Synthesis and spectroscopic identification of certain imidazole-semicarbazone conjugates bearing benzodioxole moieties: New antifungal agents

Article abstract of DOI:10.3390/molecules24010200

During the last three decades the extent of life-threatening fungal infections has increased remarkably worldwide. Synthesis and structure elucidation of certain imidazole-semicarbazone conjugates 5a–o are reported. Single crystal X-ray analysis of compound 5e unequivocally confirmed its assigned chemical structure and the (E)-configuration of its imine double bond. Compound 5e crystallized in the triclinic system, P-1, a = 6.3561 (3) ?, b = 12.5095 (8) ?, c = 14.5411 (9) ?, α = 67.073 (4)^?, β = 79.989 (4)^?, γ =84.370 (4)^?, V = 1048.05 (11) ?³, Z = 2. In addition, DIZ and MIC assays were used to examine the in vitro antifungal activity of the title conjugates 5a–o against four fungal strains. Compound 5e, bearing a 4-ethoxyphenyl fragment, showed the best MIC value (0.304 μmol/mL) against both C. tropicalis and C. parapsilosis species, while compounds 5c (MIC = 0.311 μmol/mL), 5k, and 5l (MIC = 0.287 μmol/mL) exhibited the best anti-C. albicans activity.

Full text of DOI:10.3390/molecules24010200

molecules
Article
Synthesis and Spectroscopic Identification of Certain
Imidazole-Semicarbazone Conjugates Bearing
Benzodioxole Moieties: New Antifungal Agents
Reem I. Al-Wabli 1,*, Alwah R. Al-Ghamdi 1, Hazem A. Ghabbour 2
,
Mohamed H. Al-Agamy 3,4 and Mohamed I. Attia 1,5,
*
1
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457,
Riyadh 11451, Saudi Arabia; toto24se@hotmail.com
Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;
ghabbourh@yahoo.com
Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451,
Saudi Arabia; malagamy@ksu.edu.sa
Microbiology and Immunology Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt
Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research
Division, National Research Centre (ID: 60014618), El Bohooth Street, Dokki, Giza 12622, Egypt
Correspondence: ralwabli@ksu.edu.sa (R.I.A.-W.); mattia@ksu.edu.sa (M.I.A.);
Tel.: +966-11-805-2620 (R.I.A.-W.); +966-146-77337 (M.I.A)
2
3
4
5
*
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 28 November 2018; Accepted: 3 January 2019; Published: 7 January 2019
Abstract: During the last three decades the extent of life-threatening fungal infections has increased
remarkably worldwide. Synthesis and structure elucidation of certain imidazole-semicarbazone
conjugates 5a
its assigned chemical structure and the (E)-configuration of its imine double bond. Compound 5e
crystallized in the triclinic system, P-1, a = 6.3561 (3) Å, b = 12.5095 (8) Å, c = 14.5411 (9) Å, = 67.073
=84.370 (4) , V = 1048.05 (11) Å3, Z = 2. In addition, DIZ and MIC assays were
used to examine the in vitro antifungal activity of the title conjugates 5a against four fungal strains.
Compound 5e, bearing a 4-ethoxyphenyl fragment, showed the best MIC value (0.304 mol/mL)
mol/mL), 5k
–o are reported. Single crystal X-ray analysis of compound 5e unequivocally confirmed
α
◦
◦
β = 79.989 (4) , γ
◦
(4) ,
–
o
µ
against both C. tropicalis and C. parapsilosis species, while compounds 5c (MIC = 0.311
and 5l (MIC = 0.287 µmol/mL) exhibited the best anti-C. albicans activity.
µ
,
Keywords: crystal structure; imidazole; benzodioxole; semicarbazones; antifungal
1. Introduction
The extent of life-threatening fungal infections has increased remarkably during the last three
decades. Drug-resistance to the available antifungal agents and increasing morbidity due to
life-threatening fungal infections have become a global health burden, particularly among individuals
with organ transplants, AIDS, autoimmune diseases or those receiving anticancer chemotherapeutic
agents [1–4]. Therefore, there is an urgent therapeutic need to develop new broad spectrum safe
antifungal candidates with excellent activity toward various pathogenic fungi.
Azoles are the mainstay of antifungal therapy against different invasive fungal species owing to
their broad antifungal spectrum and good pharmacokinetic profile [
moieties are the most common azole fragments in the therapeutically used antifungal azoles [
inhibit the fungal biosynthesis of ergosterol through inhibiting lanosterol 14 -demethylase (CYP51)
which leads to accumulation of lanosterol and depletion of ergosterol along with the inability for
normal growth of the fungi [ ]. A two-carbon bridge separating the imidazole pharmacophore moiety
5
]. Imidazole and 1,3,4-triazole
6
]. Azoles
α
7
Molecules 2019, 24, 200; doi:10.3390/molecules24010200
www.mdpi.com/journal/molecules

Molecules 2019, 24, 200
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and the aromatic portion of the molecule is prevalent in the available antifungal agents, while a
three-carbon bridge is present in few antifungal candidates [ 10]. Thus, it was of interest to focus on
8–
the design of new imidazole-bearing compounds having a three-carbon bridge between the imidazole
fragment and the aromatic moiety to examine their antifungal potential.
Semicarbazones are the products of an addition–elimination reaction between aldehydes or
ketones with certain semicarbazides. In the solid state, semicarbazones principally exist in the keto-like
form, while they manifest a keto-enol like tautomerism in the solution state giving rise to an effective
electron delocalization along the semicarbazone fragment [11]. The presence of nitrogen and oxygen
atoms as donor atoms in the core structure of semicarbazones gave them a special importance in
both organic and medicinal chemistry due to their ability to coordinate with many metal ions [12].
Therefore, the research has recently focused on the biological importance of this type of compounds.
An extensive literature review revealed that semicarbazones have exhibited a prominent antibacterial,
anticonvulsant, antitumor, antioxidant, and antifungal activities [13–16].
The abovementioned premises persuaded us to design a series of imidazole-semicarbazone
conjugates bearing 1,3-benzodioxole fragments. The incorporation of 1,3-benzodioxole moiety as
an aromatic pharmacophore part in the title compounds 5a
potential [17 18]. Compounds 5a feature a three-carbon spacer separating the imidazole
pharmacophore and the aromatic 1,3-benzodioxole pharmacophore part. The assigned chemical
structures of the target compounds 5a were assured with the aid of various spectroscopic approaches.
