Crystal structures and antibacterial activity of hydrazone derivatives from 1H-indol-3-acetohydrazide

Article abstract of DOI:10.1134/S0022476613010216

A series of three new hydrazone derivatives C₂₂H ₁₉N₃O₂ (1), C₁₇H ₁₃ClN₄O₃ (2), and C₂₁H ₂₄N₄O₂·CH₄O (3) obtained by the condensation of ¹H-indol-3-acetohydrazide with 2-methoxynaphthaldehyde, 2-chloro-5-nitrobenzaldehyde, and 4- diethylaminosalicylaldehyde, respectively, in methanol, ia prepared. The compounds are characterized by elemental analysis, IR spectra, ¹H NMR spectra, and single crystal X-ray diffraction. Compound 1 crystallizes in the monoclinic space group P2₁/n with unit cell dimensions a = 17.740(2) A, b = 5.621(1) A, c = 18.573(3) A, β = 92.659(2), V = 1850.0(6) A³, Z = 4, R₁ = 0.0610 and wR₂ = 0.1155. Compound 2 crystallizes in the monoclinic space group C2/c with unit cell dimensions a = 29.178(2) A, b = 8.195(1) A, c = 14.372(1) A, β = 109.446(2), V = 3240.5(5) A³, Z = 8, R ₁ = 0.0452 and wR₂ = 0.1028. Compound 3 crystallizes in the monoclinic space group Pc with unit cell dimensions a = 6.579(1) A, b = 15.112(2) A, c = 10.676(2) A, β = 90.030(2), V = 1061.4(3) A³, Z = 2, R₁ = 0.0535 and wR₂ = 0.1123. The single crystal X-ray structural determination reveals that the molecules of the compounds are much twisted due to the lack of efficient conjugation. Preliminary biological tests indicate that the compounds are effective antibacterial material.

Full text of DOI:10.1134/S0022476613010216

Journal of Structural Chemistry. Vol. 54, No. 1, pp. 148-154, 2013
Original Russian Text Copyright © 2013 by F. Zhi, N. Shao, Q. Wang, Y. Zhang, R. Wang, Y. Yang
CRYSTAL STRUCTURES AND ANTIBACTERIAL
ACTIVITY OF HYDRAZONE DERIVATIVES
FROM 1H-INDOL-3-ACETOHYDRAZIDE
F. Zhi,1 N. Shao,2 Q. Wang,2 Y. Zhang,2 R. Wang,1
©
DOI: 10.1134/S0022476613010216
and Y. Yang2
A series of three new hydrazone derivatives C22H19N3O2 (1), C17H13ClN4O3 (2), and C21H24N4O2⋅CH4O (3)
obtained by the condensation of 1H-indol-3-acetohydrazide with 2-methoxynaphthaldehyde, 2-chloro-5-
nitrobenzaldehyde, and 4-diethylaminosalicylaldehyde, respectively, in methanol, ia prepared. The
1
compounds are characterized by elemental analysis, IR spectra, H NMR spectra, and single crystal X-ray
diffraction. Compound 1 crystallizes in the monoclinic space group P21/n with unit cell dimensions
3
a = 17.740(2) Å, b = 5.621(1) Å, c = 18.573(3) Å, β = 92.659(2)°, V = 1850.0(6) Å , Z = 4, R1 = 0.0610 and
wR2 = 0.1155. Compound 2 crystallizes in the monoclinic space group C2/c with unit cell dimensions
3
a = 29.178(2) Å, b = 8.195(1) Å, c = 14.372(1) Å, β = 109.446(2)°, V = 3240.5(5) Å , Z = 8, R1 = 0.0452
and wR2 = 0.1028. Compound 3 crystallizes in the monoclinic space group Pc with unit cell dimensions
3
a = 6.579(1) Å, b = 15.112(2) Å, c = 10.676(2) Å, β = 90.030(2)°, V = 1061.4(3) Å , Z = 2, R1 = 0.0535 and
wR2 = 0.1123. The single crystal X-ray structural determination reveals that the molecules of the
compounds are much twisted due to the lack of efficient conjugation. Preliminary biological tests indicate
that the compounds are effective antibacterial material.
Keywords: hydrazone derivative, synthesis, X-ray diffraction, antibacterial activity.
INTRODUCTION
The condensation of carbonyl-containing compounds with primary amines produces Schiff base compounds bearing
C=N double bonds, which is an essential structural requirement for biological activities, especially for the antibacterial,
antimicrobial, antifungi, and antitumor activities [1-4]. Hydrazone derivatives are a kind of special Schiff bases bearing
C=N–NH–CO functional groups. As is well known, nicotinohydrazide derivatives exhibit effective activities against
pulmonary tuberculosis. In recent years, considerable attention has been focused on the preparation and biological activities
of hydrazone derivatives [5-7]. During the search of the literature, we can observe that most of the reported hydrazone
derivatives bear a rigid backbone. In order to investigate the crystal structures and antibacterial activities of flexible
hydrazone derivatives, in the present paper, 1H-indol-3-acetohydrazide, an expensive flexible hydrazide, was used to prepare
three hydrazone derivatives: C22H19N3O2 (1), C17H13ClN4O3 (2), and C21H24N4O2⋅CH4O (3).
1
Modern Medical Research Center, Third Affiliated Hospital of Suzhou University, Changzhou, P. R. China.
2
Department of Neurosurgery, Third Affiliated Hospital of Suzhou University, Changzhou, P. R. China;
yangyilin_szu@126.com. The text was submitted by the authors in English. Zhurnal Strukturnoi Khimii, Vol. 54, No. 1,
pp. 155-161, January-February, 2013. Original article submitted October 7, 2011.
148
0022-4766/13/5401-0148

