, Ar–C, –N–CH=
CH–N=, –N–CH=N–), 148.3, 149.2 (Ar–C), 154.8
+
+
(C=N); MS m/z (ESI): 418.1 [M + H] , 419.1 [(M + 1) + H] .
(1E)-1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)-N-{[3,5-bis(trifluromethyl)benzyl]oxy} propan-1-imine
(
1
Vn). Yield 55%; light brown viscous oil; IR (KBr):
ν
(cm 1) 3014, 2900, 1670 (C=N), 1504, 1446,
−
1
232, 754; H-NMR (CDCl ):
δ
(ppm) 3.24 (t, J = 6.9 Hz, 2H, –CH2–CH –N), 4.22 (t, J = 6.9 Hz, 2H,
3
2
–
CH –CH2–N), 5.26 (s, 2H, –CH2–C H ), 5.99 (s, 2H, –O–CH –O–), 6.78 (d, J = 8.1 Hz, 1H, Ar–H),
2
6
4
2
6
.89 (s, 1H, –N–CH=CH–N=), 6.92 (dd, J = 1.5, 8.1 Hz, 1H, Ar–H), 7.03 (s, 1H, –N–CH=CH–N=),
13
7
.06 (d, J = 1.3 Hz, 1H, Ar–H), 7.65 (s, 1H, –N–CH=N–), 7.84–7.86 (m, 3H, Ar–H); C-NMR (CDCl3):
(ppm) 29.1 (– H –CH –N), 43.9 (–CH – H –N), 74.8 (– H –C H ), 101.6 (–O–CH –O–), 106.2, 108.3
δ
C
C
C
2
2
2
2
2
6
4
2
(
Ar–CH), 119.1 (–N–
C
H=CH–N=), 120.6, 121.9, 124.4, 128.1, 128.2, 131.7, 131.9, 136.8, 140.3 (Ar–CH,
+
Ar–C, –N–CH=
4
C
H–N=, –N–CH=N–), 148.3, 149.4 (Ar–C), 155.4 (C=N); MS m/z (ESI): 486.1 [M + H] ,
+
87.1 [(M + 1) + H] .
3
.3. Crystal Structure Determination
Compound Vi was obtained as single crystals by slow evaporation from ethanolic solution of
the pure compound at room temperature. Data were collected on a Bruker APEX-II D8 Venture area
diffractometer, equipped with graphite monochromatic Mo K radiation, = 0.71073 Å at 293 (2) K. Cell
refinement and data reduction were carried out by Bruker SAINT. SHELXT [22 23] was used to solve the
structure. The final refinement was performed by full-matrix least-squares techniques with anisotropic
thermal data for non-hydrogen atoms. In compound Vi, C H BrN O the crystallographic data and
α
λ
,
20
18
3
3,
refinement information are summarized in Table S1. The crystallographic data of compound Vi have
been deposited with the Cambridge Crystallographic Data Center (CCDC-1577844) and can be found
in Supplementary Materials. Copies of the data may be obtained free of charge from the Director,
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (deposit@ccdc.cam.ac.uk).

Molecules 2017, 22, 1895
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3
.4. Antifungal Activity
3
.4.1. Materials
The reference standard antifungal drugs, fluconazole and ketoconazole, were obtained from
Shouguang-Fukang Pharmaceutical Ltd. (Weifang, China) and from Sigma-Aldrich Co. (St. Louis,
MO, USA), respectively. Liquid RPMI 1640 medium supplemented with L-glutamine was purchased
from Gibco-BRL, Life Technologies (Paisley, Scotland). Sabouraud Dextrose Agar (SDA) was obtained
from Merck Co. (Darmstadt, Germany). Dimethyl sulfoxide (100%) was used to dissolve the reference
standards and/or the tested compounds Va–n to afford an initial concentration of 2048 mg/L.
3
.4.2. Organisms
Candida albicans (ATCC 90028), Candida tropicalis (ATCC 66029), Candida parapsilosis (ATCC 22019),
and Aspergillus niger (ATCC 16404) were used to assess antifungal activity.
3
.4.3. Preparation of Fungal Inocula
Fungal inocula were prepared as previously reported [21].
3
.4.4. Preparation of the Tested Compound Solutions
Briefly, a twofold dilution series of the tested compounds Va–n was prepared in a double-strength
RPMI 1640 culture medium. Ten serial dilutions were prepared to afford concentrations ranging from
024 mg/L to 2 mg/L.
1
3
.4.5. Antifungal Susceptibility Studies
The MIC values of the tested compounds Va–n were determined as previously reported [21].
4
. Conclusions
The synthesis and spectroscopic characterization of certain new oximino ethers Va–n bearing
imidazole pharmacophore moiety have been reported. Single crystal X-ray analysis of compound
Vi confirmed the assigned (E)-configuration of the imine functionality of the target compounds
Va
assays. Compound Ve emerged as the most active compound toward Candida albicans, being nearly
equipotent with the reference antifungal drug FLC with an MIC value of 0.050 mol/mL. On the
other hand, compounds Vi and Vn exhibited the most potent activity towards Candida parapsilosis,
with an MIC value of 0.002 mol/mL—about twenty-three times more potent than FLC. It seems that
the replacement of the phenyl ring in compounds Va with the 1,3-benzodioxole scaffold, which gave
their respective compounds Vh , did not show superior antifungal activity against the tested fungal
–n. The in vitro antifungal potential of compounds Va–n was assessed using DIZ and MIC
µ
µ
–g
–n
strains except towards Candida parapsilosis. The antifungal results of the current investigation might
support the development of new potent and safer azole antifungal agents to be harnessed in the clinic.
Supplementary Materials: Supplementary Materials are available online.
Acknowledgments: The authors would like to extend their sincere appreciation to the Deanship of Scientific
Research at King Saud University for its funding of this research through the Research Group Project No. RGP-196.
Author Contributions: R.I.A.-W. and A.R.A.-G. prepared and characterized the title compounds. H.A.G. performed
the X-ray analysis. M.H.A.-A. carried out the in vitro antifungal assessment of the target compounds. M.I.A.
proposed the work, prepared the single crystals of compound Vi and prepared the manuscript for publication.
All authors discussed the contents of the manuscript.
Conflicts of Interest: The authors have declared no conflict of interest.

Molecules 2017, 22, 1895
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Denning, D.W.; Hope, W.W. Therapy for fungal diseases: Opportunities and priorities. Trends Microbiol. 2010
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