In addition, single crystal X-ray analysis of compound 5e confirmed unequivocally the assigned
–o could potentiate their antifungal
,
–o
–o
chemical structures of the title compounds 5a–o and established the (E)-configuration of their
imine functionality.
2. Results and Discussion
2.1. Chemistry
Scheme 1 presents the pathway which was adopted to prepare the target compounds 5a
The reaction sequence commenced using the commercially available acetophenone derivative
to afford the ketone according to the previously reported procedure [19]. The appropriate
semicarbazides 4a were added to the ketone with water elimination under mild conditions to
furnish the respective semicarbazones 5a in moderate yields. The mild synthetic conditions used to
obtain the target semicarbazones 5a plays the pivotal role to get the pure geometrical (E)-isomers of
compounds 5a as confirmed by the single crystal X-ray analysis of compound 5e as a representative
example of this type of compounds. The assigned chemical structures of the title compounds 5a
–o.
1
3
–o
3
–
o
–
o
–
o
–
o
were assured via different spectroscopic tools. Thus, they displayed IR bands in the range of 3390–3209,
1793–1645, 1664–1506 cm−1, corresponding to NH, C=O, and C=N, respectively. The 1H-NMR spectra
of compounds 5a
protons of the methylenes of (CH2–CH2–N) and other triplets appeared at
the protons of the other methylenes (CH2–CH2–N). The benzodioxole protons (–O–CH2–O–) were
observed as singlets in the range of = 6.05–6.09 (ppm). The imidazole protons (–N–CH=CH–N=)
were noticed as singlet signals in the range of = 6.85–6.97 ppm, another singlet signals appeared in
the range of = 7.17–7.37 ppm for the imidazole protons (–N–CH=CH–N=), while the third imidazole
protons (–N–CH=N–) were noted as singlet signals in the range of = 7.61–7.86 ppm. The aromatic
protons appeared in the region of = 6.61–8.25 ppm. Additionally, two singlet signals in the range of
–
o
showed triplets in the
δ
= 3.19–3.53 ppm range which were assigned to the two
δ
= 4.02–4.30 ppm for
δ
δ
δ
δ
δ
δ
= 7.44–9.73 and 9.76–10.63 ppm were assigned for the two protons of the semicarbazone (NH) groups.
The amine protons (NH2) of compound 5o were observed as a singlet at δ = 6.56 ppm.
The 13C-NMR spectra of the semicarbazones 5a
–o exhibited signals in the δ = 28.5–28.9,
42.6–43.1, 101.7–101.9, 119.9–120.8, 131.4–136.8, and 137.3–137.8 ppm range indicating (CH2-CH2-N),
(CH2-CH2-N), (O–CH2–O–), (-N–CH=CH–N=), (–N–CH=CH–N=), and (–N–CH=N–) carbons,
respectively. While the aromatic carbons appeared in the
δ = 106.3–148.3 ppm range, the carbonyl

Molecules 2019, 24, 200
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(C=O) carbons were noted in the range of
δ
= 148.2–152.1 ppm and the (C=N) carbons were observed
in the δ = 148.8–155.7 ppm range.
The mass (ESI) spectra of compounds 5a
–o displayed their anticipated molecular ion peaks in the
protonated forms [M + 1]+, except for compounds 5a
,
5k, 5m, and 5o which showed their anticipated
1]− due to their measurement in the negative
molecular ion peaks in the deprotonated forms [M
(ESI) mode.
−
O
O
O
O
O
O
O
O
N
ii
i
N(CH3)2 .HCl
CH3
N
O
1
2
3
R
NH
O
NH
N
O
O
N
N
5a-o
Compound
No.
Compound
No.
Compound
No.
Compound
No.
R
R
R
R
5a
5b
5c
C6H5
5e
5f
5g
5h
4-OC2H5-C6H4
4-F-C6H4
4-OCH3-C6H4
2-CH3-C6H4
5i
5j
5k
5l
3-CH3-C6H4
4-CH3-C6H4
3-CF3-C6H4
2,4-Cl2-C6H3
5m
5n
5o
3,4-Cl2-C6H3
4-Br-C6H4
3-Cl-C6H4
4-Cl-C6H4
C6H9
H
5d
Scheme 1. Synthesis of the target semicarbazones 5a
(CH2O)n, conc. HCl, ethanol, reflux, 2 h; (ii) Imidazole, water, reflux, 5 h; (iii) Appropriate
semicarbazide 4a , ethanol, acetic acid, rt, 18 h or semicarbazide hydrochloride (4o), anhydrous
–
o
. Reagents and conditions: (i) HN(CH3)2 HCl,
·
–
n
sodium acetate, ethanol, rt, 18 h for 5o.
2.2. Crystal Structure of Compound 5e
The crystallographic data and refinement information of compound 5e (C22H23N5O4,) are
summarized in Table S1. The selected bond lengths and bond angles are listed in Table 1.
The asymmetric unit is containing one independent molecule as shown in Figure 1.
Figure 1. ORTEP diagram of compound 5e. Displacement ellipsoids are plotted at the 40% probability
level for non-H atoms.

Molecules 2019, 24, 200
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◦
Table 1. Selected geometric parameters (Å, ) of compound 5e.
O1—C1
O1—C7
O2—C6
O2—C7
O3—C14
O4—C18
O4—C21
N1—C10
1.362 (7)
1.425 (7)
1.376 (7)
1.427 (6)
1.229 (8)
1.372 (7)
1.430 (7)
1.443 (11)
1.366 (14)
105.0 (4)
105.1 (4)
118.5 (4)
126.2 (8)
128.4 (8)
105.2 (9)
104.5 (11)
118.3 (4)
117.6 (5)
125.7 (6)
110.4 (5)
128.1 (4)
129.5 (4)
109.0 (4)
107.8 (5)
N1—C13
N2—C12
N2—C13
N3—N4
N3—C8
N4—C14
N5—C14
N5—C15
1.366 (14)
1.399 (18)
1.293 (17)
1.380 (7)
1.294 (7)
1.372 (8)
1.345 (9)
1.431 (8)
N1—C11
C1—O1—C7
C6—O2—C7
C18—O4—C21
C10—N1—C11
C10—N1—C13
C11—N1—C13
C12—N2—C13
N4—N3—C8
N3—N4—C14
C14—N5—C15
O1—C1—C6
O1—C1—C2
O2—C6—C5
O2—C6—C1
O1—C7—O2
N3—C8—C3
N3—C8—C9
115.0 (4)
125.8 (5)
112.8 (5)
107.5 (10)
109.4 (12)
113.3 (11)
116.4 (6)
119.5 (6)
124.1 (6)
117.9 (5)
122.4 (6)
126.2 (5)
114.6 (5)
106.5 (5)
N1—C10—C9
N1—C11—C12
N2—C12—C11
N1—C13—N2
N4—C14—N5
O3—C14—N4
O3—C14—N5
N5—C15—C20
N5—C15—C16
O4—C18—C17
O4—C18—C19
O4—C21—C22
All the bond lengths and angles are within normal ranges [20]. Compound 5e was found in the
(E)-configuration regarding its imine double bond C8=N3 as shown in Figure 1. The molecules
are packed together in the crystal structure along the b axis by one classical hydrogen bond
between N4-H1N1.....O3 and three non-classical hydrogen bonds, where C5, C9 and C21 atoms act as
H-donors and O1, O3 and N2 act as H- acceptors. In addition, one intra-molecular hydrogen bond
between N5-H1NB.....N3 which stabilizes the configuration of the molecule (Figure S1 and Table 2).
