Synthesis and antibacterial evaluation of new N-acylhydrazone derivatives from dehydroabietic acid

Article abstract of DOI:10.3390/molecules17044634

A series of new N-acylhydrazone derivatives were synthesized in good yields through the reactions of dehydroabietic acid hydrazide with a variety of substituted arylaldehydes. The structures of the synthesized compounds were confirmed by IR, 1Hand 13C-NMR, ESI-MS, elemental analysis and single crystal X-ray diffraction. From the crystal structure of compound 4l, the C=N double bonds of these N-acylhydrazones showed (E)-configuration, while the NMR data of compounds 4a-q indicated the existence of two rotamers for each compound in solution. The target compounds were evaluated for their antibacterial activities against four microbial strains. The result suggested that several compounds exhibited pronounced antibacterial activities. Particularly, compound 4p exhibited good antibacterial activity against Staphylococcus aureus and Bacillus subtilis comparable to positive control. The possible antibacterial metabolism and the strategy for further optimization of this compound were also discussed.

Full text of DOI:10.3390/molecules17044634

Molecules 2012, 17, 4634-4650; doi:10.3390/molecules17044634
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis and Antibacterial Evaluation of New N-acylhydrazone
Derivatives from Dehydroabietic Acid
Wen Gu *, Rongrong Wu, Shilong Qi, Chenhai Gu, Fanjunnan Si and Zhuhui Chen
College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China
* Author to whom correspondence should be addressed; E-Mail: njguwen@163.com;
Tel.: +86-25-8542-8369.
Received: 26 March 2012; in revised form: 1 April 2012 / Accepted: 5 April 2012 /
Published: 20 April 2012
Abstract: A series of new N-acylhydrazone derivatives were synthesized in good yields
through the reactions of dehydroabietic acid hydrazide with a variety of substituted
1
arylaldehydes. The structures of the synthesized compounds were confirmed by IR, H-
13
and C-NMR, ESI-MS, elemental analysis and single crystal X-ray diffraction. From the
crystal structure of compound 4l, the C=N double bonds of these N-acylhydrazones
showed (E)-configuration, while the NMR data of compounds 4a–q indicated the existence
of two rotamers for each compound in solution. The target compounds were evaluated for
their antibacterial activities against four microbial strains. The result suggested that several
compounds exhibited pronounced antibacterial activities. Particularly, compound 4p
exhibited good antibacterial activity against Staphylococcus aureus and Bacillus subtilis
comparable to positive control. The possible antibacterial metabolism and the strategy for
further optimization of this compound were also discussed.
Keywords: N-acylhydrazone; dehydroabietic acid; synthesis; antibacterial activity
1. Introduction
Microbial infections remain a pressing human health problem because of a combination of factors,
including emerging infectious diseases and the rapid development of multi-drug resistance pathogens
worldwide [1,2]. In spite of many antibiotics and chemotherapeutics available, there will still be a vital
need to discover new and effective antimicrobial agents. In recent years, the N-acylhydrazone moiety
has proved to be an important pharmacophore structure in pharmaceutical research [3]. These structures

