Synthesis, x-ray single crystal structure, molecular docking and DFT computations on N-[(1E)-1-(2H-1,3-benzodioxol-5-yl)-3-(1H-imidazol-1-yl) propylidene]-hydroxylamine: A new potential antifungal agent precursor

Article abstract of DOI:10.3390/molecules22030373

Mycoses are serious health problem, especially in immunocompromised individuals. A new imidazole-bearing compound containing an oxime functionality was synthesized and characterized with different spectroscopic techniques to be used for the preparation of new antifungal agents. The stereochemistry of the oxime double bond was unequivocally determined via the single crystal X-ray technique. The title compound 4, C₁₃H₁₃N₃O₃·C₃H₈O, crystallizes in the monoclinic space group P2₁ with a = 9.0963(3) ?, b = 14.7244(6) ?, c = 10.7035(4) ?, β = 94.298 (3)°, V = 1429.57(9) ?³, Z = 2. The molecules were packed in the crystal structure by eight intermolecular hydrogen bond interactions. A comprehensive spectral analysis of the title molecule 4 has been performed based on the scaled quantum mechanical (SQM) force field obtained by density-functional theory (DFT) calculations. A molecular docking study illustrated the binding mode of the title compound 4 into its target protein. The preliminary antifungal activity of the title compound 4 was determined using a broth microdilution assay.

Full text of DOI:10.3390/molecules22030373

molecules
Article
Synthesis, X-ray Single Crystal Structure, Molecular
Docking and DFT Computations on N-[(1E)-1-(2H-1,3-
Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)
propylidene]-hydroxylamine: A New Potential
Antifungal Agent Precursor
Reem I. Al-Wabli , Alwah R. Al-Ghamdi , Hazem A. Ghabbour , Mohamed H. Al-Agamy 3,4
1
1
1,2
,
James Clemy Monicka , Issac Hubert Joe and Mohamed I. Attia 1,7,*
5
6
1
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457,
Riyadh 11451, Saudi Arabia; ralwabli@KSU.EDU.SA (R.I.A.-W.); 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
2
3
Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451,
Saudi Arabia; malagamy@ksu.edu.sa
4
Microbiology and Immunology Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt
Muslim Arts College, Thiruvithancode 629174, Tamil Nadu, India; clemymonicka@gmail.com
Centre for Molecular and Biophysics Research, Mar Ivanios College, Thiruvananthapuram 695015, Kerala,
India; hubertjoe@gmail.com
Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research
Division, National Research Centre (ID: 60014618), El Bohooth Street, Dokki, Giza 12622, Egypt
Correspondence: mattia@ksu.edu.sa; Tel.: +966-11-4677-337
5
6
7
*
Academic Editor: Diego Muñoz-Torrero
Received: 4 January 2017; Accepted: 21 February 2017; Published: 28 February 2017
Abstract: Mycoses are serious health problem, especially in immunocompromised individuals. A new
imidazole-bearing compound containing an oxime functionality was synthesized and characterized
with different spectroscopic techniques to be used for the preparation of new antifungal agents.
The stereochemistry of the oxime double bond was unequivocally determined via the single crystal
X-ray technique. The title compound
4
, C H N O C H O, crystallizes in the monoclinic space
·
13
13
3
3 3 8
◦
3
group P2 with a = 9.0963(3) Å, b = 14.7244(6) Å, c = 10.7035(4) Å,
β
= 94.298 (3) , V = 1429.57(9) Å ,
Z = 2. The molecules were packed in the crystal structure by eight intermolecular hydrogen bond
interactions. A comprehensive spectral analysis of the title molecule has been performed based
on the scaled quantum mechanical (SQM) force field obtained by density-functional theory (DFT)
calculations. A molecular docking study illustrated the binding mode of the title compound into its
was determined using a
1
4
4
target protein. The preliminary antifungal activity of the title compound
broth microdilution assay.
4
Keywords: crystal structure; imidazole; benzodioxole; oxime; DFT
1
. Introduction
The incidence of systemic fungal infections (mycoses) has increased drastically in recent years,
mainly in immunosuppressed or immunocompromised individuals with AIDS, cancer or undergoing
organ transplantation [ ]. Failure of the available antifungal agents to treat fungal infections is
1,2
primarily due to dramatic increase in resistance to the conventional antifungal drugs leading to
morbidity and mortality in patients facing life-threatening fungal infections. In order to overcome
Molecules 2017, 22, 373; doi:10.3390/molecules22030373
www.mdpi.com/journal/molecules

Molecules 2017, 22, 373
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this serious problem, the development of new alternative antifungal drug therapies with improved
efficacy, broader activity and favorable safety profile has attracted a great deal of interest [3,4].
Azole-based compounds having either an imidazole or triazole pharmacophore moiety in their
structure, constitute the mainstay of the antifungal chemotherapeutic agents used in the clinic [
Azoles competitively inhibit cytochrome P450-dependent lanosterol 14 -demethylase (CYP51)
resulting in depletion of ergosterol in fungi making them unable to grow in a normal way [ ].
5,6].
α
7,8
A screening the literature revealed that most of the available imidazole-bearing antifungal agents have
two carbon spacers between the imidazole moiety and an aromatic residue, while few antifungals
have a three carbon spacer between the pharmacophore and the aromatic part [9–11].
On the other hand, the benzodioxole moiety is found in a sizable number of biologically active
compounds with a wide range of activities [12–16]. The title molecule features both the 1,3-benzodioxole
moiety and the imidazole nucleus connecting to each other through a three carbon bridge. Therefore,
the current investigation deals with the synthesis, molecular characterization and single crystal X-ray
structure of a new oxime derivative, namely N-[(1E)-1-(2H-1,3-benzodioxol-5-yl)-3-(1H-imidazol-1-
yl)propylidene]hydroxylamine (
4) to be utilized as a potential precursor for imidazole-bearing
antifungal agents. The stereochemistry of the imine functionality in the title molecule
4
was certainly
determined via the single crystal X-ray crystallography technique. In addition, density-functional
theory (DFT) computations were also performed as a useful tool to investigate the electronic structure
and molecular geometry of the title molecule
4. Molecular docking studies were conducted in order to
predict the biological activity of compound 4.
2
. Results and Discussion
2
.1. Chemistry
Scheme 1 illustrates the synthetic pathway which was adopted to synthesize the target
compound . The synthesis commenced with a Mannich reaction under acidic conditions using the
commercially available 1-(2H-1,3-benzodioxol-5-yl)ethanone ( ). Subsequently, the formed Mannich
base hydrochloride was smoothly transformed in aqueous solution into the ketone via a nucleophilic
substitution reaction using imidazole. The target oxime was ultimately obtained using the standard
4
1
2
3
4
procedure for oxime formation with hydroxylamine hydrochloride in ethanol in the presence of
potassium hydroxide [17].
O
O
O
O
O
O
O
O
O
CH3
i
N(CH ) .HCl
ii
N
3 2
N
1
2
3
iii
OH
N
O
O
N
N
4
Scheme 1. Synthesis of the target oxime
4
. Reagents and conditions: (i) HN(CH ) .HCl, (CH O)
n
, conc.
3
2
2
HCl, ethanol, reflux, 2 h; (ii) Imidazole, water, reflux, 5 h; (iii) H NOH.HCl, KOH, ethanol, reflux, 18h.
2