EXPERIMENTAL
Materials and methods. 1H-Indol-3-acetohydrazide, 2-methoxynaphthaldehyde, 2-chloro-5-nitrobenzaldehyde, and
4-diethylaminosalicylaldehyde were obtained commercially from Lancaster Research Chemicals. The solvents used were of
analytical grade. Elemental analyses (CHN) were performed on a Perkin-Elmer 240C elemental analyzer. IR spectra were
1
recorded on a Perkin Elmer Paragon 1000 spectrophotometer. H NMR spectra were recorded on a Bruker DPX-400
instrument at 400 MHz with tetramethylsilane as the internal reference.
Synthesis of (E)-2-(1H-indol-3-yl)-N′-((2-methoxynaphthalen-1-yl)methylene)acetohydrazide (1). 1H-Indol-3-
acetohydrazide (1.0 mmol, 0.189 g) was added with stirring to 2-methoxynaphthaldehyde (1.0 mmol, 0.186 g) in methanol.
The mixture was heated under reflux for 1 h and cooled to room temperature. After filtration and slow evaporation in air for a
few days, colorless block-shaped single crystals formed. The crystals were collected by filtration, washed three times with
methanol. Yield, 0.273 g (76%). Anal. Calcd. (%) for C22H19N3O2: C, 73.9; H, 5.4; N, 11.8. Found (%): C, 73.7; H, 5.4; N,
–1
1
11.9. Characteristic IR data (KBr, cm ): 1646 (s) (vC=N). HNMR data (d-DMSO, ppm): δ = 3.65 (s, 2H), 3.79 (s, 3H), 7.08
(m, 2H), 7.17 (s, 1H), 7.30 (m, 2H), 7.4-8.1 (m, 5H), 8.93 (s, 1H), 11.32 (s, 1H), 12.71 (s, 1H).
Synthesis of (E)-N′-(2-chloro-5-nitrobenzylidene)-2-(1H-indol-3-yl)acetohydrazide (2) and (E)-N′-(4-
(diethylamino)-2-hydroxybenzylidene)-2-(1H-indol-3-yl)acetohydrazide (3). Compounds 2 and 3 were synthesized by the
same method as that described for 1, with 2-methoxynaphthaldehyde replaced by 2-chloro-5-nitrobenzaldehyde (1.0 mmol,
0.186 g) for 2, and with 2-methoxynaphthaldehyde replaced by 4-diethylaminosalicylaldehyde (1.0 mmol, 0.193 g) for 3. The
filtrates for the two compounds were stood still in air to slow evaporate the solvent to yield yellow (for 2) and colorless (for
3) needle-shaped single crystals. For 2: Yield, 0.312 g (87%). Anal. Calcd. (%) for C17H13ClN4O3: C, 57.2; H, 3.7; N, 15.7.
–1
1
Found (%): C, 57.4; H, 3.6; N, 15.6. Characteristic IR data (KBr, cm ): 1643 (s) (vC=N). HNMR data (d-DMSO, ppm):
δ = 3.65 (s, 2H), 7.08 (m, 2H), 7.17 (s, 1H), 7.30 (d, 1H), 7.63 (d, 1H), 7.73 (d, 1H), 8.21 (d, 1H), 8.43 (s, 1H), 8.92 (s, 1H),
11.27 (s, 1H), 12.53 (s, 1H). For 3: Yield, 0.290 g (73%). Anal. Calcd. (%) for C22H28N4O3: C, 66.6; H, 7.1; N, 14.1. Found
–1
1
(%): C, 66.7; H, 7.3; N, 14.3. Characteristic IR data (KBr, cm ): 1645 (s) (vC=N). HNMR data (d-DMSO, ppm): δ = 1.14 (t,
6H), 3.38 (q, 4H), 3.65 (s, 2H), 6.26 (s, 1H), 6.35 (d, 1H), 7.08 (m, 2H), 7.17 (s, 1H), 7.30 (m, 2H), 7.3-7.7 (m, 3H), 8.77 (s,
1H), 11.13 (s, 1H), 12.54 (s, 1H).
X-ray crystallography. Suitable single crystals of the three compounds were mounted on glass fibers for X-ray
measurements. Reflection data were collected at room temperature on a Bruker AXS SMART APEX II CCD diffractometer
with graphite monochromatized MoKα radiation (λ = 0.71073 Å). Crystal structures of the three compounds were solved by
the direct method. All non-hydrogen atoms were refined anisotropically. Indole H and amino H atoms were located from
differrence Fourier maps and refined isotropically with the N–H distances restrained to 0.90(1) Å. The other hydrogen atoms
were fixed at calculated positions and refined by using riding models. All calculations were performed using the SHELX-97
program [8]. Crystal data and details of the data collection and the structure refinement are given in Table 1. Hydrogen
bonding information is given in Table 2.
Antibacterial test. The compounds were tested for their in vitro antibacterial activities against Staphylococcus
aureus var. Oxford 6538, Escherichia coli ATCC 10536, Klebsiella pneumoniae ATCC 100131, and Candida albicans
ATCC 10231 strains using the paper disc diffusion method (for the qualitative determination) and the serial dilutions in the
liquid broth method (for the determination of MIC) [9]. Tetracycline was used as the reference drug.
149