Molecules 2012, 17
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have received much attention due to their chemotherapeutic potential in the development of novel
antimicrobial agents [4,5]. Some widely used antibacterial drugs such as furacilin, furazolidone and
ftivazide are known to contain such kind of moieties [6]. In addition, many N-acylhydrazone
derivatives have been reported to exhibit an array of biological activities such as antimalarial [7],
antiviral [8], antitumor [9], anti-inflammatory [10], anticonvulsant [11], antidepressant [12] and
vasodilative activities [13].
Naturally occurring diterpenoids with an abietane skeleton are often discovered and isolated from
higher plants and their diverse bioactivities have been reported [14,15]. Among them, dehydroabietic
acid (DHA, 1) is one of the major tricyclic diterpenoid constituents of pine resin and can be readily
obtained from commercial disproportionated rosin. DHA and its derivatives have exhibited a
broad spectrum of biological activities such as antimicrobial, antitumor, antiviral, antioxidant,
anti-inflammatory and gastroprotective activities [16–21], which indicate that the compound is a
potentially useful starting material for the synthesis of industrially or pharmacologically important
products. In view of these findings, it would be worthwhile to design, synthesize new derivatives of
DHA bearing N-acylhydrazone moiety and evaluate their potential antimicrobial activities.
In continuation of our previous study on new antimicrobial derivatives of resin acids [22], we report
herein the synthesis and characterization of a series of new N-acylhydrazones starting from DHA.
Their in vitro antibacterial activities against several test microbes are also presented.
2. Results and Discussion
2.1. Synthesis
The synthetic procedures for the target compounds 4a–q are outlined in Scheme 1. The key
intermediate dehydroabietic acid hydrazide (3) was synthesized by hydrazination of dehydroabietate
chloride (2), which was prepared by the reaction of dehydroabietic acid (1) with thionyl chloride [23].
In the former literature, the synthesis of hydrazides was usually carried out by hydrazination of
methyl/ethyl esters of the corresponding carboxylic acids [24,25]. However, in this case, it was found
that ethyl dehydroabietate could hardly be converted to the hydrazide 3, possibly because of the low
reactivity of the ester or the steric hindrance caused by the adjacent moieties of the molecule [26].
Alternatively the hydrazide could be synthesized in good yield from dehydroabietate chloride (2) with
higher reactivity. Then the hydrazide 3 was condensed with different substituted aromatic aldehydes in
refluxing ethanol to afford the corresponding N-acylhydrazones 4a–q in good yield.
2.2. Structural Analysis
The structures of the synthesized N-acylhydrazone derivatives were confirmed on the basis of IR,
MS, NMR, elemental analysis and crystallographic methods. The IR spectra of 4a–q exhibited in all
cases N-H bands in the range 3,232–3,279 cm1. The strong absorption bands at 1,646–1,658 cm1
were due to the C=O stretch vibrations of the hydrazone moieties. The ESI-MS of compounds 4a–q
displayed, in all cases, quasimolecular ion peaks which confirmed their molecular weights. The
1H-NMR spectra of compounds 4a–q were similar except for the aromatic protons. In a typical
1
example, H-NMR spectra of 4a showed a doublet at δ 1.22 (1.20) ppm corresponding to six methyl

Molecules 2012, 17
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protons (H-18 and H-19) of the isopropyl group, together with a muliplet at δ 2.82 (2.78) ppm due to
the vicinal CH proton (H-17). Two singlets at δ 1.25 (1.24) and 1.40 (1.34) ppm could be assigned to
methyl protons at C-16 and C-15, respectively. Resonance peaks attributing to eight aromatic protons
in the two benzene rings appeared in the range δ 6.82–7.88 ppm. Among them, two doublets coupled
with each other at δ 7.00 (6.95) and 7.16 (7.08) ppm could be assigned to H-12 and H-11, respectively.
The singlet at δ 6.87 (6.82) ppm was due to the signal of H-14. Because of the symmetry of
monosubstituted benzene ring, the signals of H-2 and H-6 appeared as a doublet at δ 7.72 (7.88) ppm,
while the signals at δ 7.38–7.52 ppm could be assigned to H-3, H-4 and H-5. The N=CH proton
appeared as a singlet at δ 8.21 (8.03) ppm, and the amide NH proton resonated as a broad singlet at δ
13
8.83 (9.29) ppm. In the C-NMR spectra, the signal at δ 23.9 (23.8) ppm could be assigned to C-18
and C-19. The carbon atoms of the two benzene rings resonated as ten pairs of absoption peaks
because of the symmetry of substituent. In addition, the peaks at δ 146.1 (145.8) and 175.2 (176.8)
1
13
ppm could be attributed to the signals of C=N and C=O carbons, respectively. The H- and C-NMR
signals of other N-acylhydrazones were assigned by comparing with those of 4a.
Scheme 1. Synthetic route of hydrazone derivatives (4a–q) from dehydroabietic acid.
Interestingly, in their 1H-NMR spectra, there were, if discriminable, two sets of signals observed for
all groups, which resulted from the equilibrium and interconversion between rotamers (and/or
configurational isomers) of each compound in solution [27,28]. It was known that N-acylhydrazones
may exist in four possible forms in respect to (E/Z)-configurational isomers relative to the C=N double
bonds and (E/Z)-rotamers caused by the inversion of amide bonds (Figure 1). However, the E/Z
isomerization was not observed since these N-acylhydrazones exist primarily or completely in the
(E)-configuration because of the steric hindrance relative to the moiety [29], which was supported by
means of relative free energy calculations in a former report [30]. As for the characteristic peaks of