Molecules 2017, 22, 373
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2
.2. Crystal Structure of the Title Compound 4
The configuration of the target compound
4
was confirmed via X-ray crystallography. A suitable
single colorless crystal of dimensions, 0.40
The labeled displacement ellipsoid plot of this molecule is shown in Figure 1. Figure 2 depicts the
packing of the molecules in the crystal structure.
×
0.23
×
0.11 mm, was selected for X-ray diffraction analysis.
Figure 1. ORTEP diagram of the title compound drawn at 40% ellipsoids for non-hydrogen atoms
showing two molecules and one isopropanol molecule as a solvent.
Figure 2. Crystal packing showing intermolecular hydrogen bonds as dashed lines along the b and
c axes.
The single crystal X-ray molecular structure therefore conformed the assigned (E)-configuration
of the imine group in the target compound. The crystal structure contains two independent
molecules with one isopropanol molecule as a solvent in the asymmetric unit. The benzodioxole
◦
◦
ring (C1/C2/O1/C3/O2/C4–C7) forms dihedral angles of 44.04(3) and 20.04(2) with the imidazole
ring (N2/C11/N3/C12/C13) for molecules A and B, respectively. The crystal structure is stabilized by
eight hydrogen bonds along the b and c-axis (Table 1).

Molecules 2017, 22, 373
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◦
Table 1. Hydrogen-bond geometry (Å, ) of the title molecule 4.
D–H···A
D–H
H···A
D···A
D–H···A
i
O3A–H3OA···N3A
1.00(5)
0.98(6)
0.91(7)
0.9900
0.9900
0.9500
0.9500
0.9500
0.9900
1.73(5)
1.70(6)
2.38(7)
2.4900
2.3600
2.2700
2.5600
2.5200
2.5800
2.722(5)
2.672(5)
3.127(6)
3.128(6)
3.080(6)
3.179(7)
3.459(6)
3.424(6)
3.502(6)
176(6)
175(8)
139(6)
122.00
129.00
159.00
158.00
160.00
154.00
ii
O3B–H3OB···N3B
O4–H1O4···N1A
C3A–H3AB···O3A
iii
ii
iv
C3B–H3BB···O3B
C11A–H11A···O4
C13A–H13A···O2A
C13B–H13B···O2B
iv
iii
C9B–H9BB···N1A v
Symmetry codes: (i) x − 1, y, z; (ii) x + 1, y, z; (iii) x, y, z − 1; (iv) x, y, z + 1; (v) −x + 1, y + 1/2, −z + 1.
2
.3. Structural Geometry Analysis
Equilibrium structural geometry of the title molecule
energy surface (PES) scan study. The flexible dihedral angles of C –C –N –C , C –C –C –C
4
4
has been evaluated by a potential
11
12
13
14
11
10
5
◦
◦
and C –C –N –O were scanned from 0 to 360 and their optimum energy was studied to
11
10
18
19
identify stable conformations of the title compound
and –893.49 Hartree for the conformers of compound
4
. The global minimum energy is –893.45
4
in the gas and solution phases, respectively
(
various conformers of compound
identified the minimum energy conformer of this molecule which was chosen for the subsequent
studies. The optimized structure of the studied compound with atoms numbering is depicted in
4 are shown in Figure S1). From this PES analysis, we have
4
Figure 3. Optimized bond lengths, bond angles and dihedral angles have been presented in Table 2.
The formation of intramolecular hydrogen bonding is exposed by the intramolecular contacts to
H22···N18 occur with H···O distance of 2.455 Å, which is shorter than the van der Waals separation
between the O and H atoms (2.75 Å) [18]. Shortening of the C–N bond lengths N –C , N –C ,
13
14
13
17
N –C and N –C is typical for double bonds and it is due to resonance interactions. The linear
16
17
16
15
fitting graphs (Figure S2) are drawn to study the correlation between the average experimental values
and computed results. Statistical analysis revealed that the results of the computed solvation model
are in a good agreement with the average experimental XRD values. Therefore, this method was
considered to compute spectral vibrations, natural bond orbital and Frontier orbital energy analyses
for the title molecule 4.
Figure 3. Optimized molecular structure of compound 4.