◦
◦
The 1,3-benzodioxole plane forms dihedral angles of 64.76 and 23.43 with the ethoxyphenyl ring and
imidazole ring, respectively.
◦
Table 2. The geometry of hydrogen-bonding (Å, ) of compound 5e.
D—H···A
D—H
H···A
D···A
D—H···A
N4—H1NA···O3 i
N5—H1NB···N3
C5—H5A···O1 ii
C9—H9A···O3 i
C21—H21A···N2 iii
1.01(6)
0.68(7)
0.9300
0.9700
0.9700
1.87(6)
2.21(7)
2.5500
2.4200
2.5700
2.857(6)
2.611(7)
3.454(6)
3.182(7)
3.500(13)
167(5)
120(7)
164.00
135.00
160.00
Symmetry codes: (i) −x, −y + 2, −z; (ii) x − 1, y, z; (iii) x + 1, y − 1, z.
2.3. Antifungal Activity of the Target Semicarbazones 5a–o
Table 3 presents the antifungal potential of the target semicarbazones 5
tested fungal strains measured as the diameter of the inhibition zone (DIZ) and minimum inhibitory
concentration (MIC) assay results. Compounds 5a manifested moderate to good activity in the
DIZ assay toward the four tested fungi, with DIZ values in the range of 11–23 mm. Compound
5e, bearing a 4-ethoxyphenyl fragment, showed the best MIC value (0.304 mol/mL) against both
C. tropicalis and C. parapsilosis species. Moreover, compound 5b, bearing a 4-bromophenyl moiety,
is the most active congener among the synthesized semicarbazones 5a toward A. niger, with a
MIC value of 0.561 mol/mL, followed by the equipotent dichlorinated compounds 5l and 5m with
MIC values of 0.574 mol/mL. Compounds 5b and 5f are the weakest compounds among the tested
a–o against the four
–
o
µ
–
o
µ
µ

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semicarbazones 5a
–
o
against both C. albicans and C. tropicalis, with MIC values of more than 1.12 and
1.30
and A. niger with a MIC value of more than 1.12
the semicarbazones 5a was not favorable in the cyclohexane-bearing semicarbazone, compound 5n
or in the unsubstituted semicarbazone, compound 5o. Moreover, the para-substitution with halogen,
methyl, or alkoxy groups (compounds 5b 5d and 5j) did not give good anti-C. albicans activity
in the synthesized semicarbazones 5 , whereas, the meta-substitution with electron withdrawing
µmol/mL, respectively, whereas, compound 5d is the weakest one against both C. parapsilosis
µmol/mL. It seems that the antifungal activity of
–
o
,
,
–g
a–o
groups (compounds 5c and 5k) or the dichlorinated analogue (compound 5l) displayed the best
anti-C. albicans activity.
Table 3. Antifungal potential of the target semicarbazones 5a–o against C. albicans, C. tropicalis,
C. parapsilosis, and A. niger.
Candida albicans
MIC
Candida tropicalis
Candida parapsilosis
Asperagillus niger
MIC
Compound
No.
DIZ ± SD *
DIZ ± SD *
MIC
(µmol/mL)
DIZ ± SD *
MIC
(µmol/mL)
DIZ ± SD *
(mm)
(µmol/mL)
(mm)
(mm)
(mm)
(µmol/mL)
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
14 ± 0.60
12 ± 0.70
14 ± 0.58
14 ± 0.60
13 ± 0.40
14 ± 0.60
14 ± 0.58
14 ± 1.00
13 ± 0.40
13 ± 1.00
12 ± 0.43
14 ± 0.58
11 ± 0.30
14 ± 0.40
14 ± 0.58
18 ± 1.10
ND
0.678
> 1.12
0.311
0.622
0.607
0.648
0.628
0.654
0.654
0.654
0.287
0.287
0.574
0.668
0.850
0.051
ND
20 ± 0.90
18 ± 0.50
20 ± 0.90
17 ± 0.50
22 ± 0.80
17 ± 1.00
22 ± 0.50
19 ± 0.50
21 ± 1.00
22 ± 1.00
23 ± 0.50
21 ± 1.00
17 ± 0.80
19 ± 1.00
20 ± 0.90
19 ± 1.00
ND
0.339
> 1.12
0.311
> 1.24
0.304
> 1.30
0.314
0.654
0.327
0.327
0.287
0.574
>1.15
1.34
11 ± 0.80
15 ± 0.58
16 ± 1.10
14 ± 0.40
16 ± 0.12
14 ± 0.60
12 ± 1.20
18 ± 0.90
17 ± 0.58
17 ± 0.90
15 ± 0.60
14 ± 0.60
16 ± 0.58
19 ± 0.50
15 ± 0.90
19 ± 0.90
ND
0.678
>1.12
0.622
>1.24
0.304
0.648
0.628
0.327
0.654
0.327
0.575
0.574
>1.15
>1.24
0.850
0.047
ND
15 ± 0.50
14 ± 0.40
15 ± 0.50
0.0 ± 0.0
13 ± 1.00
16 ± 1.10
15 ± 0.50
14 ± 1.00
13 ± 0.40
15 ± 0.58
14 ± 0.80
13 ± 0.40
16 ± 0.80
13 ± 1.00
14 ± 0.10
ND
0.678
0.561
0.622
>1.24
0.607
0.648
0.628
0.654
0.654
0.654
0.575
0.574
0.574
0.668
0.850
ND
0.850
0.045
ND
Fluconazole
Ketoconazole
29 ± 0.60
0.02
* The arithmetic mean of the inhibition zone diameters in mean ± standard deviation; ND: not determined.