Molecules 2012, 17
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N-acylhydrazones, the N=CH protons appeared as expected as two separate singlets in the region δ
7.71–8.58 ppm. The amide inversion also made the CONH proton present as two broad singlets in the
range δ 8.71–10.18 ppm.
Figure 1. For possible forms of N-acylhydrazone derivatives.
The single crystal of the representative compound 4l was recrystallized from ethanol for the X-ray
diffraction to confirm the configuration. The crystal data of 4l are presented in Table 1, and its ORTEP
drawing with the atom numbering scheme is shown in Figure 2. In accordance with starting material
dehydroabietic acid, the two cyclohexane ring A (C1~C6) and B (C5~C10) bearing chair and half-chair
conformations, respectively, show a trans ring junction, with two methyl groups of C15 and C16 in the
axial positions. The molecule displays an E configuration with respect to the N2=C21 double bond
with a N1-N2-C21-C22 torsion angle of 179.5(3), and a Z conformation due to the amide bond with a
N2-N1-C20-O1 torsion angle of 1.4(6).
Table 1. Crystal structure data for compound 4l.
Empirical formula C29H38ClN3O4
F(0 0 0)
θ range for data collection () 1.93–25.38
Max. and min. transmission 0.9674 and 0.9516
1128
Formula weight
Temperature (K)
528.07
293(2)
Crystal size (mm3) 0.30 × 0.20 × 0.20 Index ranges
0 ≤ h ≤ 15
0 ≤ k ≤ 15
−21 ≤ l ≤ 21
5870
5374
0.0253
Crystal system
Space group
a (Å)
b (Å)
c (Å)
Orthorhombic
P212121
12.537(3)
13.097(3)
17.855(4)
90
Reflectons collected
Independent reflections
Rint
α ()
Data/restraints/parameters
Goodness-of-fit on F2
R1, wR2 [I > 2σ(I)]
R1, wR2 (all data)
Flack parameter
(Δρ)max (eÅ−3)
5374/3/328
1.001
0.0592/0.1567
0.0912/0.1783
−0.09(13)
0.520
β ()
90
γ ()
90
V (Å3)
Z
2931.7(10)
4
1.196
Dx (g/cm−3)
μ (mm−1)
0.167
(Δρ)min (eÅ−3)
−0.373