Molecules 2017, 22, 373
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Table 2. Optimized structural geometry parameters for compound 4.
◦
◦
Bond Length (Å)
Calculated
Bond Angle ( )
Dihedral Angle ( )
Calculated
Calculated
Parameters
Exp.
Parameters
Exp.
Parameters
Exp.
Gas Phase
Solution Phase
Gas Phase
Solution Phase
Gas Phase
Solution Phase
C1–C2
C2–C3
C3–C4
C4–C5
C5–C6
C6–C1
C1–O7
C2–O9
C3–H20
C4–H21
C5–C10
C6–H22
C8–O7
1.3947
1.3753
1.4049
1.4001
1.4181
1.3707
1.3743
1.3695
1.0821
1.0814
1.4846
1.0805
1.4317
1.4360
1.0892
1.0966
1.5127
1.2861
1.5435
1.0897
1.0912
1.4574
1.0902
1.0924
1.3815
1.3678
1.3716
1.0778
1.3751
1.0790
1.3142
1.0802
1.4067
0.9631
1.3945
1.3764
1.405
1.4005
1.4183
1.3719
1.374
1.379
1.362
1.395
1.394
1.411
1.370
1.376
1.382
0.950
0.950
1.482
0.950
1.424
1.418
0.990
0.990
1.519
1.288
1.523
0.990
0.990
1.459
0.990
0.990
1.370
1.349
1.360
0.950
1.377
0.950
1.323
0.950
1.409
0.985
C1–C2–C3
C1–C2–O9
C1–C6–C5
C1–C6–H22
C1–O7–C8
C2–C1–C6
C2–C1–O7
C2–C3–C4
C2–O9–C8
C3–C2–O9
C2–C3–H20
C4–C3–H20
C3–C4–C5
C3–C4–H21
C5–C4–H21
C4–C5–C6
C4–C5–C10
C5–C10–C11
C5–C10–N18
C5–C6–H22
C6–C5–C10
C6–C1–O7
121.40
109.69
117.55
121.74
105.45
122.44
109.26
116.93
105.31
128.89
121.55
121.52
122.28
117.57
120.15
119.38
121.01
121.63
116.24
120.71
119.60
128.27
107.29
109.53
109.50
109.38
109.17
111.71
110.75
108.46
122.12
112.49
109.89
108.47
121.44
109.67
117.55
121.53
105.50
122.37
109.35
116.98
105.44
128.87
121.72
121.30
122.18
117.55
120.27
119.48
120.74
121.26
116.28
120.91
119.78
128.27
106.84
109.56
109.44
109.46
109.18
111.99
110.32
108.41
122.46
112.05
109.89
108.56
121.60
110.05
117.05
121.62
105.41
122.65
109.85
117.25
105.57
128.35
121.41
121.44
121.95
119.03
119.03
119.62
121.35
119.86
117.56
121.63
118.95
127.61
109.45
109.83
109.81
109.80
109.81
111.31
109.42
109.42
122.83
111.10
109.42
109.43
C1–C2–C3–C4
C1–C2–C3–H20
C1–C2–O9–C8
C1–O7–C8–O9
C1–O7–C8–H23
C2–C1–O7–C8
C2–C3–C4–C5
C2–C3–C4–H21
C2–C1–C6–C5
C2–C1–C6–H22
C3–C4–C5–C6
C3–C2–C1–O7
C3–C4–C5–C10
C3–C2–O9–C8
C4–C5–C6–C1
C4–C5–C6–H22
C4–C5–C10–C11
C4–C5–C10–N18
C6–C1–C2–C3
C6–C1–C2–O9
C6–C1–O7–C8
C6–C5–C4–H21
C6–C5–C10–C11
C6–C5–C10–N18
O7–C1–C2–O9
O7–C1–C6–C5
O7–C1–C6–H22
O9–C2–C3–C4
O9–C2–C3–H20
C10–C5–C6–C1
C10–C5–C4–H21
C10–C5–C6–H22
C5–C4–C3–H20
C12–N13–C14–C15
–0.32
179.6
10.37
–0.29
179.72
10.84
1.20
–179.12
–4.10
–4.55
115.78
1.95
–1.00
178.51
1.80
–179.81
1.05
179.60
177.75
177.8
2.30
179.78
19.05
164.15
–1.60
178.55
–178.00
–179.51
159.60
17.25
1.40
179.65
0.59
16.91
17.41
135.54
–10.64
0.39
–179.8
0.21
–179.59
–0.17
–178.62
178.73
–170.62
0.13
–179.72
16.37
–163.31
0.002
178.67
170.55
–179.7
–164.46
15.85
0.06
178.42
–1.73
–178.68
1.32
–179.05
–0.79
1.09
–179.53
176.72
135.89
–10.95
0.51
–179.96
0.09
179.94
–0.44
–178.62
178.73
–170.62
0.13
–179.72
16.37
–163.31
0.004
178.67
170.55
–179.96
–164.46
15.85
0.13
178.54
–1.64
–178.61
1.52
–179.29
–1.78
0.90
–179.49
177.67
1.3695
1.0822
1.0815
1.4847
1.0808
1.4372
1.4401
1.0877
1.0943
1.5133
1.2868
1.5427
1.0894
1.0915
1.4620
1.0894
1.0911
1.3802
1.3629
1.3713
1.0776
1.3795
1.0792
1.3197
1.0798
1.4061
0.9647
C8–O9
C8–H23
C8–H24
C10–C11
C10–N18
C11–C12
C11–H25
C11–H26
C12–N13
C12–H27
C12–H28
N13–C14
N13–C17
C14–C15
C14–H29
C15–N16
C15–H30
N16–C17
C17–H31
N18–O19
O19–H32
O7–C8–O9
O7–C8–H23
O7–C8–H24
O9–C8–H23
O9–C8–H24
C10–C11–C12
C10–C11–H25
C10–C11–H26
C11–C10–N18
C11–C12–N13
C12–C11–H25
C12–C11–H26
178.55
–1.53
–178.45
–1.11
1.52
178.63
176.55
The used numbering of atoms is as shown in Figure 3.

Molecules 2017, 22, 373
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2
.4. Natural Bond Orbital Analysis
Natural bond orbital (NBO) analysis describes the (hyper)conjugative interactions between
donor–acceptor orbitals in order to understand intramolecular charge–transfer phenomenon of the
molecular system [19]. Selective donor–acceptor interactions of the oxime are listed along with
their occupancy and stabilization energy values in Table 3. The hyperconjugative interactions
of (C –C )→π*(C –C ), (C –C )→π*(C –C ), (C –C )→π*(C –C ),
(C –C )→π*(C –C ),
(C –C )→π*(C –C ), and
4
π
π
π
π
1
6
2
3
1
6
4
5
2
3
1
6
2
3
4
5
π
π
(C –C )→π*(C –C ) were 20.27, 17.86, 18.94, 19.07, 17.00 and
4
5
1
6
4
5
2
3
17.47 kcal/mol, respectively. This could be attributed to the charge delocalization leading to ring
resonance effect. The lone pair conjugative interactions of LP(2)O7→π*(C –C ), LP(2)O →π*(C –C ),
1
6
9
2
3
LP1(N )→π*(C –C ), and LP1(N )→π*(N –C ) have stabilization energy of 25.80, 27.07, 30.67,
13
14
15
13
16
17
and 46.28 kcal/mol, respectively. The large E(2) values revealed the occurrence of strong electron
delocalization over the ring moieties. These interactions were observed as an increase in the electron
density (ED) of the C–C antibonding orbital, which weakens the respective bonds. The C =N bond
10
18
length (1.2861 Å) is significantly shorter than the other –CN bonds and the electron density (ED) of
this antibonding orbital was decreased to 0.18707, which is an evidence for the rehybridization [20].
More conjugative and hyperconjugative interactions were formed in the lone-pair, C–C and C–C bond
orbital overlap which confirms the intramolecular charge-transfer (ICT) causing the stabilization of the
molecular structure of the title oxime 4.
Table 3. Second-order perturbation theory analysis of Fock matrix in natural bond orbital basis for
compound 4.
E(2) a
kcal/mol
E(j) – E(i) b
F(i,j) c
(a.u)
Donor (i)
π(C –C )
Occupancy(e)
Acceptor (j)
π*(C –C )
Occupancy(e)
(a.u)
1.70639
1.70639
1.69340
1.69340
1.69274
1.69274
1.69274
1.85899
1.85977
1.85270
1.55644
1.55644
1.95533
1.99160
1.90883
0.36424
0.37847
0.33036
0.37847
0.33036
0.36424
0.18707
0.37926
0.33036
0.36424
0.30606
0.37926
0.03261
0.01285
0.18707
a
20.27
17.86
18.94
19.07
17.00
17.47
17.62
14.88
25.80
27.07
30.67
46.28
8.70
0.29
0.30
0.30
0.30
0.29
0.28
0.28
0.28
0.36
0.35
0.29
0.28
0.83
1.11
0.35
0.070
0.067
0.068
0.069
0.063
0.063
0.064
0.061
0.090
0.093
0.087
0.103
0.076
0.024
0.068
1
6
2
3
π(C –C )
π*(C –C )
1
6
4 5
π(C –C )
π*(C –C )
1 6
2
3
π(C –C )
π*(C –C )
2
3
4 5
π(C –C )
π*(C –C )
1 6
4
5
π(C –C )
π*(C –C )
4
5
2 3
π(C –C )
π*(C10–N18
π*(N16–C17
)
)
4
5
π(C14–C15
LP2(O7)
LP2(O9)
)
π*(C –C )
1
6
π*(C –C )
2
3
LP1(N13
LP1(N13
LP1(N18
LP1(O19
LP2(O19
)
)
)
)
)
π*(C14–C15
π*(N16–C17
σ*(C10–C11
σ*(C11–H25
π*(C10–N18
)
)
)
)
)
0.67
15.97
b
The used numbering of atoms is as shown in Figure 3. : E(2) means energy of stabilization interactions; : Energy
difference between donor-to-acceptor, i and j NBO orbitals; : F(i,j) is the Fock matrix element between i and j
c
NBO orbitals.
2
.5. Vibrational Analysis
The title molecule
0 normal modes. FT-Raman and FT-IR spectra of the title compound
respectively. Theoretical and experimental spectral data of the target oxime
4
consists of 32 atoms and their characteristic vibrations are described by
are shown in Figures 4 and 5,
are presented in Table 4,
9
4
4
including calculated and fundamental wavenumbers, FT-IR- and FT-Raman intensities along with
the tentative vibrational assignment. The calculated vibrational wavenumbers were corrected by
scaled quantum mechanical force-field (SQMFF) method [21] by selective scaling factor approach [22].
Using this force-field method, the calculated wavenumbers are reproducing the experimental values
–1
with a mean deviation of 15 cm . Internal valence coordinates and scaling factors information of the
title compound 4 modes are given in Tables S1 and S2, respectively.