3. Experimental
3.1. General Information
Melting points were measured using Gallenkamp melting point device, and are uncorrected.
A Perkin Elmer BX FT-IR spectrometer (Perkin Elmer, Shelton, CT, USA) was used to record the
infrared (IR) spectra from KBr disks. A Bruker NMR spectrometer (Bruker, Reinstetten, Germany)
was used to carry out the NMR measurements of the prepared samples in DMSO-d6 at 500 MHz
for 1H and 125.76 MHz for 13C. Chemical shifts are indicated in
δ-values (ppm) in relation to TMS
used as an internal standard. Elemental analyses of the target compounds were obtained using a
Vario EL III analyzer (Langenselbold, Darmstadt, Germany) and the results agreed favorably with the
proposed structures within
±
0.4% of the theoretical values. Mass spectra were obtained using an
Agilent Quadrupole 6120 LC/MS (Agilent Technologies, Palo Alto, CA, USA) with an ESI (electrospray
ionization) source. Silica gel TLC (thin layer chromatography) fluorescent plates were secured from
Merck (Darmstadt, Germany) and visualization was achieved by illumination with a UV light source
(254 nm).
3.2. Synthesis
3.2.1. General Procedure for the Synthesis of Semicarbazones 5a–n
A reaction mixture containing the appropriate semicarbazide 4a–n [21,22] (10 mmol), the ketone 3
(0.24 g, 10 mmol), and 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 re-crystallization from ethanol to furnish the corresponding semicarbazones 5a–n.

Molecules 2019, 24, 200
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(2E)-2-[1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)propylidene]-N-phenylhydrazinecarboxamide (5a). Yield
0.26 g (26%); white powder m.p. 162–164 ◦C; IR (KBr):
ν
(cm−1) 3385 (NH), 3198, 2968, 1793 (C=O),
1
1621 (C=N), 1521, 1262, 756; H-NMR (DMSO-d6):
δ (ppm) 3.29 (s, 2H, –CH2–CH2–N), 4.14 (s, 2H,
–CH2–CH2–N), 6.07 (s, 2H, –O–CH2–O–), 6.90 (d, J = 8.0 Hz, 1H, Ar–H), 6.97 (s, 1H, –N–CH=CH–N=),
7.04 (t, J =6.5 Hz, 1H, Ar–H), 7.27–7.33 (m, 3H, Ar–H, –N–CH=CH–N=), 7.38 (s, 1H, Ar–H), 7.61–7.63
(m, 3H, Ar–H), 7.86 (s, 1H, –N–CH=N–), 8.98 (s, 1H, NH), 10.18 (s, 1H, NH); 13C-NMR (DMSO-d6):
δ
(ppm) 28.6 (–CH2–CH2–N), 43.1 (–CH2–CH2–N), 101.7 (–O–CH2–O–), 107.1, 108.3 (Ar-CH), 120.4
(–N–CH=CH–N=), 120.6, 121.2, 123.0, 127.5, 128.9, 131.6 (Ar-CH, Ar–C, –N–CH=CH–N=), 137.6
(–N–CH=N–), 139.5, 145.1, 148.2, 148.5, 154.0 (Ar–C, C=O, C=N); MS m/z (ESI): 376.0 [M − H]−.
(2E)-2-[1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)pr◦opylidene]-N-(4-bromophenyl)hydrazine carboxamide
(
5b). Yield 0.37 g (37%); white powder m.p. 193–195 C; IR (KBr): ν
(cm−1) 3342 (NH), 3211, 2968, 1751
(C=O), 1664 (C=N), 1442, 1251, 755; 1H-NMR (DMSO-d6):
δ (ppm) 3.28 (t, J = 7.0 Hz, 2H, –CH2–CH2–N),
4.09 (t, J = 7.0 Hz, 2H, –CH2–CH2–N), 6.07 (s, 2H, -O-CH2-O-), 6.86 (s, 1H, –N–CH=CH–N=), 6.90
(d, J = 8.5 Hz, 1H, Ar–H), 7.26 (d, J = 1.5 Hz, 1H, Ar-H), 7.27 (s, 1H, –N–CH=CH–N=), 7.44 (d, J =
3.5 Hz, 1H, Ar–H), 7.47 (d, J = 8.5 Hz, 2H, Ar-H), 7.62 (s, 1H, –N–CH=N–), 7.65 (d, J = 8.5 Hz, 2H,
Ar-H), 9.01 (s, 1H, NH), 10.20 (s, 1H, NH); 13C-NMR (DMSO-d6):
δ (ppm) 28.7 (–CH2–CH2–N), 42.7
(–CH2–CH2–N), 101.7 (-O-CH2-O-), 107.3, 108.2 (Ar-CH), 119.9 (–N–CH=CH–N=), 120.7, 121.4, 122.6,
128.7, 131.5, 132.0 (Ar-CH, Ar–C, –N–CH=CH–N=), 137.8 (–N–CH=N–), 140.0, 145.7, 148.1, 148.5, 154.0
(Ar–C, C=O, C=N); MS m/z (ESI): 456.0 [M + H]+, 457.0 [(M + 1) + H]+, 458.0 [(M + 2) + H]+, 459.0 [(M
+ 3) + H]+, 478.0 [M + 23]+, 494.0 [M + 39]+.