Molecules 2012, 17
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Figure 2. Crystal structure of compound 4l.
2.3. Antibacterial Activity
The synthesized compounds 3 and 4a–q were evaluated for their antibacterial activities against four
bacterial strains. The minimal inhibitory concentration (MIC) values of these compounds against the
test microorganisms were listed in Table 2. Also included were the MICs of positive control amikacin.
The result revealed that the MICs of the tested compounds differed greatly ranging from 1.9 to
>100 μg/mL. It was found that compounds 4c, 4d, 4l–n and 4p exhibited significant activities
(1.9–7.8 μg/mL) against Gram-positive bacteria (S. aureus and B. subtilis). Among them, compound
4p showed the strongest activities against S. aureus and B. subtilis with MIC values (1.9 μg/mL)
comparable to those of amikacin. Compounds 4l, 4n and 4p also showed strong inhibitions (3.9–7.8 μg/mL)
against the Gram-negative strains Escherichia coli and Pseudomonas fluorescens. In addition,
compounds 3, 4a, 4e, 4g, 4h and 4k exhibited moderate activities (15.6–31.2 μg/mL) against at least
one strain of the four bacteria, while 4b, 4f, 4i, 4j, 4o and 4q showed marginal or no inhibitions against
the four strains.
According to structure-activity relationships (SAR) studies, it could be concluded that different
substitutions on aromatic rings affected drastically the antibacterial activities of the synthesized
compounds. Compounds with electron-withdrawing substituents (halo and nitro) in the aromatic ring
showed greater antibacterial activities than those with electron-donating groups (methyl and methoxy).
The results of antibacterial assay indicated that the introduction of the halogen atom at 4-position
generally increased antibacterial activity, particularly F and Cl atoms, and compound 4n with 3-Cl
substituent also showed marked antibacterial activity. Previous literatures revealed that the
introduction of halogen atoms into the pharmacophore structure could, in many cases, be beneficial to
antibacterial activity [31,32]. On the other hand, compounds 4l, 4m and 4p with NO2 substituents
exhibited good activities against the test bacteria, indicating that the introduction of NO2 group was
essential for the antibacterial activity of these compounds.
Some N-acylhydrazone derivatives with nitrophenyl and nitrofuranyl moieties have been reported
to demonstrate pronounced antibacterial activities [33,34]. Among them, nifuroxazide, a notable
example bearing nitrofuran moiety has been used as an intestinal antiseptic [34]. Previous
investigations suggested that the possible antibacterial mechanism of these derivatives could be related

Molecules 2012, 17
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to the reduction of the nitro group by microbial nitroreductase together with the formation of toxic
intermediates such as nitro radical-anion, nitroso, hydroxylamine derivatives and/or reactive oxygen
species [35,36]. However, enzymatic nitroreduction of nitrofurans has also been found in animal
tissues, implying that toxic and mutagenic effects could also occur in mammalian cells [36]. A number
of literatures demonstrated that some nitrofuran antibiotics such as nitrofurantoin and nitrofurazone
showed mutagenic or carcinogenic effects on mammalian cells and tissues [36,37]. A prodrug strategy
might give some clue to resolve this problem. The functional groups of a drug can be modified by
chemical reactions such as esterification, amide formation, etc. to prepare a prodrug with better
physico-chemical properties, which can be bioconverted to the parental drug in vivo. Some recent
studies on the prodrugs of metronidazole and nitrofurazone suggested that the prodrug approach may
increase the biological activity and decrease the genotoxicity of these nitro compounds by improving
the physico-chemical properties [38]. In light of these findings, further derivatization of compound 4p
such as the introduction of various groups on the benzene ring, together with the in-depth SAR study
and mutagenic assay are still required.
Table 2. Antibacterial activities of compounds 4a–q.
Test
Minimum inhibitory concentration (μg/mL)
compounds
S. aureus
31.2
31.2
>100
7.8
B. subtilis
31.2
62.5
62.5
3.9
15.6
31.2
62.5
15.6
31.2
>100
62.5
15.6
3.9
3.9
7.8
62.5
1.9
>100
0.9
E. coli
62.5
>100
>100
31.2
31.2
>100
>100
31.2
>100
>100
>100
31.2
15.6
15.6
15.6
>100
7.8
P. fluorescens
31.2
62.5
>100
>100
62.5
>100
>100
62.5
>100
>100
>100
15.6
7.8
31.2
3
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
Amikacin
7.8
31.2
>100
62.5
62.5
>100
>100
15.6
3.9
7.8
3.9
>100
1.9
62.5
0.9
7.8
>100
3.9
>100
0.9
>100
1.9
3. Experimental
3.1. General
Melting points were measured on an XT-4 apparatus (Taike Corp., Beijing, China) and were
uncorrected. IR spectra were measured on a Nexus 870 FT-IR spectrometer. The ESI-MS spectra were
recorded on a Mariner System 5304 mass spectrometer. 1H-NMR spectra were accomplished in CDCl3