TABLE 1. Crystal Data and Refinement Parameters for the Compounds
Compound
1
2
3
Empirical formula
Molecular weight
Crystal color, habit
Crystal size, mm
Crystal system
Space group
Unit cell dimensions
a, Å
C22H19N3O2
357.4
C17H13ClN4O3
356.8
C22H28N4O3
396.5
Colorless, block
0.17×0.15×0.15
Monoclinic
P21/n
Yellow, needle
0.30×0.27×0.27
Monoclinic
C2/c
Colorless, needle
0.17×0.13×0.12
Monoclinic
Pc
17.740(2)
5.621(1)
29.178(2)
8.195(1)
6.579(1)
15.112(2)
10.676(2)
90.030(2)
1061.4(3)
2
b, Å
c, Å
18.573(3)
14.372(1)
109.446(2)
3240.5(5)
8
92.659(2)
β, deg
3
V, Å
1850.0(6)
Z
4
–3
1.283
1.463
1.241
d
calc, g⋅cm
–1
0.084
0.261
0.084
Absorption coefficient μ, mm
θ range collected, deg
3.10-27.00
0.986 and 0.988
10082/3986 (0.0620)
3986/2/251
1577
2.59-27.00
0.926 and 0.933
8555/3505 (0.0340)
3505/2/232
2109
2.34-26.99
0.986 and 0.990
5489/3614 (0.0416)
3614/4/272
2372
Tmin and Tmax
Reflections collected/unique (Rint)
Data/restraints/parameters
Observed reflections [I ≥ 2σ(I)]
R1, wR2 [I ≥ 2σ(I)]
0.0610, 0.1155
0.1740, 0.1571
0.984
0.0452, 0.1028
0.0866, 0.1224
1.022
0.0535, 0.1123
0.0866, 0.1279
0.994
R1, wR2 (all data)
GOOF on F 2
3
Largest differences in peak/hole, e/Å )
0.123 and –0.141
0.167 and –0.211
0.146 and –0.168
TABLE 2. Geometrical Parameters for Hydrogen Bonds
D–H⋯A,
deg
D–H⋯A,
deg
D–H⋯A
H⋯A, Å D⋯A, Å
D–H⋯A
H⋯A, Å D⋯A, Å
D–H, Å
D–H, Å
1
3
i
N2–H2⋯O1
0.90(1)
1.98(1) 2.864(3)
170(3) O2–H2A⋯N3
0.82
0.82
1.95
2.654(3)
2.740(4)
2.883(4)
2.805(4)
143
174
iv
2
O3–H3⋯O1
1.92
ii
N2–H2⋯N1
0.90(1)
0.90(1)
2.41(1) 3.268(3)
2.05(1) 2.893(2)
161(2)
N2–H2⋯O3
0.90(1)
0.90(1)
2.01(2)
1.98(2)
164(3)
154(4)
iii
v
N1–H1⋯O1
159(2) N1–H1⋯O1
Symmetry transformation used to generate the symmetry related atoms: (i) 1–x, 1–y, –z; (ii) x, –1+y, z; (iii) 1/2–x,
3/2–y, 1–z; (iv) 1+x, y, z; (v) 1+x, 1–y, –1/2+z.
RESULTS AND DISCUSSION
Structural description of the compounds. The molecular structures of compounds 1 and 2, and methanol solvated
compound 3 are shown in Figs. 1, 2, and 3 respectively. In each compound, the hydrazone molecule adopts an E
configuration with respect to C=N double bonds. The distances between C11 and N3 (1.276(3) Å in 1, 1.275(3) Å in 2, and
1.262(4) Å in 3) conform them as typical double bonds. The distances between C10 and N2 (1.345(3) Å in 1, 1.360(3) Å in 2,
and 1.317(4) Å in 3) are intermediate between single and double bonds due to the conjugation effects of
C11⋯N3⋯N2⋯C10⋯O1 moieties. It is notable that the C11–N3 and C10–N2 distances are comparable to each other in 1
150

