(2E)-2-[1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)propylidene]-N-(4-methoxyphenyl)hydrazinecarboxamide: Synthesis, crystal structure, vibrational analysis, DFT computations, molecular docking and antifungal activity

Article abstract of DOI:10.1016/j.molstruc.2018.04.017

Fungal infections are a growing health threat to mankind. The development of novel potent antifungal agents is a challenge to overcome the resistance to the available antifungal medications. The current report focuses on the synthesis and spectroscopic characterization of a new imidazole-bearing antifungal agent. The vibrational characteristics of the title compound are explored using Fourier transform infrared and Raman spectroscopy with the aid of density functional theory. Highest occupied and lowest unoccupied molecular orbital investigations and natural bond orbital analysis of the title molecule are performed to investigate the possible intermolecular delocalisation or hyper-conjugation, and the possible interactions with the target protein. Single crystal X-ray analysis confirms the assigned (E)-configuration of the imine double bond structure of the title compound. The molecular structure of the title compound is crystallised in a monoclinic space group, namely, P2₁/c, a = 10.7007 (4) ?, b = 7.3072 (3) ?, c = 24.9088 (8) ?, β = 97.178 (2)°, V = 1932.41 (12) ?³ and Z = 4. The antifungal potential of the title compound is in vitro assessed against four fungal strains. In addition, molecular docking of the title molecule predicts its binding orientation in the active site of the target protein.

Full text of DOI:10.1016/j.molstruc.2018.04.017

Accepted Manuscript
(2E)-2-[1-(1,3-benzodioxol-5-yl)-3-(1H-imidazole-1-yl)propylidene]-N-(4-
methoxyphenyl)hydrazinecarboxamide: Synthesis, crystal structure, vibrational
analysis, DFT computations, molecular docking and antifungal activity
Reem I. Al-Wabli, Alwah R. Al-Ghamdi, I.P. Primsa, Hazem A. Ghabbour, Mohamed
H. Al-Agamy, I. Hubert Joe, Mohamed I. Attia
PII:
S0022-2860(18)30448-4
10.1016/j.molstruc.2018.04.017
MOLSTR 25090
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 11 February 2018
Revised Date: 3 April 2018
Accepted Date: 3 April 2018
Please cite this article as: R.I. Al-Wabli, A.R. Al-Ghamdi, I.P. Primsa, H.A. Ghabbour, M.H. Al-
Agamy, I.H. Joe, M.I. Attia, (2E)-2-[1-(1,3-benzodioxol-5-yl)-3-(1H-imidazole-1-yl)propylidene]-N-
(
4-methoxyphenyl)hydrazinecarboxamide: Synthesis, crystal structure, vibrational analysis, DFT
computations, molecular docking and antifungal activity, Journal of Molecular Structure (2018), doi:
0.1016/j.molstruc.2018.04.017.
1
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
(2E)-2-[1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)propylidene]-N-(4-
methoxyphenyl)hydrazinecarboxamide: Synthesis, crystal structure,
vibrational analysis, DFT computations, molecular docking and antifungal
activity
a
a
b,c
a,d
Reem I. Al-Wabli , Alwah R. Al-Ghamdi , I. P. Primsa , Hazem A. Ghabbour , Mohamed
e,f
b
a,g*
H. Al-Agamy , I. Hubert Joe and Mohamed I. Attia
a
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457,
Riyadh 11451, Saudi Arabia
Centre for Molecular and Biophysics Research, Department of Physics, Mar Ivanios College,
b
Thiruvananthapuram 695 015, Kerala, India
c
Department of Physics, Sree Narayana College, Sivagiri, Varkala, Thiruvananthapuram 695 145, Kerala, India
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,
d
e
Saudi Arabia
f
Microbiology and Immunology Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt
Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research
g
Division, National Research Centre (ID: 60014618), El Bohooth Street, Dokki, Giza 12622, Egypt
Keywords: Synthesis; Crystal structure; Imidazole; Antifungal; DFT
1

ACCEPTED MANUSCRIPT
Abstract
Fungal infections are a growing health threat to mankind. The development of novel
potent antifungal agents is a challenge to overcome the resistance to the available antifungal
medications. The current report focuses on the synthesis and spectroscopic characterisation of
a new imidazole-bearing antifungal agent. The vibrational characteristics of the title
compound are explored using Fourier transform infrared and Raman spectroscopy with the
aid of density functional theory. Highest occupied and lowest unoccupied molecular orbital
investigations and natural bond orbital analysis of the title molecule are performed to
investigate the possible intermolecular delocalisation or hyper-conjugation, and the possible
interactions with the target protein. Single crystal X-ray analysis confirms the assigned (E)-
configuration of the imine double bond structure of the title compound. The molecular
structure of the title compound is crystallised in a monoclinic space group, namely, P2 /c, a =
1
3
1
0.7007 (4) Å, b = 7.3072 (3) Å, c = 24.9088 (8) Å, β = 97.178 (2)°, V = 1932.41 (12) Å and
Z = 4. The antifungal potential of the title compound is in vitro assessed against four fungal
strains. In addition, molecular docking of the title molecule predicts its binding orientation in
the active site of the target protein.
1
. Introduction
Global morbidity due to life-threatening fungal infections has dramatically increased
in recent decades, particularly among individuals suffering from cancer, autoimmune
diseases, organ transplants or AIDS [1-3]. Candida albicans is a leading cause for ~70% of
fungal infections in humans [4]. The emergence of drug resistance to the currently available
antifungal medications has become the key focus of many researchers and pharmaceutical
companies, motivating them to develop novel antifungal agents capable of overcoming this
resistance, as well as possessing potent activity, low toxicity and a broad spectrum of activity
[
5].
During the past 35 years, azole compounds bearing either imidazole or triazole
pharmacophore moieties have been the most widely used antifungal drugs and have had a
substantial impact on the management of systemic fungal infections [6]. Azoles are an
important class of antifungal chemotherapeutic agents that prevent the biosynthesis of
ergosterol by inhibiting cytochrome P450-dependent sterol 14α-demethylaseenzyme [7, 8].
Alternatively, literature screening exposed that a number of compounds bearing the
semicarbazone fragment in their chemical structure exhibit significant antifungal and
antibacterial activities [9, 10]. In addition, a plethora of bioactive molecules incorporate the
1
,3-benzodioxole scaffold in their structure [11-13].
2

ACCEPTED MANUSCRIPT
It was on this basis that the title compound, namely, (2E)-2-[1-(1,3-benzodioxol-5-
yl)-3-(1H-imidazol-1-yl)propylidene]-N-(4-methoxyphenyl)hydrazine carboxamide, was
designed and synthesised as a molecular hybrid incorporating the imidazole pharmacophore,
as well as semicarbazone and 1,3-benzodioxole fragments. The assigned chemical structure
of the title compound was determined with different spectroscopic techniques and the
configuration of its imine double bond was unambiguously proved via single crystal X-ray
analysis. The antifungal potential of the title molecule was assessed using a minimum
inhibitory concentration (MIC) assay towards four fungal strains. Furthermore, a detailed
vibrational spectral analysis was conducted with the aid of density functional theory (DFT)
computations in order to gain insight into the inter- and intramolecular interactions of the title
compound. Natural bond orbital (NBO) analysis of the title molecule was performed to
determine the possible intermolecular delocalisation or hyperconjugation, while HOMO-
LUMO investigations explored the possible interactions between the title compound and its
target protein. A molecular docking study predicted the binding pose of the title compound to
its target protein.
2
2
. Experimental details
.1. General
The FT-IR spectrum of the title compound was recorded using a Perkin-Elmer RXL
-1
spectrophotometer in the region of 4000–400 cm , with samples in the KBr pellet method
-1
-1
with a resolution of 2 cm . The Raman spectrum was recorded in the region of 3500–50 cm
-1
using a Bruker RFS 27 standalone FT-Raman spectrometer with a resolution of 2 cm .
.2. Synthesis
A reaction mixture containing N-(4-methoxyphenyl)hydrazinecarboxamide [14] (1.81
2
g, 10 mmol), ketone 3 [15] (0.24 g, 10 mmol) and a few drops of glacial acetic acid in
absolute ethanol (15 mL) was stirred at room temperature for 18 h. The reaction mixture was
evaporated under reduced pressure and the residue was purified by recrystallisation from
ethanol to furnish the title semicarbazone 4. Yield 0.51 g (51%); white powder m.p. 161–163
1
°
C; H-NMR (DMSO-d ): δ (ppm) 3.26 (t, J = 6.5 Hz, 2H, –CH –CH –N), 3.75 (s, 3H,
6
2
2
OCH ), 4.09 (t, J = 6.5 Hz, 2H, –CH –CH –N), 6.07 (s, 2H, -O-CH -O-), 6.86 (s, 1H, –N–
3
2
2
2
CH=CH–N=), 6.89 (d, J = 2.0 Hz, 1H, Ar-H), 6.91 (s, 2H, Ar–H), 7.26 (dd, J = 1.5, 8.5 Hz,
1
H, Ar–H), 7.28 (s, 1H, –N–CH=CH–N=), 7.51 (d, J = 8.5 Hz, 2H, Ar–H), 7.64 (br.s, 2H,
13
Ar-H, –N–CH=N–), 8.77 (s, 1H, NH), 10.05 (s, 1H, NH); C-NMR (DMSO-͘ ): ꢀ(ppm)
6
2
8.6 (–CH –CH –N), 42.7 (–CH –CH –N), 55.7 (OCH ), 101.7 (-O-CH -O-),107.2, 108.2,
2 2 2 2 3 2
1
14.1 (Ar-CH), 119.9 (–N–CH=CH–N=), 121.2, 122.9, 128.7, 131.7, 132.4 (Ar-CH,Ar–C, –
3