Molecules 2017, 22, 373
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Table 4. Calculated vibrational wavenumbers, observed FT-IR and FT-Raman frequencies, FT-IR and
FT-Raman intensities and their assignments with PED % for compound 4.
Wavenumber
Intensity
Expt.
Calc.
IR a
Raman b
(m ·sr
Assignment with PED % (≥10%)
νIR
νRaman
ν
Scal
(km·mol–1)
2
−1
)
cm–1)
(cm
–1
)
(cm–1)
(
3
830
131.118
1.497
7.45
8.37
ν (O19–H32) (100)
νring II (C–H) (99)
3
3
3
-
144
121
114
3145
3120
3118
3073
-
3001
-
2970
2946
-
3128
3118
3103
3096
3056
3026
3017
2977
2944
2934
2927
2889
2836
1629
1591
1581
1560
1504
1492
1490
1457
1444
1442
1424
1390
2.054
4.324
3.035
1.286
2.149
3.215
9.230
29.934
23.671
4.531
7.851
10.20
6.57
νring II (C–H) (99)
νring II (C–H) (99)
νring II (C–H) (99)
νring I (C–H) (99)
νring I (C–H) (99)
νring I (C–H) (99)
νas (CH2) Me III(93)
νas (CH2) Me I (75) + νs (CH2) Me I (25)
νs (CH2) Me III (98)
3018
3007
2993
-
5.39
10.90
11.70
2.62
17.60
11.10
7.86
10.60
27.20
73.10
100.00
20.60
14.40
2.85
6.28
6.84
4.35
21.40
19.50
5.77
2
-
945
-
-
-
-
-
νas (CH2) Me II (93)
νs (CH2) Me II (98)
2908
2845
1629
1606
-
6.873
118.557
14.078
24.766
3.985
νs (CH2) Me I (74) + νas (CH2) Me I (26)
ν (C10–N18) (71)
νring I (CC) (53) + β (CH) Ring I (16)
νring I (CC) (58) + β (CH) Ring I (14)
Sci(HC) Me I (89)
β (CH) Ring II (41) + ν (C17–N16) (28) +ν (NC) (12)
β (CH) Ring I (50) + νring I (CC) (32)
ν (C14–C15) (35) + β (CH) Ring II (29) +ν (NC) (11)
Sci (CH2) Me II (37) + τ (CN) (31) + Sci (CH2) Me III (16)
ω (CH2) Me I (88)
Sci (CH2) Me II + τ (CN) (25) + Sci (CH2) Me III (14)
νring I (CC) (44) + β (CH) Ring I (34)
τ (CN) (47) + ω (CH2) Me III (30)
ν (NC) (28) + τ (CN) (17) + ω (CH2) Me III (12) + ρ (CH2) Me III (12) +
twi (CH2) Me III (12)
1
-
-
1
595
503
-
0.336
1516
-
1494
-
-
1440
-
1403
44.673
179.197
17.736
14.740
3.326
25.303
55.376
17.021
-
1
1
-
493
450
1439
1428
1401
13.50
1
364
-
1369
2.376
5.68
1
1
-
350
313
1346
1314
-
1291
1271
1341
1324
1301
1293
1276
2.477
15.10
10.90
46.50
28.50
10.70
β (CH) Ring II (39) + ν (C17–N16) (31) + ν (NC) (15)
β (CH) Ring I (40) + ν (CC) (37) + δa (Ring I) (10)
νring I (CC) (32) + β (CH) Ring I (15)
β (CH) Ring II (55) + ν (C17–N16) (16)
ω (CH2) Me II (62)
Twi (CH2) Me II (34) + τ (CN) (24) + ρ (CH2) Me III (10) +
Twi (CH2) Me III (10)
ω (CH2) Me I (37)
β (NOH) (23) + CO (13) + CC (12)
ν (NC) (16) + CN (13) + β (CH) Ring II (13) + Twi (CH2) Me I (11)
β (NOH) (23) + νring I (CC) (16) + ν (CO) (10) + β (CH) Ring I (10)
νring I (CC) (30) + ν (C5–C10) (10) + β (NOH) (10)
νring I (CC) (25) + β (CH) Ring I (25)
38.626
90.153
9.747
1
-
280
255
225
18.733
1
1254
1251
4.921
3.83
-
1
-
-
1225
1224
1222
1208
1202
1151
1136
1124
1111
1097
1079
1032
1019
1000
972
26.089
199.125
78.688
103.083
120.699
4.028
28.90
31.10
30.70
19.30
19.90
2.22
2.61
2.44
7.30
15.00
13.80
19.20
4.74
1232
-
-
-
1174
1141
-
1107
1083
1050
1030
-
-
-
1
1
-
173
147
6.792
5.682
2
ν (NC) (28) + Twi (CH ) Me I (14) + νring I (CC) (14) + β (CH) Ring I (12)
ρ (CH2) Me I (56) + τ (CO) (10) + νring I (CC) (10)
ν (NC) (32) + β (CH) Ring II (25) + ν (C14–C15) (11)
δ (Ring I) (20) + ν (CO) (16) + ν (NC) (14)
β (CH) Ring II (43) + ν (NC) (32) + ν (C14–C15)(15)
τ (CN) (25) + ρ (CH2) Me III (21) + Twi (CH2) Me III (21)
ν (OC) (36) + τ (CN) (11)
ν (CC) (26) + νring I (CC) (14)
ν (CC)(66)
δ (Ring I) (34) + ν (NC) (27) + ν (CN) (13)
ω (CH) Ring I (86)
1
1
-
1
1
9
-
108
085
12.714
54.779
51.301
12.857
121.778
50.386
6.193
035
016
57
956
-
-
9.32
14.00
14.90
3.29
9
-
36
966
935
16.460
3.579
-
ν (N18–O19) (34) + τ (CN) (14) +ρ (CH2) Me III (10) + Twi (CH2)
Me III (10)
9
24
922
921
100.257
9.39
8
8
8
-
95
78
54
893
-
850
-
896
883
851
841
818
809
798
785
756
54.208
61.051
24.434
2.112
6.21
8.07
2.27
2.68
4.86
7.71
28.60
4.73
6.19
ν (CO) (70) + δ (Ring I) (14)
ν (CO) (24) + ν (N18–O19) (16) + δ (Ring I) (13)
ω (CH) Ring I (77)
ω (CH) Ring II(87)
γ (Ring II) (89)
-
-
7.104
8
7
7
7
08
99
52
43
814
21.360
13.387
32.319
2.956
ω (CH) Ring I (84)
-
-
-
νring I (CC) (33) + ν (CO) (18) + ν (CO) (13)
ω (CH) Ring II (77) + ORO (11)
τ (CN) (40) + ρ (CH2) Me III (17) + twi (CH2) Me III (17)