(2E)-2-[1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)propylidene]-N-(3-chlorophenyl)hydrazine carboxamide
◦
(
5c). Yield 0.36 g (36%); white powder m.p. 182–184 C; IR (KBr):
ν
(cm−1) 3367 (NH), 3086, 2935, 1676
(C=O), 1525 (C=N), 1448, 1236, 750; 1H-NMR (DMSO-d6):
δ
(ppm) 3.35 (t, J = 7.0 Hz, 2H, –CH2–CH2–N),
4.10 (t, J = 7.0 Hz, 2H, –CH2–CH2–N), 6.07 (s, 2H, –O–CH2–O–), 6.86 (s, 1H, –N–CH=CH–N=), 6.90 (d,
J = 8.0 Hz, 1H, Ar–H), 7.08 (d, J = 6.5 Hz, 1H, Ar–H), 7.27 (br.s, 2H, –N–CH=CH–N=, Ar-H), 7.33 (t,
J = 8.0 Hz, 1H, Ar–H), 7.63 (s, 3H, Ar-H, –N–CH=N–), 7.85 (s, 1H, Ar-H), 9.05 (s, 1H, NH), 10.23 (s,
1H, NH); 13C-NMR (DMSO-d6):
δ (ppm) 28.7 (–CH2–CH2–N), 42.7 (–CH2–CH2–N), 101.7 (-O-CH2-O-),
107.3, 108.2, 119.0 (Ar-CH), 119.9 (–N–CH=CH–N=), 121.4, 122.6, 128.7, 130.5, 131.5, 133.3 (Ar-CH,
Ar–C, –N–CH=CH–N=), 137.8 (–N–CH=N–), 141.1, 145.9, 148.1, 148.5, 154.0 (Ar-C, C=O, C=N); MS
m/z (ESI): 412.0 [M + H]+, 413.0 [(M + 1) + H]+, 414.1 [(M + 2) + H]+, 434.1 [M + 23]+, 450.1 [M + 39]+.
(2E)-2-[1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)propylidene]-N-(4-chlorophenyl)hydrazine carboxamide
◦
(
5d). Yield 0.21 g (21%); white powder m.p. 198–200 C; IR (KBr):
ν
(cm−1) 3344 (NH), 3209, 2904, 1676
(C=O), 1533 (C=N), 1490, 1232, 753; 1H-NMR (DMSO-d6):
δ
(ppm) 3.27 (t, J = 7.0 Hz, 2H, –CH2–CH2–N),
4.09 (t, J = 6.5 Hz, 2H, –CH2–CH2–N), 6.07 (s, 2H, –O–CH2–O–), 6.86 (s, 1H, –N–CH=CH–N=), 6.90
(d, J = 8.0 Hz, 1H, Ar–H), 7.26–7.27 (m, 2H, Ar–H, –N–CH=CH–N=), 7.36 (d, J = 9.0 Hz, 2H, Ar–H),
7.62 (br.s, 2H, Ar–H, –N–CH=N–), 7.70 (d, J = 8.5 Hz, 2H, Ar-H ), 9.01 (s, 1H, NH), 10.20 (s, 1H,
NH); 13C-NMR (DMSO-d6):
δ (ppm) 28.7 (–CH2–CH2–N), 42.7 (–CH2–CH2–N), 101.7 (-O-CH2-O-),
107.3, 108.2 (Ar-CH), 119.9 (–N–CH=CH–N=), 121.4, 122.1, 122.2, 126.7, 128.7, 131.5 (Ar-CH, Ar–C,
–N–CH=CH–N=), 137.8 (–N–CH=N–), 138.5, 145.7, 148.1, 148.5, 154.1 (Ar-C, C=O, C=N); MS m/z (ESI):
412.1 [M + H]+, 413.0 [(M + 1) + H]+, 414.1 [(M + 2) + H]+.
(2E)-2-[1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)pr◦opylidene]-N-(4-ethoxyphenyl)hydrazine carboxamide
(
5e). Yield 0.42 g (42%); white powder m.p. 135–140 C; IR (KBr): ν
(cm−1) 3367 (NH), 3086, 2889, 1676
(C=O), 1525 (C=N), 1448, 1236, 754; 1H-NMR (DMSO-d6):
δ (ppm) 1.33 (t, J = 6.9 Hz, 3H, CH2-CH3),
3.26 (t, J = 6.9 Hz, 2H, –CH2–CH2–N), 4.09 (q, J = 6.9 Hz, 2H, CH2–CH3), 4.30 (t, J = 6.6 Hz, 2H,
–CH2–CH2–N), 6.06 (s, 2H, -O-CH2-O-), 6.86 (s, 1H, –N–CH=CH–N=), 6.89–6.91 (m, 3H, Ar–H), 7.26 (d,
J = 8.1 Hz, 1H, Ar–H), 7.28 (s, 1H, –N–CH=CH–N=), 7.49 (d, J = 8.9 Hz, 2H, Ar–H), 7.63–7.65 (m, 2H,
Ar-H, –N–CH=N–), 8.76 (s, 1H, NH), 10.05 (s, 1H, NH); 13C-NMR (DMSO-d6):
δ
(ppm) 15.2 (-CH2-CH3),
28.7 (–CH2–CH2–N), 42.7 (–CH2–CH2–N), 63.6 (–CH2–CH3), 101.7 (–O–CH2–O–), 107.8, 108.6, 114.6

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(Ar-CH), 119.9 (–N–CH=CH–N=), 121.2, 122.9, 128.7, 131.7, 132.3 (Ar–CH, Ar–C, –N–CH=CH–N=),
137.8 (–N–CH=N–), 144.9, 148.2, 148.3, 152.1, 154.8 (Ar–C, C=O, C=N); MS m/z (ESI): 422.2 [M + H]+.
(2E)-2-[1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)propylidene]-N-(4-fluorophenyl)hydrazine carboxamide
◦
(
5f). Yield 0.51 g (51%); white powder m.p. 172–174 C; IR (KBr):
ν
(cm−1) 3390 (NH), 3194, 2904, 1683
(C=O), 1517 (C=N), 1442, 1211, 750; 1H-NMR (DMSO-d6):
δ
(ppm) 3.27 (t, J = 6.8 Hz, 2H, –CH2–CH2–N),
4.09 (t, J = 6.9 Hz, 2H, –CH2–CH2–N), 6.09 (s, 2H, –O–CH2–O–), 6.86 (s, 1H, –N–CH=CH–N=), 6.91 (d,
J = 8.2 Hz, 1H, Ar–H), 7.13–7.17 (m, 2H, Ar–H, –N–CH=CH–N=), 7.62–7.27 (m, 2H, Ar–H), 7.63–7.66
(m, 4H, Ar–H, –N–CH=N–), 8.95 (s, 1H, NH), 10.14 (s, 1H, NH); 13C-NMR (DMSO-d6):
δ
(ppm) 28.7
(–CH2–CH2–N), 42.7 (–CH2–CH2–N), 101.7 (–O–CH2–O–), 107.3, 108.2 (Ar–CH), 115.4 (d, JC-30, F& C-50, F
0
0
= 21.6 Hz, C-3 and C-5 ), 119.9 (–N–CH=CH–N=), 121.3, 128.7, 131.6 (Ar–CH, Ar–C, –N–CH=CH–N=),
122.8 (d, JC-20, F& C-60, F = 7.8 Hz, C-20 and C-60), 135.8 (d, JC-10, F = 2.3 Hz, C-10), 137.8 (–N–CH=N–),
145.3, 148.2, 148.5, 154.3 (–N–CH=N–, Ar-C, C=O, C=N), 158.4 (d, JC-40, F = 238.7 Hz, C-40); MS m/z
(ESI): 396.2 [M + H]+, 397.1 [(M + 1) + H]+.