ACCEPTED MANUSCRIPT
N–CH=CH–N=), 137.8 (–N–CH=N–), 144.9, 148.2, 148.4, 154.4, 155.6 (Ar–C, C=O, C=N);
+
+
+
MS m/z (ESI):408.1 [M + H] , 430.1 [M + 23] , 446.1 [M + 39] .
.3. X-ray analysis
The title compound was obtained as single crystals by slow evaporation of an
2
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 Cu
Kα radiation, λ = 1.54178 Å at 296 (2) K. Cell refinement and data reduction were carried out
by Bruker SAINT. SHELXT [16, 17] was used to solve the structure. The final refinement
was carried out by full-matrix least-squares techniques with anisotropic thermal data for non-
hydrogen atoms. The crystallographic data and refinement information of the title compound,
C H N O , are summarised in Table 1. CCDC 1555563 contains the supplementary
21
21
5
4
crystallographic data for this compound and can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Table 1. Experimental X-ray details of the title compound.
Crystal data
Chemical formula
C H N O
21 21 5 4
Mr
407.43
Crystal system, space group
Monoclinic, P2 /c
1
Temperature (K)
a, b, c (Å)
β (°)
V (Å3)
Z
296
10.7007 (4), 7.3072 (3), 24.9088 (8)
97.178 (2)
1932.41 (12)
4
Radiation type
µ (mm )
Cu Kα
0.82
−1
Crystal size (mm)
Data collection
Diffractometer
Absorption correction
Tmin, Tmax
0.36 × 0.15 × 0.11
Bruker APEX-II D8 venture diffractometer
Multi-scanSADABS Bruker 2014
0.757, 0.913
No. of measured, independent and
observed [I> 2σ(I)] reflections
Rint
9
324, 3380, 2388
0.039
Refinement
2
2
2
R[F > 2σ( F )], wR( F ), S
No. of reflections
No. of parameters
No. of restraints
0.049, 0.132, 1.06
3380
280
0
H-atom treatment
H atoms treated by a mixture of
independent and constrained refinement
0.22, −0.23
−
3
ꢀ
ρmax, ꢀρmin (e Å )
4

ACCEPTED MANUSCRIPT
2
.4. Computational techniques
Quantum chemical calculations were conducted using the Gaussian ’09 program
package [18] with the B3LYP/6-311++G(d,p) basis set [19, 20]. The vibrational frequencies
were scaled by a factor of 0.9673 to compensate for the errors due to vibrational
anharmonicities and the incompleteness of the basis set [21]. Vibrational wavenumbers were
assigned by potential energy distribution analysis using the VEDA 4 program [22]. NBO
analysis was performed by NBO the 3.1 program [23]. The molecular docking analysis was
carried out using the AutoDock 4.2 program [24].
2
.5. Antifungal activity
Fungal inocula were prepared as reported in the literature [15] and the MIC values of
the title compound were determined as previously reported [15].
3
3
. Results and discussion
.1. Synthesis
The title compound 4 was prepared as illustrated in Scheme 1. Thus, the
commercially available acetophenone derivative 1 was subjected to Mannich reaction to
furnish the Mannich base hydrochloride 2 which was subsequently elaborated to the
corresponding imidazole derivative 3. Compound 3 was allowed to react with N-(4-
methoxyphenyl)hydrazinecarboxamide to give the title compound 4.
O
O
O
O
O
O
O
O
O
CH3
i
N(CH
3
)
2
.HCl
ii
N
N
1
2
3
iii
OCH3
NH
O
N
NH
O
O
N
N
4
Reagents and conditions: i) HN(CH ) .HCl, (CH O) , conc. HCl, ethanol, reflux, 2 h; ii) Imidazole, water,
3
2
2
n
reflux, 5 h; iii) N-(4-Methoxyphenyl)hydrazinecarboxamide, ethanol, acetic acid, rt, 18 h
Scheme 1. Synthesis of the target semicarbazones 4.
5

ACCEPTED MANUSCRIPT
3
.2. X-ray analysis
The asymmetric unit contains one independent molecule, as shown in Fig. 1. All the
bond lengths and angles are in the normal ranges [25]. The 1,3-benzodioxole ring (C1-C6,
O1, C7, and O2) forms dihedral angles of 18.62° and 22.25° with the phenyl (C15-C20) and
imidazole rings (N1,C13, N2, C11 and C12), respectively. In the crystal packing, Fig. 2,
molecules are linked via one classical intermolecular hydrogen bond and three non-classical
(Table 2).
Position for Figure 1
Position for Figure 2
Table 2
.
Hydrogen-bond geometry (Å, °) of the title compound.
D—H···A
N4—H1N4···O3
C9—H9A···O3
C10—H10A···O2
C20—H20A···O3
C21—H21A···O1
D—H
0.90(2)
0.99
0.99
0.95
H···A
1.98(2)
2.60
2.45
2.33
D···A
D—H···A
i
2.869(2) 170(2)
3.575(3) 170
3.379(3) 155
2.922(3) 120
3.217(3) 132
i
ii
iii
0.98
2.48
Symmetry codes: (i) −x+2, −y+1, −z+1; (ii) −x+1, −y+1, −z+1; (iii) x+1,
y+3/2, z+1/2.
.3. Computational studies
−
3
3
.3.1. Geometry optimization
The geometrical optimisation was carried out using the B3LYP/6-311++G(d,p) basis
set and the optimised molecular structure is shown in Fig. 3. The global minimum energy for
optimisation of the title compound was found to be -1387.86 hartrees. The bond lengths,
bond angles and dihedral angles are presented in Table 3. The optimised parameters were
calculated in the gas phase and compared with the XRD results. The statistical linear
regression plots between the experimental XRD values and theoretical geometrical
parameters, such as bond lengths and angles, showed good agreement, as shown in Figs. S1a
2
and b. The R values for bond lengths and bond angles are 0.9913 and 0.9370, respectively.
The root-mean square deviation (RMSD) value of the theoretical bond lengths from the
experimental XRD values was calculated to be 0.0197 Å. Likewise, the RMSD value for the
predicted bond angles was found to be 0.3663° from their experimental XRD results. This
indicates that the calculated bond lengths and bond angles are in better agreement with the
experimental XRD values. C15-N16 manifested the shortest C-N bond length (1.291 Å),
while C41-N44 displayed the longest C-N bond length (1.4558 Å), which is shorter than the
normal C-N bond length (1.480 Å). The conjugation of π-type electrons of the carbonyl group
and nitrogen atom causes the possible deviation of the bond lengths of C19-N17 (1.4053 Å)
6