Molecules 2012, 17
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on a Bruker AV-500 NMR spectrometer using TMS as internal standard. Elemental analyses were
performed on a CHN-O-Rapid instrument and were within ±0.4% of the theoretical values. Reactions
and the resulted products were monitored by TLC which was carried out on silica gel IB-F flexible
sheets from Mallinckrodt Baker Inc., Germany and visualized in UV light (254 nm). Silica gel
(300–400 mesh) for column chromatography was purchased from Qingdao Marine Chemical Factory,
China. The reagents (chemicals), all being of A.R. grade, were purchased from Shanghai Chemical
Reagent Company (Shanghai, China). The substituted aryl aldehydes were purchased from Alfa Aesar
Co. (Tianjing, China). Disproportionated rosin was provided by Zhongbang Chemicals Co., Ltd.
(Zhaoqing, China), from which dehydroabietic acid (1, 97%) was isolated according to the published
method [39].
3.2. Crystallographic Studies
X-ray single-crystal diffraction data for compound 4l was collected on an Enraf-Nonius CAD-4
diffractometer at 293(2) K using MoKα radiation (λ = 0.71073 Å) by the ω scan mode. The structure
was solved by direct methods using the SHELXS program of the SHELXTL package and refined by
full-matrix least-squares methods with SHELXL [40]. All non-hydrogen atoms of compound 4l were
refined with anisotropic thermal parameters. All hydrogen atoms were generated theoretically onto the
parent atoms and refined with riding model position parameters and fixed isotropic thermal factors.
CCDC 848482 contains the supplementary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK; Fax: +44-122-333-6033; E-Mail: deposit@ccdc.cam.ac.uk).
3.3. Chemistry
3.3.1. Dehydroabietic Acid Hydrazide (3)
SOCl2 (2.18 mL, 3.57 g, 0.03 mol) was added slowly to a solution of dehydroabietic acid (6 g, 0.02 mol)
in benzene (20 mL). The mixture was then refluxed for 3 h. After cooling, the solvent and excess
SOCl2 were removed in vacuo to yield dehydroabietate chloride (2) as a yellow oily product. The
product was dissolved in CH2Cl2 (30 mL) and cooled to 0 C, which was then added dropwise under
stirring to a solution of hydrazine hydrate (12 mL, 80%) in CH2Cl2 (30 mL) at 0 C. The mixture was
stirred for 1–2 h, and the reaction progress was monitored by TLC. At the end of the reaction, the
mixture was poured into cold water. The aqueous phase was extracted with CH2Cl2 (3 × 100 mL). The
organic layer was combined, washed with water and brine, dried over anhydrous Na2SO4 and
concentrated to give a crude product, which was subject to a silica gel column chromatography
(petroleum ether-acetone 25:1, v/v) to give compound 3 as a whitish solid (4.02 g, 64%), m.p. 166–168 C,
1
IR (KBr, υ, cm1): 3392, 3325, 1652, 1603, 1496, 1445, 1382, 1255, 832. H-NMR (CDCl3): 1.22 (d,
J = 6.8 Hz, 6H, H-18 and H-19), 1.25 (s, 3H, CH3, H-16), 1.41 (s, 3H, CH3, H-15), 1.52–1.88 (m, 7H,
H-2, H-3, Ha-4 and H-10), 2.27 (d, J = 12.0 Hz, 1H, H-6), 2.36 (d, J = 12.9 Hz, 1H, He-4), 2.82–2.90
(m, 3H, H-9 and H-17), 4.03 (brs, 2H, NH2), 6.89 (s, 1H, H-14), 7.01 (d, J = 8.1 Hz, 1H, H-12), 7.16
(d, J = 8.1 Hz, 1H, H-11), 8.39 (s, 1H, CONH). MS (ESI) m/z 315 ([M+H]+). Anal. Calcd for
C20H30N2O: C, 76.39; H, 9.62, N, 8.91; found C, 76.51; H, 9.79; N, 8.78.