Molecules 2017, 22, 373
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Table 4. Cont.
Wavenumber
Expt.
Intensity
Calc.
IR a
Raman b
(m ·sr
Assignment with PED % (≥10%)
νIR
νRaman
ν
Scal
(km·mol–1)
2
−1
)
cm–1)
(cm
–1
)
(cm–1)
(
-
-
7
7
-
-
-
743
733
706
704
690
650
629
614
592
582
530
447
440
424
405
361
341
333
303
260
222
215
180
138
126
91
2.742
9.478
33.336
3.019
5.722
5.478
17.050
18.672
11.347
14.299
5.947
5.385
19.054
86.609
13.261
1.486
1.034
0.753
4.676
1.201
0.661
0.930
0.384
0.183
7.961
5.187
1.075
0.692
1.601
1.176
0.169
5.72
τ (CN) (26) + ρ (CH2) Me III (11) + twi (CH2) Me III (11)
τ (CN) (37) + ρ (CH2) Me III (15) + twi (CH2) Me III (15)
ω (CH) Ring II (82) + τ (CN) (14)
γ (Ring I) (18) + δ (Ring I) (11) + γ (Ring I) (11)
puc (Ring I) (61) + ω (CC) (13) + τa (Ring I) (10)
ω (CC) (15) + τa (Ring I) (12) + τ (Ring I) (10)
τa (Ring II) (69) + τ (CN) (17)
δ (Ring II) (17) + ν (C12–N13) (15) + ν (CC) (11)
τa (Ring II) (62) + ω (CC) (11)
δ (Ring I) (30)
τ (CN) (20) + ω (CC) (14) + puc (14)
γ (Ring I) (20) + OC (19) + δ (Ring I) (15)
β (CNO) (21) + δ (Ring I) (15) + ν (CC) (10)
τ (NO) (72)
τa (Ring I) (36) + butt (35) + τ (Ring I) (14)
τ (CN) (26) + β (CN) (20) + τ (CN) (10)
τ (CN) (30) + Sci (13) + OC (12)
τ (CN) (67) + β (CN) (11)
12.10
14.00
15.40
5.12
2.91
1.48
4.91
7.42
9.94
2.11
7.04
7.96
9.89
4.70
7.82
10.40
9.09
15.80
20.60
34.50
29.90
13.60
22.60
18.10
119.00
156.00
162.00
104.00
312.00
328.00
25
16
721
-
-
692
658
626
573
-
6
6
5
5
4
-
4
4
4
-
-
-
-
-
-
-
-
-
58
21
78
56
92
-
490
-
449
-
33
25
17
-
387
-
330
303
277
230
-
-
-
-
-
-
-
-
-
-
τ (CN) (38) + τ (CN) (15) + butt (11)
τ (CN) (69)
τ (CN) (51) + ρ (OC) (10)
τa (Ring II) + (24) + τ (Ring I) (24)
τ (CN) (73) + β (CC) (10)
τ (CN) (37) + Sci (20)
-
-
-
-
-
-
-
τ (Ring I) (40) + τ (CN)(18) + τ (CN) (18) + τ (CN) (14)
τ (CN) (27) + τ (Ring I) (17) + ω (CC) (12) + τ (CN)(10)
τ (CN) (99)
τ (CN) (78)
τ (CN) (98)
72
64
29
20
τ (CN) (99)
τ (CN) (86)
16
a: IR intensity; : Raman intensity; Ring I: benzodioxole ring; Ring II: imidazole ring;
νs: symmetric stretching; νas: asymmetric stretching; : bending; : torsion; puc: puckering;
twi: twisting; : rocking; Sci: scissoring; : out-of-plane bending; : in-plane bending; butt: butterfly mode;
τa: out-of-plane torsion.
b
ν
: stretching; Me: methylene;
: wagging;
β
τ
δ
ω
ρ
γ
Figure 4. Experimental (upper) and simulated (lower) FT-Raman spectra of compound 4.

Molecules 2017, 22, 373
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Figure 5. Experimental (upper) and simulated (lower) FT-IR spectra of compound 4.
2
.5.1. Imidazole Ring Vibrations
The calculated IR and Raman imidazole C–H stretching vibrations at 3118 and 3145 cm are
–1
–1
in close agreement with the experimental wavenumbers observed at 3144, 3125, 3120 cm
[23,24].
–1
The FT-IR bands observed at 1503, 1350, 1280 and 1108 cm and the FT-Raman ones at 1516, 1346, 1291,
107 and 1050 cm–1 are definitely attributed to imidazole CH in-plane bend modes which are coupled
1
–1
with several other modes. The FT-IR bands at 752 and 725 cm and the weak FT-Raman bands at
7
–1
21 cm , can be assigned to the out-of-plane C–H wagging modes, as supported by theliterature
data [25]. The C =C stretching mode is the most characteristic vibration of the heterocyclic imidazole
1
4
15
–
1
ring which was observed as medium intensity bands at 1493 (FT-IR) and at 1494 (FT-Raman) cm .
The FT-IR and FT-Raman vibrations of the imidazole ring out-of-plane torsion modes appeared at 658,
78 (FT-IR) and 573 (FT-Raman) cm .
–1
5
2
.5.2. Methylene Group Vibrations
The neighboring rings
hybridized methylene moiety. Methylene asymmetric and symmetric C–H stretching vibrations usually
π
-system and nitrogen lone pair affects the spectral behavior of sp3
–
1
–1
appear in the region 2960–2840 cm
[
26]. The asymmetric (2970 and 2946 cm ) and symmetric (2908
and 2845 cm ) stretching contributing bands appeared as a medium intensity band in the FT-Raman
spectrum of the title compound . Lowering of symmetric stretching wavenumbers could be attributed
to the hyperconjugative interaction between the nitrogen lone pair and *(C–H) bond. The rocking,
wagging and twisting vibrational modes of compound appeared in the region of 1400–900 cm
The CH scissoring mode appeared as a characteristic band near 1450 and 1439 cm in the FT-IR
–1
4
σ
–1
4
[27].
–1
2
–1
spectrum and at 1440 cm in the FT-Raman spectrum of the title oxime
analysis (NCA) supports the FT-Raman bands at 1254 and 1271 cm–1 and the FT-IR bands at 1255 cm
4
. The normal coordinate
–1
for the unambiguous assignment of CH twisting and wagging modes.
2
2
.5.3. Benzodioxole Ring Vibrations
–1
Aromatic C–H stretching mode appears in the region of 3000–3100 cm . Weak FT-Raman bands
identified at 3073 and 3001 cm–1 have been assigned to the C–H stretching mode. Usually the bands
due to ring C–H in-plane and out-of-plane bending vibrations are observed in the region of 1000–1300
–1
and 750–1000 cm , respectively. In the title compound 4, the C–H in-plane bending vibration has
–
1
–1
been observed as a medium intensity FT-IR band at 1313 cm and as a weak band at 1314 cm in the
FT-Raman spectrum. The medium to weak intensity bands observed at 854 (FT-IR), 850 (FT-Raman),
8
14 (FT-Raman) and 808 (FT-IR) cm–1 have been assigned to C–H out-of-plane bending mode. Ring