ACCEPTED MANUSCRIPT
and C19-N21 (1.3621 Å). The lone pair interactions of the nitrogen atoms in the imidazole
ring affect the C45-N44 (1.369Å) and C45-N46 (1.3131 Å) bond lengths and make them
shorter than other C-N bonds in the imidazole ring. The distance between O20…and H29 is
2
.251 Å, which is shorter than the van der Waal’s radius (2.75 Å), suggesting the possibility
of hydrogen bonding (C24-H29….O20). The bond lengths between N17-H18 and N21-H22
are 1.0134 and 1.0116 Å, respectively, and they showed a slight deviation from the normal
N-H bond lengths, possibly due to the carbonyl group conjugation. The calculated bond
length of N16-N17 is 1.3536 Å. C38-C41 manifested a relatively longer bond length (1.5464
Å) than the other C-C bonds. The C-H bond lengths in the phenyl ring vary from 1.0795 Å
(C24-H29) to 1.0857 Å (C28-H37) and it seems that the C-H bond lengths in the other rings
do not deviate much. The para substituted phenyl ring is planar with a C19-N21-C23-C28
amide dihedral angle of 178.64°. The calculated bond angles C2-O1-C9 (105.23°), C7-O8-C9
(105.29°) and C24-C23-C28 (118.81°) seem to be consistent with the experimental values.
Moreover, the computed dihedral angles of H10-C3-C4-C5 (179.86°), H12-C6-C7-C2
(178.47°) and N17-C19-N21-C23 (178.67°) closely agree with the experimental values.
Position for Figure 3
Table 3. Selected structural geometry parameters of the title compound along with the
recorded XRD results.
Bond
Lengths
Calculated
Values
Expt.
Values
(Å)
Bond Angles
Calculated Expt.
Dihedral Angles
Calculated Expt.
Values
Values
Values
Values
0
0
0
0
(Å)
( )
( )
( )
( )
O1-C2
O1-C9
C2-C3
C2-C7
C3-C4
C3-H10
C4-C5
C4-H11
C5-C6
C5-1C15
C6-C7
1.3698 1.377
1.4355 1.423
1.3763 1.364
1.3938 1.375
1.4041 1.396
1.0822 0.951
1.4017 1.385
1.0818 0.950
1.4171 1.403
1.4846 1.496
1.372 1.358
1.0807 0.949
1.3736 1.375
1.433 1.423
1.0889 0.990
1.0966 0.990
1.291 1.278
1.5142 1.515
1.3536 1.371
1.0134 0.900
1.4053 1.382
1.2203 1.229
1.3621 1.346
1.0116 0.862
1.4129 1.414
1.3952 1.378
1.4036 1.388
C2-O1-C9
O1-C2-C3
O1-C2-C7
C3-C2-C7
C2-C3-C4
C2-C3-H10
C4-C3-H10
3C-4C-5C
C3-C4-H11
C5-C4-H11
C4-C5-C6
C4-C5-C15
C6-C5-C15
C5-C6-C7
C5-C6-H12
C7-C6-H12
C2-C7-C6
C2-C7-O8
C6-C7-O8
C7-O8-C9
O1-C9-O8
O1-C9-H13
O1-C9-H14
O8-C9-H13
O8-C9-H14
H13-C9-H14
C5-C15-N16
105.2337 105.60
128.9061 128.66
109.6409 110.27
121.3972 121.07
117.0375 117.29
121.5067 121.37
121.4556 121.34
122.23 122.00
117.5103 118.97
120.2351 119.02
119.2841 119.17
121.6416 121.89
119.0708 118.94
117.7374 117.89
120.7218 121.05
121.5337 121.07
122.3085 122.55
109.3309 109.41
128.2959 128.03
105.2907 106.18
107.2095 108.46
109.422 109.95
109.2187 110.06
109.5322 110.00
109.4294 109.96
111.9128 108.41
116.5815 114.33
C9-O1-C2-C3
C9-O1-C2-C7
C2-O1-C9-O8
C2-O1-O9-H13
C2-O1-C9-H14
O1-C2-C3-C4
O1-C2-C3-H10
C7-C2-C3-C4
C7-C2-C3-H10
O1-C2-C7-C6
O1-C2-C7-O8
C3-C2-C7-C6
C3-C2-C7-O8
C2-C3-C4-C5
C2-C3-C4-H11
H10-C3-C4-C5
H10-C3-C4-H11
C3-C4-C5-C6
C3-C4-C5-C15
H11-C4-C5-C6
H11-C4-C5-C15
C4-C5-C6-C7
C4-C5-C6-H12
C15-C5-C6-C7
C15-C5-C6-H12
C4-C5-C15-N16
C4-C5-C15-C38
-171.920 179.36
10.8116 -1.48
-17.5815 2.67
-136.289 -117.64
100.8927 123.00
-177.285 -179.91
2.8252 0.03
-0.2992 1.01
179.8108 -179.05
177.5332 178.98
0.233 -0.31
0.0234 -1.79
-177.277 178.92
-0.0265 0.21
-178.224 -179.81
179.8636 -179.73
1.666 0.25
C6-H12
C7-O8
O8-C9
C9-H13
C9-H14
C15-N16
C15-C38
N16-N17
N17-H18
N17-C19
C19-O10
C19-N21
N21-H22
N21-C23
C23-C24
C23-C28
0.6158 -0.72
-178.704 179.66
178.7656 179.31
-0.554 -0.32
-0.8648 0.00
178.1835 179.94
178.4724 179.64
-2.4793 -0.42
155.1131 161.61
-28.6074 -20.82
7