(2E)-2-[1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)propylidene]-N-(4-methoxyphenyl)hydrazine
carboxamide (5g). Yield 0.51 g (51%); white powder m.p. 161–163 ◦C. The spectral data of
compound 5g are consistent with previously reported data [23].
(2E)-2-[1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)propylidene]-N-(2-methylphenyl)hydrazine carboxamide
(
5h). Yield 0.65 g (65%); white powder m.p. 177–179 ◦C; IR (KBr): (cm−1) 3257 (NH), 2939, 2827,
ν
1645 (C=O), 1562 (C=N), 1450, 1236, 751; 1H-NMR (DMSO-d6):
δ (ppm) 2.28 (s, 3H, CH3), 3.28 (t, J =
7.0 Hz, 2H, –CH2–CH2–N), 4.11 (t, J = 7.0 Hz, 2H, –CH2–CH2–N), 6.07 (s, 2H, –O–CH2–O–), 6.87 (s, 1H,
–N–CH=CH–N=), 6.91 (d, J = 8.0 Hz, 1H, Ar–H), 7.03–7.06 (m, 1H, Ar–H ), 7.20–7.26 (m, 3H, Ar–H), 7.29
(s, 1H, –N–CH=CH–N=), 7.55 (s, 1H, Ar–H), 7.64 (s, 1H, –N–CH=N–), 7.74 (d, J = 7.5 Hz, 1H, Ar–H),
8.63 (s, 1H, NH), 10.25 (s, 1H, NH); 13C-NMR (DMSO-d6):
δ (ppm) 17.9 (–CH3), 28.8 (–CH2–CH2–N),
42.7 (–CH2–CH2–N), 101.8 (–O–CH2–O–), 106.7, 108.3 (Ar-CH), 119.9 (–N–CH=CH–N=), 121.1, 123.2,
124.2, 126.6, 128.7, 130.2, 130.6, 131.6 (Ar-CH, Ar–C, –N–CH=CH–N=), 137.3 (–N–CH=N–), 137.8, 144.8,
148.3, 148.5, 154.2 ( Ar–C, C=O, C=N); MS m/z (ESI): 392.2 [M + H]+.
(2E)-2-[1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)propylidene]-N-(3-methylphenyl)hydrazine carboxamide
(
5i). Yield 0.54 g (54%); white powder m.p. 176–179 ◦C; IR (KBr): (cm−1) 3367 (NH), 3099, 2893,
ν
1687 (C=O), 1546 (C=N), 1433, 1236, 750; 1H-NMR (DMSO-d6):
δ (ppm) 2.31 (s, 3H, CH3), 3.27 (t, J
= 7.0 Hz, 2H, –CH2–CH2–N), 4.10 (t, J = 7.0 Hz, 2H, –CH2–CH2–N), 6.07 (s, 2H, -O-CH2-O-), 6.86
(s, 2H, –N–CH=CH–N=, Ar–H), 6.91 (d, J = 8.5 Hz, 1H, Ar–H), 7.17–7.21 (m, 1H, Ar–H), 7.25 (d, J =
1.5 Hz, 1H, Ar-H), 7.28 (s, 1H, –N–CH=CH–N=), 7.45 (s, 2H, Ar–H ), 7.60 (d, J = 1.5 Hz, 1H, Ar–H),
7.63 (s, 1H, –N–CH=N–), 8.80 (s, 1H, NH), 10.11 (s, 1H, NH); 13C-NMR (DMSO-d6):
δ (ppm) 21.6
(CH3), 28.7 (–CH2–CH2–N), 42.7 (–CH2–CH2–N), 101.7 (–O–CH2–O–), 107.2, 108.3, 117.8 (Ar–CH),
119.9 (–N–CH=CH–N=), 121.1, 121.3, 123.8, 128.7, 128.8, 131.6 (Ar-CH, Ar–C, –N–CH=CH–N=), 137.8
(–N–CH=N–), 138.1, 139.3, 145.3, 148.1, 148.5, 154.0 (Ar–C, C=O, C=N); MS m/z (ESI): 392.2 [M + H]+.
(2E)-2-[1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)propylidene]-N-(4-methylphenyl)hydrazine carboxamide
(
5j). Yield 0.43 g (43%); white powder m.p. 149–151 ◦C; IR (KBr): (cm−1) 3219 (NH), 3105, 2904,
ν
1664 (C=O), 1506 (C=N), 1446, 1307, 752; 1H-NMR (DMSO-d6):
δ (ppm) 2.28 (s, 3H, CH3) 3.27 (t, J =
7.0 Hz, 2H, –CH2–CH2–N), 4.09 (t, J = 7.0 Hz, 2H, –CH2–CH2–N), 6.07 (s, 2H, –O–CH2–O–), 6.86 (s,
1H, –N–CH=CH–N=), 6.90 (d, J = 8.5 Hz, 1H, Ar–H), 7.12 (d, J = 8.0 Hz, 2H, Ar–H), 7.26 (d, J = 8.5 Hz,
1H, Ar–H), 7.28 (s, 1H, –N–CH=CH–N=), 7.51 (d, J = 8.0 Hz, 2H, Ar–H), 7.61 (s, 1H, Ar-H), 7.63 ( s,
1H, –N–CH=N–), 8.79 (s, 1H, NH), 10.07 (s, 1H, NH); 13C-NMR (DMSO-d6):
δ (ppm) 20.9 (CH3), 28.7
(–CH2–CH2–N), 42.7 (–CH2–CH2–N), 101.7 (-O-CH2-O-), 107.2, 108.3 (Ar-CH), 119.9 (–N–CH=CH–N=),
120.8, 121.2, 128.7, 129.3, 131.6, 131.9, 136.8 (Ar-CH, Ar–C, –N–CH=CH–N=), 137.8 (–N–CH=N–), 145.1,
148.2, 148.4, 154.1 (Ar-C, C=O, C=N); MS m/z (ESI): 392.2 [M + H]+, 414.1 [M + 23]+, 430.1 [M + 39]+.