Molecules 2017, 22, 373
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C–C stretching modes have been identified in the FT-IR spectrum of the target compound
1
asymmetric deformation and torsion modes have been identified at 716, 556, 492 and 417 cm in the
FT-IR and at 490 cm–1 in the FT-Raman spectra of the title molecule 4.
4
at 1595,
428 and 1173 cm–1 while they appeared at 1606 and 1174 cm in the FT-Raman spectrum. The ring
–1
–
1
2
.6. Frontier Molecular Orbital Analysis
A detailed knowledge of molecular electron density distribution and electron motion are necessary
to understand molecular recognition and chemical reactivity of the molecule. The LUMO and HOMO
orbital energy analysis of the title compound has been computed using DFT method in the solution
4
phase (isopropanol). The electron charge cloud is located at the piperonal ring in highest occupied
molecular orbital (HOMO) while it is located mainly at the phenyl ring in the lowest unoccupied
molecular orbital (LUMO). The energy of the HOMO is
−
6.23 eV and LUMO is
−
1.60 eV giving
rise to a HOMO-LUMO energy gap of 4.63 eV. The HOMO-LUMO energy gap value supports the
intramolecular charge-transfer interactions within the title molecule. The HOMO and LUMO orbital
diagram is shown in Figure 6.
Figure 6. (a) HOMO (b) LUMO orbital of compound 4.
2
.7. NMR Chemical Shift Analysis
The carbon and hydrogen chemical shift values of the title oxime
4 were calculated based on
Gauge-independent atomic orbital (GIAO) method at B3LYP/6-311++G(d,p) level of theory [28].
The computed values are presented in Table 5. The correlation graphs were plotted over the observed
and predicted chemical shift values of the title molecule
Figure S3.
4 and the linear fitting plots are shown in
Table 5. Calculated and experimental chemical shift values for compound 4.
Carbon Atoms (13C)
Value (ppm)
Hydrogen Atoms ( H)
Value (ppm)
1
Atoms
Atoms
Calc.
Exp.
Calc.
Exp.
C1
C2
C3
C4
C5
127.25
127.81
89.62
107.84
107.85
89.80
87.78
132.24
29.66
148.0
148.3
108.5
120.5
130.3
106.1
101.7
153.7
28.2
H20
H21
H22
H23
H24
H25
H26
H27
H28
H29
H30
H31
5.81
7.01
5.89
5.40
5.20
1.92
2.23
3.40
3.64
6.05
5.94
6.38
6.84
7.06
7.13
6.04
6.04
3.14
3.14
4.17
4.17
6.89
7.19
7.66
C6
C8
C10
C11
C12
C14
C15
C17
38.54
43.3
100.78
109.30
115.68
119.9
128.3
137.5
The used numbering of atoms is as shown in Figure 3.

Molecules 2017, 22, 373
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The phenyl carbons signals usually appear in the region of 120–140 ppm. The C1 and C2 in the
title molecule were observed at 148.0 and 148.3 ppm, respectively. This downfield chemical shift
4
values revealed that, these carbon atoms bounded with the electronegative oxygen atoms. In general,
1
imidazole ring protons signals occur in the region of 6–8 ppm. The H-NMR spectrum of the target
oxime
4 showed signals at 6.89, 7.19 and 7.66 ppm which correspond to the protons of the imidazole
ring. The aromatic piperonal ring protons were observed at 6.84 (as doublet), 7.06 (as doublet) and
7
.13 (as singlet) ppm. There is a good agreement between the calculated and observed chemical shift
2
13
values of the title molecule
4
with a correlation coefficient (R ) values = 0.994 and 0.953 for C and
1
H, respectively.
2
.8. Molecular Docking Study
Molecular docking is an important technique to predict the biological activity of chemical
compounds [29]. The target compound was energy minimized using DFT method with
the help of Gaussian program [30]. The target protein (cytochrome P450-dependent (CYP51)
lanosterol 14 -demethylase enzyme) for antifungal azoles has been identified based on a multilevel
neighborhoods of atoms’ (MNAs) algorithm model by the PASS online server [31]. This target protein
PDB code: 1EA1) was downloaded from the research collaboratory structural bioinformatics (RCSB)
protein data bank [32]. The target compound was docked using AutoDock Tools 1.5.4 (The Scripps
Research Institute, La Jolla, CA, USA) interfaced with the AutoDock 4.2 program in the rigid docking
methodology [33 34]. The binding free energy and inhibition constant of the proper conformation of
the title compound was predicted to be 5.06 kcal/mol and 195.75 M, respectively. The hydrogen
bond interaction of protein-ligand complex is shown in Figure 7. The amino acid residues LEU321 and
PRO386 of the target protein are bounded with the title compound by an intermolecular hydrogen
bonding interaction. The docking study illustrated the affinity of compound toward its target protein
4
α
(
4
,
4
−
µ
4
4
with a good binding energy value (–5.06 kcal/mol) and hence its suitability as a potential precursor to
prepare new antifungal agents.
Figure 7. Binding pose of compound 4 with its target protein.
2
.9. Antifungal Activity of the Title Compound 4
Table 6 presents the preliminary antifungal activity of the tested oxime
4
as well as the reference
mol/L against C. albicans,
C. tropicalis, C. parapsilosis and Aspergillus niger in the broth microdilution assay. While inactive itself,
standard drug, ketoconazole. Compound
4 exhibited a MIC value of 987.43 µ
taken together the body of evidence suggests that compound
prepare new antifungal agents with better antifungal profile.
4 could be used as a starting material to