ACCEPTED MANUSCRIPT
C24-C25
C24-H29
C25-C26
C25-H30
C26-C27
C26-O31
C27-C28
C27-H36
C28-H37
O31-C32
C32-H33
C32-H34
C32-H35
C38-H39
C38-H40
C38-C41
C41-H42
C41-H43
C41-N44
N44-C45
N44-C48
C45-N46
C45-H49
N46-C47
C47-C48
C47-H50
C48-H51
1.3974 1.394
1.0795 0.951
1.3945 1.377
1.0817 0.950
1.3994 1.382
1.3678 1.379
1.3844 1.370
1.0832 0.950
1.0857 0.950
1.4201 1.409
1.0958 0.980
1.0889 0.981
1.0957 0.980
1.0942 0.990
1.0893 0.990
1.5464 1.533
1.0924 0.990
1.0916 0.990
1.4558 1.459
1.369 1.340
1.3823 1.358
1.3131 1.312
1.0804 0.950
1.3753 1.354
1.3713 1.341
1.0789 0.950
1.0779 0.950
C5-C15-C38
119.9474 118.63
123.359 126.99
120.9458 122.41
123.0733 127.45
122.0215 117.65
113.5665 114.62
118.9839 120.75
113.716 114.43
127.2964 124.82
114.53 111.72
128.1819 128.99
117.2736 119.20
123.8852 124.45
117.3035 116.65
118.8112 118.90
120.2076 120.30
119.7105 119.81
120.0818 119.89
120.6921 120.04
118.3096 119.90
120.9984 120.06
119.0912 119.66
124.973 124.74
115.9358 115.60
120.2394 120.16
118.8928 119.92
120.8678 119.92
C6-C5-C15-N16
C6-C5-C15-C38
C5-C6-C7-C2
C5-C6-C7-O8
H12-C6-C7-C2
H12-C6-C7-O8
C2-C7-O8-C9
C6-C7-O8-C9
C7-O8-C9-O1
-24.2078 -18.02
152.0717 159.55
0.5662 1.23
177.3195 -179.62
-178.474 -178.71
-1.7206 0.44
-11.1949 1.97
171.7128 -177.27
17.7249 -2.87
136.3608 117.41
-100.613 -123.27
176.2862 179.78
0.146 2.45
148.9786 175.63
31.9565 56.95
-88.5126 -63.71
-35.0053 -7.15
-152.027 -125.82
87.5035 113.52
6.9786 8.38
N16-C15-C38
C15-N16-N17
N16-N17-H18
N16-N17-C19
H18-N17-C19
N17-C19-O20
N17-C19-N21
O20-C19-N21
C19-N21-H22
C19-N21-C23
H22-N21-C23
N21-C23-C24
N21-C23-C28
C24-C23-C28
C23-C24-C25
C23-C24-H29
C25-C24-H29
C24-C25-C26
C24-C25-H30
C26-C25-H30
C25-C26-C27
C25-C26-O31
C27-C26-O31
C26-C27-C28
C26-C27-H36
C28-C27-H36
C7-O8-C9-H13
C7-O8-C9-H14
C5-C15-N16-N17
C38-C15-N16-N17
C5-C15-C38-H39
C5-C15-C38-H40
C5-C15-C38-C41
N16-C15-C38-H39
N16-C15-C38-H40
N16-C15-C38-C41
C15-N16-N17-H18
C15-N16-N17-C19
N16-N17-C19-O20
N16-N17-C19-N21
H18-N17-C19-O20
H18-N17-C19-N21
N17-C19-N21-H22
N17-C19-N21-C23
172.9117 -177.98
-176.004 -175.61
4.6533 4.37
-8.8427 -1.16
171.8147 178.82
-2.7691 -1.41
178.6681 -178.05
3
.3.2. Natural bond orbital (NBO) analysis
Hyperconjugative and conjugative interactions, hydrogen bonding, intramolecular
charge transfer interactions and charge delocalisation within the molecule are better
explained with the help of NBO analysis. The title compound was subjected to NBO analysis
using the NBO 3.1 program and the results are presented in Table 4. The charge transfer
interaction from LP(1) O20 to σ* (C24-H29) confirms the intramolecular C-H…O hydrogen
bonding with an energy (E(2)) of 10.53 kcal/mol. LP(1) O20 → σ* C24-H29 with an energy
value of 10.53 kcal/mol manifested the interaction between electron donors and acceptors.
The energy of the π (C2-C3) →π* (C6-C7) interaction is 19.43 kcal/mol, which is greater
than π (C2-C3) →π* (C4-C5) due to the attachment of the electronegative O8 to C7. The
interaction energy of σ (C2-C3) →σ* (C2-C7) is 14.47 kcal/mol and it is greater than σ (C2-
C3) →σ* (C3-C4) (12.51 kcal/mol) due to the nearby oxygen. The LP(2) O20 → σ* (N17-
C19) interaction yielded an energy of 25.28 kcal/mol, while LP(2) O20 → σ* (C19-N21)
gave an energy of 23.08 kcal/mol. The former energy is higher due to the attachment of N16
to N17. The interaction energies of LP(2) O31 → σ* (C32-H33) and LP(2) O31 → π* (C25-
C26) are 10.71 and 28.52 kcal/mol, respectively. The higher E(2) value of the latter
interaction implies that the presence of oxygen and nitrogen nearby the phenyl ring affects
the intramolecular charge transfer. The lone pair LP(2) O31 interacts with the antibonding
8

ACCEPTED MANUSCRIPT
orbital σ* C32-H33 with an energy value of 10.71 kcal/mol, confirming the C-H…O
hydrogen bonding and giving rise to the possibility of binding of the title compound to its
target protein. Moreover, the results of the NBO analysis can identify the efficiency of donor
and acceptor groups within the title compound, which supports its interaction with the target
protein.
Table 4. Selected donor-acceptor interactions results of the title compound based on second-
order perturbation theory in Fock matrix.
a
b
c
Donor (i)
ED (i)e
Acceptor (i)
ED (j)e
E(2)
kcal/mol)
E(j)-E(i)
(a..u.)
0.30
0.30
0.28
0.28
0.27
0.29
0.30
1.27
1.29
0.28
0.29
0.29
0.29
0.28
0.35
0.36
0.78
0.29
0.64
0.71
1.17
0.30
0.34
0.69
0.28
F(i,j)
(
(a..u.)
0.069
0.069
0.064
0.062
0.059
0.070
0.067
0.068
0.051
0.065
0.070
0.066
0.068
0.061
0.092
0.091
0.083
0.087
0.116
0.117
0.022
0.090
0.094
0.058
0.102
π C2 - C3
π C2 - C3
π C4 - C5
π C4 - C5
π C4 - C5
π C6 - C7
π C6 - C7
σ C2 - C3
1.68826 π * C4-C5
1.68826 π * C6-C7
1.68925 π * C2-C3
1.68925 π * C6-C7
0.38017
0.34163
0.36664
0.34163
19.02
19.43
17.75
17.02
15.63
19.90
18.03
14.47
12.51
18.36
20.47
17.94
18.93
15.10
26.94
26.03
10.80
31.90
25.28
23.08
10.53
32.67
28.52
10.71
45.67
1.68925 π* C15-N16 0.23453
1.70539 π * C2-C3
1.70539 π * C4-C5
1.97482 σ * C2-C7
1.97482 σ * C3-C4
1.66396 π* C25-C26 0.39083
1.67132 π* C23-C24 0.38080
1.73229 π *C23-C24 0.38080
1.73229 π* C25-C26 0.39083
1.85707 π* C45-N46 0.37848
0.36664
0.38017
0.03933
0.01177
σ C2 - C3
π C23 - C24
π C25 - C26
π C27 - C28
π C27 - C28
π C47 - C48
LP (2) O1
LP (2) O8
LP (1) N16
LP (1) N17
LP (2) O20
LP (2) O20
LP (1) O20
LP (1) N21
LP (2) O31
LP (2) O31
LP (1) N44
1.85282 π * C2-C3
1.85920 π * C6-C7
0.36664
0.34163
1.91031 σ* C15-C38 0.03546
1.70419 π* C15-N16 0.23453
1.84694 σ* N17-C19 0.08098
1.84694 σ* C19-N21 0.07040
1.97871 σ* C24-H29 0.01421
1.68358 π* C23-C24 0.38080
1.84921 π* C25-C26 0.39083
1.84921 σ* C32-H33 0.01950
1.56078 π* C45-N46 0.37848
a
b
Energy of hyperconjugative interactions; Energy difference between donor and
acceptor i and j NBO orbitals; Fock matrix element between i and j NBO orbitals.
c
3
.3.3. Natural population analysis (NPA) and Molecular electrostatic potential (MEP)
The calculation of atomic charges plays an important role in molecular systems.
Molecular properties, like electronic structure, molecular polarisability and dipole moment,
are influenced by atomic charges. The atomic charges of the title compound were calculated
by natural population analysis. It is an effective method to calculate the atomic charges
within the molecule and it gives the exact charge on the atoms. Natural population analysis of
the title compound was calculated using the DFT/B3LYP/6-311++G(d,p) level of basis set. A
plot of the charge distribution is shown in Fig. 4. Carbon atom C19 (0.8038 e) manifested the
9

ACCEPTED MANUSCRIPT
highest positive charge in the title molecule due to its direct attachment with the
electronegative atoms O20, N17 and N21 and O20 participates in the C24-H29…O20
hydrogen bonding. Moreover, the carbon atoms C2 (0.274 e), C7 (0.267 e), C9 (0.305 e), C15
(0.225 e), C23 (0.132 e), C26 (0.302 e) and C45 (0.206 e) showed more positive charges than
the other carbon atoms in the molecule due to their direct attachment to either oxygen or
nitrogen electronegative atoms. All hydrogen atoms showed positive charges, whereas H18
and H22 displayed more positive charges owing to their direct attachment to N17 and N21,
respectively.
Position for Figure 4
The molecular electrostatic potential (MEP) analysis helps the understanding of
relative polarity, partial charges and sites of chemical reactivity and hydrogen bonding of the
molecule. The molecular electrostatic potential maps of the title compound in solid, mesh and
transparent forms are shown in Fig. S2 a, b and c, respectively. The MEP map of the title
-2
-2
molecule is in the range of -5.638e × 10 to 5.638e × 10 . Its range of electrostatic potential
can be analysed by different colour codes. Electrostatic potential is in the following order: red
<
orange < yellow < green < blue. In the MEP plot the regions around the electronegative
atoms like oxygen and nitrogen have negative potential and shows slight red and orange
colours. Whereas, the carbon and hydrogen atoms have positive potential and the regions
around these atoms show green and blue colours. The red colour around O20 atom suggests
the possibility of formation of C24-H29….O20 hydrogen bonding.
3
.3.4. Frontier molecular orbital (FMO) analysis
The kinetic stability of a molecule is determined by the highest occupied molecular
orbital (HOMO) and lowest unoccupied molecular orbital (LUMO), and their energy gap
reflects the chemical reactivity of the molecule. The frontier molecular orbital plays an
important role in the electric and optical properties of the molecule [26]. The HOMO, LUMO
and their energy gap for the title compound were calculated using the DFT/B3LYP/6-
3
11++G(d,p) level of basis set. The HOMO value is related to the ionisation potential (IP = -
EHOMO), whereas the LUMO value is related to the electron affinity (EA = -ELUMO). HOMO
and LUMO plots are shown in Fig. 5. The HOMO is mainly localised on the phenyl ring,
while the LUMO is localised on the benzodioxole ring. The HOMO and LUMO energies
were found to be -5.72 and -1.81 eV, respectively, and the calculated value of the energy gap
is 3.91 eV. The HOMO-LUMO energy gap reveals the possibility of intramolecular charge
1
0