(2E)-2-[1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)propylidene]-N-(3-(trifluoromethyl)phenyl)
hydrazinecarboxamide (5k). Yield 0.51 g (51%); white powder m.p. 192–194 ◦C; IR (KBr):
ν

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1
(cm−1) 3209 (NH), 3088, 2904, 1670 (C=O), 1543 (C=N), 1448, 1236, 750; H-NMR (DMSO-d6):
δ
(ppm) 3.31 (t, J = 6.6 Hz, 2H, –CH2–CH2–N), 4.13 (t, J = 6.5 Hz, 2H, –CH2–CH2–N), 6.07 (s, 2H,
-O-CH2-O-), 6.92 (d, J = 8.2 Hz, 1H, Ar–H), 6.94 (s, 1H, –N–CH=CH–N=), 7.29 (dd, J = 1.2, 8.5 Hz, 1H,
Ar–H), 7.35–7.37 (m, 2H, Ar–H, –N–CH=CH–N=), 7.53–7.56 (m, 1H, Ar–H), 7.64 (s, 1H, –N–CH=N–),
7.80 (s, 1H, Ar-H), 7.96 (d, J = 7.4 Hz, 1H, Ar–H), 8.12 (s, 1H, Ar-H), 9.30 (s, 1H, NH), 10.31 (s, 1H,
NH); 13C-NMR (DMSO-d6):
δ (ppm) 28.7 (–CH2–CH2–N), 43.0 (–CH2–CH2–N), 101.8 (-O-CH2-O-),
107.3, 108.3 (Ar-CH), 116.5, 119.2 120.3, 121.4, 123.7, 124.1, 125.8, 127.8, 129.9, 131.5 (Ar-CH, Ar–C,
–N–CH=CH–N=, –N–CH=CH–N=), 137.7 (–N–CH=N–), 140.5, 145.9, 148.1, 148.6, 154.1 (Ar-C, C=O,
C=N); MS m/z (ESI): 444.0 [M − H]−, 445.0 [(M + 1) − H]−.
(2E)-2-[1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)propylidene]-N-(2,4-dichlorophenyl)hydrazine
carboxamide (5l). Yield 0.52 g (52%); white powder m.p. 215–217 ◦C; IR (KBr):
3089, 2910, 1691 (C=O), 1523 (C=N), 1440, 1232, 751; H-NMR (DMSO-d6):
ν
(cm−1) 3338 (NH),
(ppm) 3.36 (t, J =
1
δ
7.0 Hz, 2H, –CH2–CH2–N), 4.09 (t, J = 7.5 Hz, 2H, –CH2–CH2–N), 6.08 (s, 2H, –O–CH2–O–), 6.85
(s, 1H, –N–CH=CH–N=), 6.94 (d, J = 8.0 Hz, 1H, Ar–H), 7.24 (d, J = 8.0 Hz, 1H, Ar–H), 7.27 (s, 1H,
–N–CH=CH–N=), 7.40 (s, 1H, Ar–H), 7.44 (dd, J = 2.0, 9.0 Hz, 1H, Ar-H), 7.62 (s, 1H, –N–CH=N–),
7.70 (d, J = 2.0 Hz, 1H, Ar–H), 8.24 (d, J = 9.0 Hz, 1H, Ar–H), 9.13 (s, 1H, NH), 10.63 (s, 1H, NH);
13C-NMR (DMSO-d6):
δ (ppm) 28.9 (–CH2–CH2–N), 42.8 (–CH2–CH2–N), 101.9 (-O-CH2-O-), 106.3,
108.5 (Ar-CH), 119.9 (–N–CH=CH–N=), 121.2, 122.4, 123.9, 127.3, 128.4, 128.7, 129.0, 131.3, 134.9
(Ar-CH, Ar–C, –N–CH=CH–N=), 137.8 (–N–CH=N–), 146.3, 148.3, 148.8, 153.5 (Ar–C, C=O, C=N); MS
m/z (ESI): 446.0 [M + H]+, 447.0 [(M + 1) + H]+, 448.1 [(M + 2) + H]+.
(2E)-2-[1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)propylidene]-N-(3,4-dichlorophenyl)hydrazine
carboxamide (5m). Yield 0.37 g (37%); white powder m.p. 174–176 ◦C; IR (KBr):
3197, 3082, 1685 (C=O), 1521 (C=N), 1475, 1238, 750; H-NMR (DMSO-d6):
ν
(cm−1) 3365 (NH),
δ (ppm) 3.30 (s, 2H,
1
–CH2–CH2–N), 4.13 (s, 2H, –CH2–CH2–N), 6.07 (s, 2H, –O–CH2
−
O ), 6.90 (d, J = 8.0 Hz, 1H, Ar–H),
−
6.97 (s, 1H, –N–CH=CH–N=), 7.28 (dd, J = 1.5, 8.0 Hz, 1H, Ar–H), 7.29 (s, 1H, –N–CH=CH–N=), 7.53
(d, J = 9.0 Hz, 1H, Ar–H), 7.62 (s, 1H, –N–CH=N–), 7.68 (d, J = 7.5 Hz, 1H, Ar–H), 7.85–7.86 (m, 1H,
Ar–H), 8.04 (d, J = 1.5 Hz, 1H, Ar–H), 9.25 (s, 1H, NH), 10.33 (s, 1H, NH); 13C-NMR (DMSO-d6):
δ
(ppm) 28.6 (–CH2–CH2–N), 43.1 (–CH2–CH2–N), 101.7 (–O–CH2–O–), 107.3, 108.2 (Ar–CH), 120.4,
120.5, 121.4, 124.3, 127.3, 127.4, 130.7, 131.1, 131.4 (Ar–CH, Ar–C, –N–CH=CH–N=, –N–CH=CH–N=),
137.6 (–N–CH=N–), 139.9, 145.9, 148.1, 148.6, 153.9 (Ar–C, C=O, C=N); MS m/z (ESI): 444.0 [M
445.0 [(M + 1) − H]−, 446.0 [(M + 2) − H]−.
−
H]−,
(2E)-2-[1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)propylidene]-N-cyclohexylhydrazine carboxamide (5n).