Molecules 2017, 22, 373
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Table 6. Antifungal activity of compound
Aspergillus niger.
4 and ketoconazole against different Candida species and
MIC (µmol/L)
Compound No.
C. albicans
C. tropicalis
C.parapsilosis
Aspergillus niger
4
987.43
7.53
987.43
15.05
987.43
15.05
987.43
15.05
Ketoconazole
3
. Experimental
3
.1. General
Melting points were measured using a Gallenkamp melting point device, and are uncorrected.
Infrared (IR) spectra (as KBr disks) were recorded on FT-IR Spectrum BX device (Perkin Elmer, Ayer
Rajah Crescent, Singapore). The NMR samples were dissolved in either CDCl or DMSO-d and
3
6
the NMR spectra were recorded using a Bruker NMR spectrometer (Bruker, Reinstetten, Germany),
1
13
at 500 MHz 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
δ
internal standard. Mass spectra were recorded using a Quadrupole 6120 LC/MS equipped with
an electrospray ionization (ESI) source (Agilent Technologies, Palo Alto, CA, USA). Silica gel TLC
(thin layer chromatography) plates (silica gel precoated aluminium cards with 254 nm fluorescent
indicator) from Merck (Darmstadt, Germany) were used for thin layer chromatography. Visualization
was performed by illumination with a UV light source (254 nm).
3
.2. Synthesis
3
.2.1. Synthesis of 1-(2H-1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)propan-1-one (3)
A catalytic amount of concentrated hydrochloric acid (0.5 mL) was added to a mixture
containing paraformaldehyde (0.81 g, 9.0 mmol), dimethylamine hydrochloride (2.20 g, 27 mmol)
and1-(2H-1,3-benzodioxol-5-yl)ethanone ( , 3.28 g, 20 mmol) in absolute ethanol (15 mL). The reaction
mixture was refluxed for two hours, cooled and acetone (30 mL) was added to precipitate the Mannich
base hydrochloride ( ) which was collected by filtration and dried. Imidazole (1.36 g, 20 mmol) was
added to a solution of compound (2.58 g, 10 mmol) in water (10 mL) and the solution was refluxed
for five hours, cooled and the precipitated solid was filtered off to afford compound . Compound
1
2
2
3
3
was re-crystallized from ethanol to give 1.15 g (47%) of the pure pivotal ketone
3
as a white solid m.p.
◦
–1
1
150–152 C. IR (KBr):
ν
(cm ) 3115, 2968, 1757 (C=O), 1637 (C=N), 1600, 1494, 1255, 750; H-NMR
(
CDCl3):
δ
(ppm) 3.37 (t, J = 6.5 Hz, 2H, –CH –CH –N), 4.42 (t, J = 6.5 Hz, 2H, –CH –CH –N), 6.05 (s, 2H,
2
2
2
2
–
O–CH –O–), 6.84 (d, J = 8.0 Hz, 1H, Ar–H), 6.99 (s, 1H, –N–CH=CH–N=), 7.04 (s, 1H, –N–CH=CH–N=),
2
13
7
(
1
.39 (d, J = 1.5 Hz, 1H, Ar–H), 7.50 (dd, J = 1.5, 8.0 Hz, 1H, Ar–H), 7.64 (s, 1H, –N–CH=N–); C-NMR
CDCl3): (ppm) 39.6 (–CH –CH –N), 41.7 (–CH –CH –N), 102.0 (–O–CH –O–), 107.7 (Ar–CH),
08.0 (Ar–CH), 119.2 (–N–CH=CH–N=), 124.4, 129.1 (Ar–CH, –N–CH=CH–N=), 131.0, (Ar–C), 137.4
δ
2
2
2
2
2
+
(–N–CH=N–), 148.4, 152.3 (Ar–C), 194.6 (C=O); MS m/z (ESI): 245.0 [M + H] .
3
.2.2. Synthesis of (1E)-1-(2H-1,3-Benzodioxol-5-yl)-N-hydroxy-3-(1H-imidazol-1-yl)propan-1-imine (
Potassium hydroxide (1.12 g, 20 mmol) was added to a mixture containing hydroxylamine
hydrochloride (1.39 g, 20 mmol), ketone (2.44 g, 10 mmol) in ethanol (10 mL). The reaction mixture
4)
3
was refluxed under stirring for 18 hours, cooled to room temperature and the insoluble matter was
collected by filtration. The filtrate was concentrated under reduced pressure and the residue was
poured onto ice-cold water (15 mL). The obtained solid was filtered off and dried to yield 1.7 g (64%) of
◦
the target oxime
4
as a white solid m.p. 142–144 C. Re-crystallization of the oxime
4
from isopropanol
(ppm)
1
gave colorless single crystals which were suitable for X-ray analysis. H-NMR (DMSO-d ):
δ
6
3
.14 (t, J = 7.0 Hz, 2H, –CH –CH –N), 4.17 (t, J = 7.0 Hz, 2H, –CH –CH –N), 6.04 (s, 2H, –O–CH –O–),
2 2 2 2 2

Molecules 2017, 22, 373
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6
.84 (d, J = 7.5 Hz, 1H, Ar–H), 6.89 (s, 1H, –N–CH=CH–N=), 7.06 (dd, J = 1.5, 8.0 Hz, 1H, Ar–H), 7.13
(
d, J = 1.0 Hz, 1H, Ar–H), 7.19 (s, 1H, –N–CH=CH–N=), 7.66 (s, 1H, –N–CH=N–), 11.41 (s, 1H, OH);
C-NMR (DMSO–d6): δ(ppm) 28.2 (–CH –CH –N), 43.3 (–CH –CH –N), 101.7 (–O–CH –O–), 106.1,
2 2 2 2 2
1
3
1
08.5 (Ar–CH), 119.9 (–N–CH=CH–N=), 120.5, 128.3 (Ar–CH, –N–CH=CH–N=), 130.3 (Ar–C), 137.5
+
(–N–CH=N–), 148.0, 148.3 (Ar–C), 153.7 (C=N–OH); MS m/z (ESI): 260.1 [M + H] .
3
.3. Crystal Structure Determination
Slow evaporation of the alcoholic (isopropanol) solution of the title compound
4
furnished its
was conducted
on a SMART APEXII CCD diffractometer (Bruker, Karlsruhe, Germany) equipped with graphite
monochromatic CuKådiation ( = 1.54178 Å) at 296 (2) K. Cell refinement and data reduction were
done by Bruker SAINT [35]. SHELXS-97 [36] was used to solve and refine the title structure. The final
colourless block single crystals. The X-ray diffraction measurement of the target oxime
4
λ
refinement of the crystal structure of the title oxime
4
was performed by full- matrix least-squares
2
techniques with anisotropic thermal data for non hydrogen atoms on F . All the hydrogen atoms
were placed in the calculated positions and constrained to ride on their parent atoms. Multi-scan
absorption correction was applied by the use of SADABS software [35]. The crystallographic data
and refinement information are summarized in Table 7. Crystallographic data of compound 4 have
been deposited with the Cambridge Crystallographic Data Center (supplementary publication number
CCDC-1508986). 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).
Table 7. The crystallographic data and refinement information.
Chemical Formula
2(C13H13N3O3)·C3H8O
Molecular weight
Crystal system, space group
Temperature (K)
578.62
Monoclinic, P21
296
a, b, c (Å)
9.0963(3), 14.7244(6), 10.7035(4)
◦
β( )
94.298(3)
1429.57(9)
2
3
V (Å )
Z
Radiation type
Cu Kα
0.81
–
1
µ (mm
)
Crystal size (mm)
0.40 × 0.23 × 0.11
Data collection
Diffractometer
Absorption correction
Tmin, Tmax
Bruker APEX-II CCD diffractometer
Multi-scan, SADABS Bruker 2014
0.740, 0.916
No. of measured, independent and
observed [I > 2σ(I)] reflections
Rint
6
654, 3851, 2788
0.039
Refinement
2
2
a
2 b
R[F > 2σ(F )] , wR(F ) , S
No. of reflections
0.059, 0.144, 1.03
3851
393
1
No. of parameters
No. of restraints
H atoms treated by a mixture of
independent and constrained refinement
0.26, −0.23
H-atom treatment
∆
ρmax, ∆ρmin (e·Å–3
)
a: R is the residual factor for the reflections; : wR is the weighted residual factor for all the reflections.
b
3
.4. FT-IR and FT-Raman Measurements
The FT-Raman spectrum of the oxime
a Bruker RFS-27 FT-Raman spectrophotometer (Bruker, Billerica, MA, USA). The 1064 nm line of
Nd:YAG laser operating at 100 mW power was used for excitation. The FT-IR spectrum of the oxime
4
was recorded in the spectral range of 3500–50 cm–1 using
4