ACCEPTED MANUSCRIPT
transfer within the molecule. The global hardness (η) and softness (σ) of the title molecule are
-1
1
.96 eV and 0.51 (eV) using the relations η=IP-EA/2 and σ=1/ η, respectively.
Position for Figure 5
3
.3.5. Vibrational spectral analysis
The spectroscopic properties of the title compound are analysed by FT-IR, FT-Raman and the
vibrational frequencies are calculated using DFT and compared with the experimental data.
The observed and simulated FT-IR and FT-Raman spectra are shown in Figs. 6 and 7,
respectively. The computed and experimental wavenumbers and their assignments with
potential energy distribution (PED) values are presented in Table 5.
•
•
Position for Figure 6
Position for Figure 7
Table 5. Vibrational assignments of the title compound based on potential energy distribution
analysis.
Calculated
Experimental
wavenumbers
wavenumbers
Assignment with PED (%)
-
1
-1
(
cm )
(cm )
IR
Raman
3
3
3
3
3
3
2
2
2
2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
462
399
325
203
132
090
998
960
944
903
664
604
580
519
441
398
346
339
311
288
267
240
175
129
3451 vw
3381 s
3316 w
3197 s
3132 m
3078 m
3001 m
2963 m
2936 m
2894 m
1660 vs
1609 s
-
-
-
-
-
-
ν N21-H22 (99) Amide
ν N17-H18
ν N21-H22
ν N17-H18
ν C48-H51 (24),C47-H50 (75)
3079 m ν C27-H36 (95)
ν41C-43H (92)
2964 m ν CH (92) MeI (42)
as
2
ν CH (91) MeII (88)
as
2
2902 w νC38-H39 (88)
1667 w ν C19=O20 (77)
1618 s
1580 vs ν N16-C15 (33)
1509 m ν C19-N21 (14)
1438 s
1395 w β H29-C24-C25 (10)
1351 w W H42-C41-H43 (48)
β H50-C47-C48 (10)
ν C27-C28 (33)
1519 vs
1436 vs
-
d H42-C41-H43 (53)
-
1338 s
1304 s
β C23-C28 (10),C23-C24 (17),C25-C26 (12)
1287 w d H29-C24-C25 (12),H30-C25-C26 (10)
β H50-C47-C48 (25),H51-C48-C47 (13)
d H40-C38-C15-C5 (17)
1179 w νR H13-C9-O8 (74)
1134 w ρ –OCH (83)
1277 s
1242 vs
1179 s
1135 s
3
1
102 s
-
β C9-O1-O8-H13 (76),H37-C28-C27 (16),H36-
1
1
9
9
103
032
94
C27-C28(25)
1044 w W H39-C38-H40 (39)
1038 vs
997 m
947 m
-
-
ϒ C23-C28 (20),C24-C25-C26 (10)
ϒ C24-C23-C25-H29 (56),H30-C25-C26-O31
20),H36-C27-C28-H37 (12)
ϒ C7-C2-O1 (67)
33
(
9
16
920 w
-
1
1

ACCEPTED MANUSCRIPT
8
8
8
8
8
7
6
6
5
5
4
82
53
38
04
00
49
68
15
85
09
54
875 w
-
-
ϒ C3-C4-C5 (22)
858 w
827 m
νC19-N21 (15),N21-C23 (13),C23-C24 (17)
ϒ H51-C48-C47-N46 (11),C47-C48-N46-H50 (81)
ϒ O1-C2-C3 (14)
ϒ C2-C7-C6 (20)
ρ H39-C38-C15-C5 (11), H42-C41-N44-C45 (19)
δ N17-C19=O20 (14)
807 w
800 m
750 m
664 m
619 w
591 m
512 w
464 vw
-
-
-
-
-
-
-
ϒ N44-C48-C47-N46 (54)
τ C25-C26-C27 (12),C5-C15-N16 (10)
τ C24-C25-C26-C27 (55),C28-C27-C26-O31 (20)
δ C3-C2-C7 (16),N17-C19-O20 (12)
ν – stretching, ν -asymmetric stretching, ν –ring stretching, β – in plane bending, W – wagging, d –
as
R
deformation, ρ – rocking, δ – bending, ϒ – out of plane bending, τ – torsion, Me I- methylene I, Me II -
methylene II, , vs- very strong, s- strong, m- medium, w- weak, vw- very weak.
3
.3.5.1. Imidazol ring vibrations
-
The calculated FT-IR imidazole C-H stretching vibrations appeared at 3145–3115 cm
1
-1
and were observed at 3132 cm . Imidazole ring C=C stretching vibrations normally appear
-1
in the region of 1605–1585 cm [27] and this vibration is experimentally recorded as a strong
-1
absorption band at 1580 cm in the FT-Raman spectrum of the title compound. The C-H in-
-1
plane bending vibrations were observed at 1395 cm in the FT-Raman spectrum of the title
-1
compound and at 1338, 1304 and 1277 cm with strong intensities in its FT-IR spectrum,
which agrees with the literature data. The C-H out-of-plane bending and torsional vibrations
-1
are observed at 619, 591 and 512 cm in the FT-IR spectrum of the title compound.
.3.5.2. Benzodioxole ring vibrations
C-H stretching vibrations are normally observed in the region of 3100–3000 cm [28].
3
-1
-1
A FT-IR band of medium intensity at 3001 cm was assigned to this vibration in the title
-1
compound. The ring stretching C-C vibration was observed at 1179 cm for both FT-IR and
-1
FT-Raman spectra of the title compound. The strong FT-IR absorption band at 1102 cm
corresponds to the C-H in-plane bending mode. The C-H out-of-plane bending vibrations are
-1
also observed for the title compound at 920, 827 and 800 cm in the FT-IR spectrum and at
-1
8
75 and 807 cm in the FT-Raman spectrum, in agreement with the reported values.
.3.5.3. Methylene groups vibrations
3
Asymmetric stretching vibrations of methylene groups are reported in the region of
-1
2
930 cm [28]. The methylene groups in the title compound showed an asymmetric
-1
stretching band of medium intensity at 2936 cm in its FT-IR spectrum. The CH vibrations
2
-1
-1
are reported in the region of 2926–2855 cm [29] and were observed at 2902 and 2894 cm
in the FT-Raman and FT-IR spectra of the title compound, respectively. The twisting and
-1
-1
wagging vibrations usually appear at 1422–719 cm and they were noticed at 1351 cm in
-1
the FT-Raman spectrum of the title compound and at 750 cm in its FT-IR spectrum.
1
2