Yield 0.33 g (33%); white powder m.p. 174–176 ◦C; IR (KBr):
ν
(cm−1) 3402 (NH), 3203, 2933, 1672
1
(C=O), 1527 (C=N), 1460, 1251, 752; H-NMR (DMSO-d6):
δ (ppm) 1.16–1.40 (m, 5 H, cyclohexyl),
1.58–1.99 (m, 5 H, cyclohexyl), 3.19 (t, J = 7.0 Hz, 2H, –CH2–CH2–N), 3.56–3.57 (m, 1H, cyclohexyl),
4.02 (t, J = 7.0 Hz, 2H, –CH2–CH2–N), 6.05 (s, 2H, –O–CH2–O–), 6.61 (d, J = 8.0 Hz, 1H, Ar–H), 6.85
(s, 1H, –N–CH=CH–N=), 6.88 (d, J = 8.0 Hz, 1H, Ar–H), 7.18 (dd, J = 1.0, 8.0 Hz, 1H, Ar–H), 7.26
(s, 1H, –N–CH=CH–N=), 7.44 (s, 1H, NH), 7.61 (s, 1H, –N–CH=N–), 9.76 (s, 1H, NH); 13C-NMR
(DMSO-d6):
δ (ppm) 25.4 (–CH2–CH2–), 25.7 (–CH2–CH2–), 28.5 (–CH2–CH2–N), 33.3 (–CH2–CH2–),
42.6 (–CH2–CH2–N), 48.6 (–CH2–CH–CH2), 101.7 (-O-CH2-O-), 106.8, 108.3, 119.9 (Ar-CH), 120.8
(–N–CH=CH–N=), 128.7 (Ar–CH), 131.9 ( –N–CH=CH–N=), 137.8 (–N–CH=N–), 143.6, 148.1, 148.2,
155.7 (Ar–C, C=O, C=N); MS m/z (ESI): 384.2 [M + H]+, 406.2 [M + 23]+, 422.2 [M + 39]+.
3.2.2. Synthesis of (2E)-2-[1-(1,3-benzodioxol-5-yl)-3-(1H-imidazol-1-yl)propylidene]hydrazine
Carboxamide (5o)
A reaction mixture containing the ketone
3 (0.49 g, 2.0 mmol), semicarbazide hydrochloride
(4o, 0.22 g, 2.0 mmol) and anhydrous sodium acetate (0.16 g, 2.0 mmol) in absolute ethanol (15 mL)
was stirred at ambient temperature for 18 hrs. The reaction mixture was filtered and the filtrate was
evaporated under vacuum. The residue was crystallized from ethanol to give 0.5 g (50%) of the

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semicarbazone 5o as a white solid m.p. 177–179 ◦C. IR (KBr):
ν
(cm−1) 3442 (NH2), 3215 (NH), 3105,
2914, 1695 (C=O), 1593 (C=N) 1499, 1269, 757; 1H-NMR (DMSO-d6):
δ (ppm) 3.53 (t, J = 6.5 Hz, 2H,
–CH2–CH2–N), 4.06 (t, J = 7.0 Hz, 2H, –CH2–CH2–N), 6.04 (s, 2H, –O–CH2–O–), 6.56 (br.s, 2H, NH2),
6.86 (d, J = 8.0 Hz, 1H, Ar–H), 6.92 (s, 1H, –N–CH=CH–N=), 7.20 (dd, J = 1.5, 8.0 Hz, 1H, Ar–H), 7.32
(s, 1H, –N–CH=CH–N=), 7.54 (d, J = 1.5 Hz, 1H, Ar-H), 7.75 (s, 1H, –N–CH=N–), 9.73 (s, 1H, NH);
13C-NMR (DMSO-d6):
δ (ppm) 28.2 (–CH2–CH2–N), 42.8 (–CH2–CH2–N), 101.6 (–O–CH2–O–), 106.8,
108.2 (Ar–CH), 120.2 (–N–CH=CH–N=),120.8, 127.9, 131.8 (Ar-CH, Ar–C, –N–CH=CH–N=), 137.6
(–N–CH=N–), 143.2, 148.1, 148.2, 157.8 ( Ar–C, C=O, C=N); MS m/z (ESI): 300.7 [M − H]−.
3.3. Crystal Structure Determination of Compound 5e
Compound 5e was obtained as single crystals by slow evaporation from the 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 = 1.542 Å at 293 (2) K. Cell
refinement and data reduction were carried out by Bruker SAINT. SHELXT [24] was used to solve
structure. The final refinement was carried out by full-matrix least-squares techniques with anisotropic
thermal data for non-hydrogen atoms on F. CCDC 1879726 contains the supplementary crystallographic
data for this compound can be obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
3.4. Antifungal Activity of the Title Semicarbazones 5a–o
The title compounds 5a–o were evaluated for their in vitro antifungal activity using diameter of
the inhibition zone (DIZ) and minimum inhibitory concentration (MIC) assays against Candida albicans,
Candida tropicalis and Aspergillus niger according to the literature protocols [25].
4. Conclusions
The synthesis of certain new imidazole-semicarbazone conjugates 5a
moieties is reported. The assigned chemical structures of the title semicarbazones 5a
verified with the aid of several spectroscopic approaches. The X-ray crystal structure of compound
5e confirmed the designated chemical structure of the target compounds 5a and confirmed
the (E)-configuration of their imine fragments. The antifungal potential of the conjugates 5a
–
o
bearing benzodioxole
–
o
have been
–
o
–
o
was assessed against four fungal strains with the aid of DIZ and MIC assays. It seems that the
antifungal activity was not favored in the cyclohexane-bearing semicarbazone, compound 5n, or
in the unsubstituted semicarbazone, compound 5o. The meta-substitution (compounds 5c and 5k
)
with electron withdrawing groups or the dichlorinated analogue (compound 5l) showed the best
anti-C. albicans activity. Our efforts are continued aiming to get new potent, broad spectrum and safe
azole-bearing antifungal drug-like candidates.
Supplementary Materials: The following are available online, Figure S1: Molecular packing of compound 5e
viewed hydrogen bonds which are drawn as dashed lines along b axis, Table S1: The refinement information and
crystallographic data of the semicarbazone 5e.
Author Contributions: R.I.A.-W. and A.R.A.-G. synthesized and carried out the spectroscopic identification of
the title compounds 5a–o. H.A.G. conducted the X-ray analysis of compound 5e. M.H.A.-A. performed the
in vitro antifungal examination of the synthesized compounds 5a–o. M.I.A. proposed the work, prepared the
single crystals of compound 5e and prepared the manuscript for publication. All authors discussed the contents
of the manuscript.
Funding: This research received no external funding
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.
Conflicts of Interest: The authors have declared that there is no conflict of interests.

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Sample Availability: Samples of the synthesized compounds are available from the corresponding authors.
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