Molecules 2017, 22, 373
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was recorded with a spectral resolution of 2 cm–1 in the 4000–400 cm–1 range. Solid sample in KBr
pellets was used in the FT-IR measurements.
3
.5. Quantum Chemical Calculations
Optimized structural geometry and harmonic vibrational wavenumbers have been calculated
at DFT/B3LYP/6-311++G(d,p) level of basis set in the gas phase. The polarizable continuum model
PCM) using the integral equation formalism (IEF) variant is the self-consistent reaction field (SCRF) to
predict the structural parameters and vibrational wavenumbers of the title molecule and isopropanol
has defined as the solvent in implicit solvation model. This calculation has been performed in the
presence of isopropanol by placing the title molecule in a cavity within the solvent reaction field.
Normal coordinate analysis (NCA) has been performed to obtain detailed explanation of the molecular
motion relating to the normal modes using the MOLVIB program version 7.0 written by Sundius [37 38].
(
4
4
,
According to the scaled quantum mechanical force-field (SQMFF) procedure [21], selective scaling
has been performed in the natural internal coordinate representation [22]. The simulated IR and
Raman spectra of the title compound 4 have been plotted using pure Lorentizian band shapes with a
–1
bandwidth of full width height maximum of 10 cm . Second order interactions between the filled
orbital of one subsystem and vacant orbitals of another subsystem have been understood with the aid
of natural bonding orbitals (NBO) analysis [19] using NBO 3.1 program [39] as implemented in the
Gaussian ‘09 package [30] at the DFT/B3LYP level. Molecular docking analysis using AutoDock 4.2
program [33] predicted the antifungal activity of the title compound 4.
3
.6. Antifungal Activity
3
.6.1. Materials
The reference standard antifungal drug, ketoconazole, was purchased from Sigma-Aldrich Co.
(St. Louis, MO, USA). Liquid RPMI 1640 medium supplemented with L-glutamine was obtained 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 ketoconazole,
and/or the tested compound 4 to give an initial concentration of 2048 mg/L.
3
.6.2. Organisms
The used fungal strains are Candida albicans (ATCC 90028), Candida tropicalis (ATCC 66029),
Candida parapsilosis (ATCC 22019) and Aspergillus niger (ATCC 16404).
3
.6.3. Preparation of Fungal Inocula
The inocula of the standard mold Aspergillus niger strain have been prepared by removing the
sporulated A. niger from the Sabouraud Dextrose agar slant with a microbiological loop and the spores
have been suspended in 10 mL of sterile water. The suspension has been filtered through sterile
gauze to remove hyphae. The resulting suspension of conidia has been vigorously mixed using a
5
vortex. The suspension has been adjusted to 1
×
10 CFU/mL using spectrophotometer. This fungal
suspension has been diluted 1:5 with RPMI medium to obtain suspensions having 2
×
of the required
4
final concentration. This conidial suspension had a final concentration of 1
with the tested solution of compound
×
10 CFU/mL when mixed
4
. On the other hand, the inocula of the standard yeast strains
of C. albicans, C. tropicalis and C. parapsilosis have been prepared by suspending five representative
colonies, obtained from 24 to 48 h culture on Sabauraud Dextrose agar medium, in sterile distilled
5
5
water. The final inoculum concentration must be between 0.5 × 10 and 2.5 × 10 CFU/mL.

Molecules 2017, 22, 373
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3
.6.4. Preparation of the Tested Compound Solution
Briefly, a twofold dilution series of the tested compound
4
has been prepared in a double strength
RPMI 1640 culture medium. Ten serial dilutions were prepared to give concentrations ranged from
024 mg/L to 2 mg/L.
1
3
.6.5. Antifungal Susceptibility Studies
Minimum Inhibitory Concentrations (MICs) have been determined by broth microdilution testing
as described previously by EUCAST [40]. The experiment was carried out in duplicate. Briefly, one
mL of RPMI 1640 medium from each of the bottle containing the corresponding concentration of the
tested compound
4
has been transferred into sterile 7 mL Sterilin tubes (Thermo Fisher Scientific,
has
Waltham, MA, USA). The RPMI 1640 medium containing 1024 mg/L of the tested compound
4
been dispensed to tube 1, the medium containing 512 mg/L has been dispensed to tube 2, the medium
containing 256 mg/L has been dispensed to tube 3 and so on to tube 10 for the medium containing
2
mg/L of the tested compound
4. One mL of the medium has been dispensed in tubes 11 (positive
control) and 12 (negative control). One mL of the diluted inoculum suspension has transferred to each
tube except tube 12 to bring the tested compound
The tubes were incubated at 35 C for 72 h. The MIC of the tested compound
by recording the degree of growth inhibition in each tube.
4
dilutions to the required final test concentrations.
◦
4 was determined visually
4
. Conclusions
The synthesis and spectroscopic characterization of N-[(1E)-1-(2H-1,3-benzodioxol-5-yl)-3-(1H-
imidazol-1-yl)propylidene]hydroxylamine ( ) as new antifungal precursor has been reported.
Computational studies on the target oxime revealed that the theoretical wavenumbers are
in a fair agreement with the observed wavenumbers except those associated with H-bonding.
CH symmetric stretching wavenumber is red-shifted due to the hyperconjugative interaction between
4
4
2
the nitrogen lone pair and
confirmed the (E)-configuration of its imine double bond. A molecular docking study predicted
the binding mode of compound into its target protein and hence its usefulness as a potential
σ*(C–H) bond. Single crystal X-ray analysis of the target molecule 4
4
precursor for new imidazole-bearing antifungal agents featuring both benzodioxole and imidazole
pharmacophore moieties.
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. synthesized and characterized the title molecule. H.A.G. carried
out the X-ray analysis of the title molecule. M.H.A.-A. performed the in vitro antifungal screening for the title
compound. J.C.M. and I.H.J. conducted the computational work. M.I.A. proposed the work, prepared the single
crystals of the title compound 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.
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©
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article distributed under the terms and conditions of the Creative Commons Attribution
CC BY) license (http://creativecommons.org/licenses/by/4.0/).
(