ACCEPTED MANUSCRIPT
3
.3.5.4. Carboxamide (secondary amide) vibrations
The absorption bands of amides are influenced by the hydrogen bonding and the
substituents on the nitrogen atom. Amide N-H stretching vibrations usually occur in the
-1
region of 3460–3300 cm [30], which was noticed as weak to strong absorptions at 3451,
-1
3
316, 3381 and 3197 cm in the FT-IR spectrum of the title molecule. The C=O stretching
-1
vibrations normally show peaks at 1680–1630 cm . The title compound manifested a very
-1
-1
strong C=O peak at 1660 cm in its FT-IR spectrum and as a weak band at 1667 cm in its
FT-Raman spectrum. Due to N-H bending motion, secondary amides have absorption bands
-1
in the range of 1570–1515 cm and they were observed as a very strong FT-IR band at 1519
-1
-1
cm and as a medium band at 1509 cm in the FT-Raman spectrum of the title molecule. The
bending motion of the O=C-N group causes amides to have bands in the region of 695–550
-1
-1
cm , which was observed as a medium band at 664 cm in the FT-IR spectrum of the title
-1
molecule. Amides also show absorption bands in the region of 520–430 cm , which occurred
-1
at 464 cm in the FT-IR spectrum of the title compound.
3
.3.5.5. Phenyl ring vibrations
The aromatic C-H stretching vibrations of the phenyl ring usually appear at 3080–
-1
-1
3
010 cm [28], which were noted as medium intense bands at 3079 and 3078 cm in the FT-
Raman and FT-IR spectra of the title compound, respectively. Strong bands at 1618 and 1609
-1
cm in the FT-Raman and FT-IR spectra of the title compound, respectively, correspond to
the aromatic C=C stretching vibrations, which normally appear in the region of 1625–1430
-1
-1
cm [30]. The in-plane C-H deformation vibrations occur at 1290–1000 cm and the band
-1
observed at 1287 cm in FT-Raman spectrum of the title compound and a very strong
-1
absorption at 1242 cm in its FT-IR were assigned to this vibration. The C-H out-of-plane
-1
vibrations were noticed at 997 and 947 cm in the FT-IR spectrum of the title molecule,
-1
which usually fall in the region of 1000–700 cm .
.3.5.6. Methoxy group vibrations
Asymmetric methoxy vibrations normally lie between 3030 and 2950 cm [29]. The
3
-1
-1
medium intense bands at 2964 cm in the FT-Raman spectrum of the title molecule and at
-1
2
963 cm in its FT-IR spectrum were assigned to these vibrations. Asymmetric methoxy
-1
-1
deformation occurs in the region of 1475–1435 cm and it was noticed at 1438 and 1436 cm
in the FT-Raman and FT-IR spectra of the title compound, respectively, with strong
-1
absorption. The OCH rocking vibrations were reported at 1190–1100 cm and were
3
-1
-1
manifested at 1134 cm in the FT-Raman spectrum of the title compound and at 1135 cm in
its FT-IR spectrum.
1
3

ACCEPTED MANUSCRIPT
3
.3.5.7. Skeletal mode vibrations
The C-N and C-C stretching vibrations usually appear in the 1150–850 cm region
30]. The C-N vibrations are difficult to identify as they usually couple with other bands. A
-1
[
-1
weak band was observed at 858 cm in the FT-IR spectrum of the title molecule, which is
attributed to this vibration.
3
.4. Antifungal activity
The antifungal activity of the title compound was assessed in vitro against C.
albicans, C. tropicalis, C. parapsilosis as well as A. niger fungal strains according to the
literature procedure [15] and the results are illustrated in Table 6. The title molecule exhibited
a MIC value of 0.628 µmol/mL against C. albicans, C. parapsilosis and A. niger, while it
showed a MIC value of 0.314 µmol/mL against C. tropicalis.
Table 6. Antifungal activity of the title compound towards C. albicans, C. tropicalis, C.
parapsilosis and A. niger.
Compound
No.
MIC (µmol/mL)
Candida albicans Candida tropicalis Candida parapsilosis Asperagillus niger
4
0.628
.051
ND
0.314
0.628
0.047
ND
0.628
ND
Fluconazole
Ketoconazole
0
0.045
ND
0.02
3
.5. Molecular docking studies
Molecular docking is used to predict the binding orientation of small drug candidate
molecules to their protein targets. Hence, docking plays an important role in rational drug
design. AutoDock is an automated procedure for predicting the interaction of ligands with bio
macromolecular targets. In the present study, AutoDock 4.2 software interfaced with
AutoDockTools v1.5.6rc3 based on the Lamarckian genetic algorithm [24] was used to
perform molecular docking investigations. The X-ray crystal structure of human CYP3A4
(PDB Code :4D6Z) [31] with a resolution of 1.93 Å was selected from the Research
Collaboratory for Structural Bioinformatics protein data bank. CYP3A4 is involved in the
metabolism of xenobiotics and can enhance the therapeutic efficiency of the co-administered
pharmaceuticals that are metabolized by CYP3A4.
Rigid docking was performed by the AutoDockTools program and visualised using
PyMOL v1.2r1 [32]. The grid box size of 100 × 100 × 100 points was set with a spacing of
0
.79 Å over the target protein binding pocket.
1
4

ACCEPTED MANUSCRIPT
The predicted of C-H…O hydrogen bonding NBO analysis, stabilises the protein-
ligand interaction. The amino acid residue ARG 105 in the active site of the CYP3A4 protein
interacts with the title molecule by C-H…O hydrogen bonding and stabilises the CYP3A4-
ligand complex (Fig. 8). While, the presence of phenyl group in the title molecule increases
its binding affinity.
Out of 100 genetic algorithm runs, the best docked conformation had a binding energy
of -8.88 kcal/mol with an estimated inhibition constant of 310.7 nM. The binding affinity of
the title compound to the CYP3A4 protein might be beneficial and promote the biological
activity of the simultaneous administered bioactive compounds that are metabolised by
CYP3A4.
Position for Figure 8
4
. Conclusions
The molecular hybrid (E)-2-(1,3-benzodioxol-5-yl)-3-(1H-imidazol-1-yl)propyl
idene-N-(4-methoxyphenyl)hydrazinecarboxamide was synthesised to be evaluated as a new
antifungal candidate. The assigned chemical structure of the title compound was confirmed
using different spectroscopic techniques. The (E)-configuration of the imine double bond of
the title compound was unambiguously determined via its single crystal X-ray analysis. DFT
computations were carried out at the DFT/B3LYP method. The optimised geometric
parameters and the calculated vibrational frequencies are in a good agreement with the
experimental values. Charge transfer interactions within the title molecule were explored by
HOMO-LUMO investigations and NBO analysis suggested possible hydrogen bonding
formation. In vitro antifungal screening of the title compound towards four fungal strains
revealed its antifungal activity against C. tropicalis with a MIC value of 0.314 µmol/mL and
against C. albicans, C. parapsilosis and A. niger with a MIC value of 0.628 µmol/mL.
Moreover, the molecular docking study showed the possible binding mode of the title
compound to the 4D6Z protein. It is believed that the results of the current study could be
harnessed to support the development of new potent and safe antifungal drug-like candidates.
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. RG-1438-083.
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7
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[
[
[
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Figures captions
Scheme 1. Synthesis of the target semicarbazone 4.
Fig. 1. ORTEP diagram of the titled compound. Displacement ellipsoids are plotted at the
4
0% probability level for non-hydrogen atoms.
Fig. 2. Molecular packing of titled compound viewed hydrogen bonds which are drawn as
dashed lines along a axis.
Fig. 3. Optimized molecular structure of the title compound.
Fig. 4. Charge distribution chart for the title compound according to the natural population
analysis.
Fig. 5. HOMO (upper) and LUMO (lower) energy plots of the title compound.
Fig. 6. (a) Experimental (b) Simulated infrared spectra of the title compound in the region
-1
4
000-500 cm .
Fig. 7. (a) Experimental (b) Simulated Raman spectra of the title compound in the region
-
1
3
500-50 cm .
Fig. 8. Binding pose diagram with protein-ligand interactions of the title compound.
1
9