Fig. 1. Thermal ellipsoid plot (30% probability level) of 1 showing the
numbering scheme.
Fig. 2. Thermal ellipsoid plot (30% probability level) of 2 showing the
numbering scheme.
Fig. 3. Thermal ellipsoid plot (30% probability level) of 3 showing
the numbering scheme.
151

Fig. 4. Packing diagram for 1 viewed along the b axis. Hydrogen bonds
are drawn as dashed lines.
Fig. 5. Packing diagram for 2 viewed along the c axis. Hydrogen bonds
are drawn as dashed lines.
and 2, and they are much longer than those in 3. This might be caused by the formation of N2–H2⋯O3 hydrogen bonds.
The other bond lengths in the three compounds are comparable to each other and are also within normal values [6, 10-13].
The molecules of the three compounds are much distorted, as evidenced by the dihedral angles between the indole ring and
the aromatic ring: 71.2(3)° for 1, 81.1(3)° for 2, and 67.9(3)° for 3. The C1–C9–C10–N2 torsion angles are 75.5(3)° for 1,
0.6(3)° for 2, and 28.7(3)° for 3. In the molecule of 3, an intramolecular O2–H2A⋯N3 hydrogen bond exists.
In the crystal structure of 1, the two adjacent molecules are linked through intermolecular N–H⋯O hydrogen bonds
to form a dimer (Fig. 4). In the crystal structure of 2, the molecules are linked through intermolecular N–H⋯O and N–H⋯N
hydrogen bonds to form chains running along the b axis (Fig. 5). In the crystal structure of 3, hydrazone and methanol
152

Fig. 6. Packing diagram for 3 viewed along the a axis. Hydrogen bonds
are drawn as dashed lines.
TABLE 3. Parameters Between the Planes for 2
Perpendicular
Perpendicular
distance of Cg(J) on
Cg(I), Å
Distance between ring
Cg
Dihedral angle, deg
distance of Cg(I) on
Cg(J), Å
centroids, Å
vi
Cg1⋯Cg1
3.621
3.719
0.02
0.03
3.245
3.551
3.245
3.551
vii
Cg2⋯Cg2
Note: Cg1 and Cg2 are the centroids of N1–C7–C2–C1–C8 and C12–C13–C14–C15–C16–C21, respectively.
Symmetry codes: (vi) 1/2–x, 5/2–y, 1–z; (vii) –x, 1–y, 1–z.
TABLE 4. Antibacterial Activity of the Compounds as MIC Values, μg/ml
Test material
Staphylococcus aureus
Escherichia coli
Klebsiella pneumoniae
Candida albicans
1
16
4
8
4
32
16
64
1.2
512
64
2
3
16
32
1.5
256
Tetracycline
0.22
> 1024
molecules are linked through intermolecular O–H⋯O and N–H⋯O hydrogen bonds to form 2D layers parallel to the ac
plane (Fig. 6). In addition, there are π⋯π stacking interactions in compound 2 (Table 3). The crystals of the three compounds
contain also C–H⋯π and N–H⋯π interactions.
Antibacterial activity. The antibacterial activities of the compounds as well as the reference drug are summarized in
Table 4. The results indicate that the compounds show from moderate to effective activities against the growth of the tested
strains. It is obvious that the activity of 2 is much more effective than that of 1 and 3, which might be caused by the Cl
substituent in the compound. The Cl-containing compounds have been proved to have interesting biological properties. The
activities against Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae are somewhat weak as compared to the
reference drug Tetracycline. However, all the compounds have stronger activities against Candida albicans than Tetracycline.
CONCLUSIONS
Three flexible hydrazone compounds derived from the condensation of 1H-indol-3-acetohydrazide with 2-
methoxynaphthaldehyde, 2-chloro-5-nitrobenzaldehyde, and 4-diethylaminosalicylaldehyde, respectively, in methanol, were
prepared and structurally characterized. The preliminary biological tests indicate that the compounds are effective
antibacterial materials.
153

CCDC-843105 for 1, 843106 for 2, and 843107 for 3 contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge at http://www.ccdc.cam.ac.uk/const/retrieving.html or from the Cambridge
Crystallographic Data Centre (CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk.
The authors thank the Third Affiliated Hospital of Suzhou University for supporting this work.
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