ACCEPTED MANUSCRIPT
Table 1. Experimental X-ray details the title compound.
Crystal data
Chemical formula
C H N O
4
21
21
5
Mr
4
07.43
Crystal system, space group
Monoclinic, P2 /c
1
Temperature (K)
a, b, c (Å)
β (°)
2
1
9
1
4
96
0.7007 (4), 7.3072 (3), 24.9088 (8)
7.178 (2)
V (Å3)
932.41 (12)
Z
Radiation type
Cu Kα
−1
µ (mm )
0
.82
Crystal size (mm)
Data collection
Diffractometer
0
.36 × 0.15 × 0.11
Bruker APEX-II D8 venture
diffractometer
Absorption correction
Tmin, Tmax
Multi-scan SADABS Bruker 2014
0.757, 0.913
9324, 3380, 2388
0.039
No. of measured, independent and
observed [I> 2σ(I)] reflections
Rint
Refinement
2
2
2
R[F > 2σ( F )], wR( F ), S
No. of reflections
No. of parameters
No. of restraints
0
3
2
0
.049, 0.132, 1.06
380
80
H-atom treatment
H atoms treated by a mixture of
independent and constrained
refinement
−
3
ꢀ
ρmax, ꢀρmin (e Å )
0
.22, −0.23

ACCEPTED MANUSCRIPT
Table 2
.
Hydrogen-bond geometry (Å, °) the title compound.
D—H···A
D—H
0.90(2)
0.99
H···A
D···A
D—H···A
i
N4—H1N4···O3
1.98(2) 2.869(2) 170(2)
i
C9—H9A···O3
2.60
2.45
3.575(3) 170
3.379(3) 155
C10—
H10A···O2
0.99
ii
C20—H20A···O3 0.95
2.33
2.48
2.922(3) 120
3.217(3) 132
C21—
0.98
iii
H21A···O1
Symmetry codes: (i) −x+2, −y+1, −z+1; (ii) −x+1, −y+1, −z+1; (iii)
x+1, −y+3/2, z+1/2.

ACCEPTED MANUSCRIPT
Table 3. Selected structural geometry parameters of the title compound along with the
recorded XRD results.
Bond Length Calculated
Value
Expt.
Value
Bond Angle
Calculated Expt.
Dihedral Angle
Calculated Expt.
Value
Value
Value
Value
0
0
0
0
(Å)
(Å)
( )
( )
( )
( )
O1-C2
1.3698 1.377
1.4355 1.423
1.3763 1.364
1.3938 1.375
1.4041 1.396
1.0822 0.951
1.4017 1.385
1.0818 0.950
1.4171 1.403
1.4846 1.496
1.372 1.358
1.0807 0.949
1.3736 1.375
1.433 1.423
1.0889 0.990
1.0966 0.990
1.291 1.278
1.5142 1.515
1.3536 1.371
1.0134 0.900
1.4053 1.382
1.2203 1.229
1.3621 1.346
1.0116 0.862
1.4129 1.414
1.3952 1.378
1.4036 1.388
1.3974 1.394
1.0795 0.951
1.3945 1.377
C2-O1-C9
O1-C2-C3
O1-C2-C7
C3-C2-C7
105.2337 105.60
128.9061 128.66
109.6409 110.27
121.3972 121.07
117.0375 117.29
121.5067 121.37
121.4556 121.34
122.23 122.00
C9-O1-C2-C3
C9-O1-C2-C7
C2-O1-C9-O8
C2-O1-O9-H13
C2-O1-C9-H14
O1-C2-C3-C4
O1-C2-C3-H10
C7-C2-C3-C4
C7-C2-C3-H10
O1-C2-C7-C6
O1-C2-C7-O8
C3-C2-C7-C6
C3-C2-C7-O8
C2-C3-C4-C5
C2-C3-C4-H11
H10-C3-C4-C5
H10-C3-C4-H11
C3-C4-C5-C6
C3-C4-C5-C15
H11-C4-C5-C6
H11-C4-C5-C15
C4-C5-C6-C7
C4-C5-C6-H12
C15-C5-C6-C7
C15-C5-C6-H12
C4-C5-C15-N16
C4-C5-C15-C38
C6-C5-C15-N16
C6-C5-C15-C38
C5-C6-C7-C2
-171.920 179.36
10.8116 -1.48
-17.5815 2.67
-136.289 -117.64
100.8927 123.00
-177.285 -179.91
2.8252 0.03
O1-C9
C2-C3
C2-C7
C3-C4
C2-C3-C4
C3-H10
C4-C5
C2-C3-H10
C4-C3-H10
3C-4C-5C
C4-H11
C5-C6
-0.2992 1.01
C3-C4-H11
C5-C4-H11
C4-C5-C6
117.5103 118.97
120.2351 119.02
119.2841 119.17
121.6416 121.89
119.0708 118.94
117.7374 117.89
120.7218 121.05
121.5337 121.07
122.3085 122.55
109.3309 109.41
128.2959 128.03
105.2907 106.18
107.2095 108.46
109.422 109.95
109.2187 110.06
109.5322 110.00
109.4294 109.96
111.9128 108.41
116.5815 114.33
119.9474 118.63
123.359 126.99
120.9458 122.41
179.8108 -179.05
177.5332 178.98
0.233 -0.31
C5-1C15
C6-C7
C6-H12
C7-O8
C4-C5-C15
C6-C5-C15
C5-C6-C7
0.0234 -1.79
-177.277 178.92
-0.0265 0.21
O8-C9
C9-H13
C9-H14
C15-N16
C15-C38
N16-N17
N17-H18
N17-C19
C19-O10
C19-N21
N21-H22
N21-C23
C23-C24
C23-C28
C24-C25
C24-H29
C25-C26
C5-C6-H12
C7-C6-H12
C2-C7-C6
-178.224 -179.81
179.8636 -179.73
1.666 0.25
C2-C7-O8
C6-C7-O8
C7-O8-C9
O1-C9-O8
O1-C9-H13
O1-C9-H14
O8-C9-H13
O8-C9-H14
H13-C9-H14
C5-C15-N16
C5-C15-C38
N16-C15-C38
C15-N16-N17
0.6158 -0.72
-178.704 179.66
178.7656 179.31
-0.554 -0.32
-0.8648 0.00
178.1835 179.94
178.4724 179.64
-2.4793 -0.42
155.1131 161.61
-28.6074 -20.82
-24.2078 -18.02
152.0717 159.55
0.5662 1.23

ACCEPTED MANUSCRIPT
C25-H30
C26-C27
C26-O31
C27-C28
C27-H36
C28-H37
O31-C32
C32-H33
C32-H34
C32-H35
C38-H39
C38-H40
C38-C41
C41-H42
C41-H43
C41-N44
N44-C45
N44-C48
C45-N46
C45-H49
N46-C47
C47-C48
C47-H50
C48-H51
1.0817 0.950
1.3994 1.382
1.3678 1.379
1.3844 1.370
1.0832 0.950
1.0857 0.950
1.4201 1.409
1.0958 0.980
1.0889 0.981
1.0957 0.980
1.0942 0.990
1.0893 0.990
1.5464 1.533
1.0924 0.990
1.0916 0.990
1.4558 1.459
1.369 1.340
1.3823 1.358
1.3131 1.312
1.0804 0.950
1.3753 1.354
1.3713 1.341
1.0789 0.950
1.0779 0.950
N16-N17-H18
N16-N17-C19
H18-N17-C19
N17-C19-O20
N17-C19-N21
O20-C19-N21
C19-N21-H22
C19-N21-C23
H22-N21-C23
N21-C23-C24
N21-C23-C28
C24-C23-C28
C23-C24-C25
C23-C24-H29
C25-C24-H29
C24-C25-C26
C24-C25-H30
C26-C25-H30
C25-C26-C27
C25-C26-O31
C27-C26-O31
C26-C27-C28
C26-C27-H36
C28-C27-H36
123.0733 127.45
122.0215 117.65
113.5665 114.62
118.9839 120.75
113.716 114.43
127.2964 124.82
114.53 111.72
C5-C6-C7-O8
177.3195 -179.62
-178.474 -178.71
-1.7206 0.44
H12-C6-C7-C2
H12-C6-C7-O8
C2-C7-O8-C9
-11.1949 1.97
171.7128 -177.27
17.7249 -2.87
136.3608 117.41
-100.613 -123.27
176.2862 179.78
0.146 2.45
C6-C7-O8-C9
C7-O8-C9-O1
C7-O8-C9-H13
128.1819 128.99
117.2736 119.20
123.8852 124.45
117.3035 116.65
118.8112 118.90
120.2076 120.30
119.7105 119.81
120.0818 119.89
120.6921 120.04
118.3096 119.90
120.9984 120.06
119.0912 119.66
124.973 124.74
115.9358 115.60
120.2394 120.16
118.8928 119.92
120.8678 119.92
C7-O8-C9-H14
C5-C15-N16-N17
C38-C15-N16-N17
C5-C15-C38-H39
C5-C15-C38-H40
C5-C15-C38-C41
N16-C15-C38-H39
N16-C15-C38-H40
N16-C15-C38-C41
C15-N16-N17-H18
C15-N16-N17-C19
N16-N17-C19-O20
N16-N17-C19-N21
H18-N17-C19-O20
H18-N17-C19-N21
N17-C19-N21-H22
N17-C19-N21-C23
148.9786 175.63
31.9565 56.95
-88.5126 -63.71
-35.0053 -7.15
-152.027 -125.82
87.5035 113.52
6.9786 8.38
172.9117 -177.98
-176.004 -175.61
4.6533 4.37
-8.8427 -1.16
171.8147 178.82
-2.7691 -1.41
178.6681 -178.05

ACCEPTED MANUSCRIPT
Table 4. Selected donor-acceptor interactions results of the title compound based on
second-order perturbation theory in Fock matrix.
a
b
c
Donor (i)
ED (i)e
Acceptor (i)
ED (j)e
E(2)
E(j)-E(i)
(a..u.)
0.30
0.30
0.28
0.28
0.27
0.29
0.30
1.27
1.29
0.28
0.29
0.29
0.29
0.28
0.35
0.36
0.78
0.29
0.64
0.71
1.17
0.30
0.34
0.69
0.28
F(i,j)
(
kcal/mol)
(a..u.)
0.069
0.069
0.064
0.062
0.059
0.070
0.067
0.068
0.051
0.065
0.070
0.066
0.068
0.061
0.092
0.091
0.083
0.087
0.116
0.117
0.022
0.090
0.094
0.058
0.102
π C2 - C3
1.68826 π * C4-C5
1.68826 π * C6-C7
1.68925 π * C2-C3
1.68925 π * C6-C7
0.38017
0.34163
0.36664
0.34163
19.02
19.43
17.75
17.02
15.63
19.90
18.03
14.47
12.51
18.36
20.47
17.94
18.93
15.10
26.94
26.03
10.80
31.90
25.28
23.08
10.53
32.67
28.52
10.71
45.67
π C2 - C3
π C4 - C5
π C4 - C5
π C4 - C5
1.68925 π* C15-N16 0.23453
π C6 - C7
1.70539 π * C2-C3
1.70539 π * C4-C5
1.97482 σ * C2-C7
1.97482 σ * C3-C4
0.36664
0.38017
0.03933
0.01177
π C6 - C7
σ C2 - C3
σ C2 - C3
π C23 - C24
π C25 - C26
π C27 - C28
π C27 - C28
π C47 - C48
LP (2) O1
LP (2) O8
LP (1) N16
LP (1) N17
LP (2) O20
LP (2) O20
LP (1) O20
LP (1) N21
LP (2) O31
LP (2) O31
LP (1) N44
1.66396 π* C25-C26 0.39083
1.67132 π* C23-C24 0.38080
1.73229 π *C23-C24 0.38080
1.73229 π* C25-C26 0.39083
1.85707 π* C45-N46 0.37848
1.85282 π * C2-C3
1.85920 π * C6-C7
0.36664
0.34163
1.91031 σ* C15-C38 0.03546
1.70419 π* C15-N16 0.23453
1.84694 σ* N17-C19 0.08098
1.84694 σ* C19-N21 0.07040
1.97871 σ* C24-H29 0.01421
1.68358 π* C23-C24 0.38080
1.84921 π* C25-C26 0.39083
1.84921 σ* C32-H33 0.01950
1.56078 π* C45-N46 0.37848

ACCEPTED MANUSCRIPT
Table 5. Vibrational assignments of the title compound based on potential energy
distribution analysis.
Calculated
Experimental
wavenumbers
wavenumbers
Assignment with PED (%)
-1
(
cm )
Raman
-
1
(
cm )
IR
3
3
3
3
3
3
2
2
2
2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
462
399
325
203
132
090
998
960
944
903
664
604
580
519
441
398
346
339
311
288
267
240
175
129
3451 vw
3381 s
3316 w
3197 s
3132 m
3078 m
3001 m
2963 m
2936 m
2894 m
1660 vs
1609 s
-
-
ν N21-H22 (99) Amide
ν N17-H18
-
-
-
-
ν N21-H22
ν N17-H18
ν C48-H51 (24),C47-H50 (75)
3079 m ν C27-H36 (95)
ν41C-43H (92)
2964 m ν CH (92) MeI (42)
as
2
ν CH (91) MeII (88)
as
2
2902 w νC38-H39 (88)
1667 w ν C19=O20 (77)
1618 s
ν C27-C28 (33)
1580 vs ν N16-C15 (33)
1509 m ν C19-N21 (14)
1519 vs
1436 vs
-
1438 s
d H42-C41-H43 (53)
1395 w β H29-C24-C25 (10)
1351 w W H42-C41-H43 (48)
β H50-C47-C48 (10)
-
1338 s
1304 s
β C23-C28 (10),C23-C24 (17),C25-C26 (12)
1287 w d H29-C24-C25 (12),H30-C25-C26 (10)
β H50-C47-C48 (25),H51-C48-C47 (13)
d H40-C38-C15-C5 (17)
1277 s
1242 vs
1179 s
1135 s
1179 w νR H13-C9-O8 (74)
1134 w ρ –OCH (83)
3
1
102 s
-
β C9-O1-O8-H13 (76),H37-C28-C27 (16),H36-
1
1
9
103
032
94
C27-C28(25)
1038 vs
997 m
1044 w W H39-C38-H40 (39)
ϒ C23-C28 (20),C24-C25-C26 (10)
-

ACCEPTED MANUSCRIPT
9
33
947 m
920 w
-
ϒ C24-C23-C25-H29 (56),H30-C25-C26-O31
20),H36-C27-C28-H37 (12)
(
9
8
8
8
8
8
7
6
6
5
5
4
16
82
53
38
04
00
49
68
15
85
09
54
-
ϒ C7-C2-O1 (67)
875 w
ϒ C3-C4-C5 (22)
858 w
827 m
-
νC19-N21 (15),N21-C23 (13),C23-C24 (17)
ϒ H51-C48-C47-N46 (11),C47-C48-N46-H50 (81)
ϒ O1-C2-C3 (14)
-
807 w
800 m
750 m
664 m
619 w
591 m
512 w
464 vw
-
-
-
-
-
-
-
ϒ C2-C7-C6 (20)
ρ H39-C38-C15-C5 (11), H42-C41-N44-C45 (19)
δ N17-C19=O20 (14)
ϒ N44-C48-C47-N46 (54)
τ C25-C26-C27 (12),C5-C15-N16 (10)
τ C24-C25-C26-C27 (55),C28-C27-C26-O31 (20)
δ C3-C2-C7 (16),N17-C19-O20 (12)
ν – stretching, ν -asymmetric stretching, ν –ring stretching, β – in plane bending, W – wagging, d
as
R
–
deformation, ρ – rocking, δ – bending, ϒ – out of plane bending, τ – torsion, Me I- methylene
I, Me II - methylene II, , vs- very strong, s- strong, m- medium, w- weak, vw- very weak.

ACCEPTED MANUSCRIPT
Table 6. Antifungal activity of the title compound towards C. albicans, C. tropicalis,
C. parapsilosis and A. niger.
Compound
MIC (µmol/mL)
No.
4
Candida albicans Candida tropicalis Candida parapsilosis Asperagillus niger
0.628
.051
ND
0.314
0.628
0.047
ND
0.628
ND
Fluconazole
Ketoconazole
0
0.045
ND
0.02

ACCEPTED MANUSCRIPT