Molecules 2012, 17
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3.3.2. Gerneral Procedure for the Syntheses of N-acylhydrazone Derivatives 4a–q
To a solution of compound 3 (0.63 g, 2 mmol) in absolute EtOH (20 mL) was added 2 mmol of
substituted aromatic aldehyde and 2 drops of glacial acetic acid. The mixture was refluxed for 2–3 h
and the reaction was monitored by TLC. The mixture was then poured into cold water and left standing
for another 4 h. The precipitate formed was filtered, washed with water and recrystalized from ethanol
to afford compound 4.
Dehydroabietic acid 2-(phenylmethylene)hydrazide (4a). White powder; yield 78%; m.p. 152–156 C;
IR (KBr, υ, cm1): 3247, 3058, 2957, 2929, 2868, 1651, 1606, 1538, 1497, 1448, 1362, 1253, 821, 756.
1H-NMR (CDCl3, 500 MHz): 1.22 (1.20) (d, J = 7.0 Hz, 6H, H-18 and H-19), 1.25 (1.24) (s, 3H, CH3,
H-16), 1.40 (1.34) (s, 3H, CH3, H-15), 1.50–1.95 (m, 7H, H-2, H-3, Ha-4 and H-10), 2.27 (2.18) (d,
J = 12.1 Hz, 1H, H-6), 2.34 (2.30) (d, J = 12.7 Hz, 1H, He-4), 2.74–2.96 (m, 3H, H-9 and H-17), 6.87
(6.82) (s, 1H, H-14), 7.00 (6.95) (d, J = 8.1 Hz, 1H, H-12), 7.16 (7.08) (d, J = 8.3 Hz, 1H, H-11),
7.38–7.52 (m, 3H, H-3, H-4 and H-5), 7.72 (7.88) (d, J = 8.2 Hz, 2H, H-2 and H-6), 8.21 (8.03) (s,
1H, N=CH), 8.83 (9.29) (s, 1H, CONH). 13C-NMR (CDCl3): 16.3 (15.8), 18.6 (18.4), 21.3 (21.2), 23.9
(23.8) (C-18 and C-19), 25.1 (25.0), 29.6 (29.8), 33.3 (33.2), 37.0 (36.9), 37.1 (37.2), 37.8 (37.7), 45.4
(45.2), 47.3 (47.1), 123.9 (123.8) (C-12), 124.1 (124.0) (C-11), 126.8 (126.7) (C-14), 127.8 (127.4)
(C-3 and C-5), 129.2 (129.1) (C-2 and C-6), 130.6 (130.5) (C-4), 134.5 (134.4) (C-8), 134.9 (134.8)
(C-1), 145.8 (145.7) (C-13), 146.1 (145.8) (C=N), 146.6 (146.5) (C-7), 175.2 (176.8) (C=O). MS (ESI)
m/z 403 ([M+H]+). Anal. Calcd for C27H34N2O: C, 80.55; H, 8.51, N, 6.96; found C, 80.76; H, 8.39;
N, 6.84.
Dehydroabietic acid 2-[(4-methylphenyl)methylene]hydrazide (4b). White powder; yield 86%; m.p.
142–144 C; IR (KBr, υ, cm1): 3247, 2957, 2928, 2868, 1650, 1610, 1541, 1498, 1362, 1255, 819.
1H-NMR (CDCl3): 1.22 (1.21) (d, J = 7.0 Hz, 6H, H-18 and H-19), 1.25 (1.24) (s, 3H, CH3, H-16),
1.39 (1.34) (s, 3H, CH3, H-15), 1.50–1.95 (m, 7H, H-2, H-3, Ha-4 and H-10), 2.25 (2.19) (d, J = 12.1 Hz,
1H, H-6), 2.33 (2.30) (d, J = 12.6 Hz, 1H, He-4), 2.36 (2.44) (s, 3H, C6H4CH3), 2.78–2.95 (m, 3H, H-9
and H-17), 6.86 (6.80) (s, 1H, H-14), 7.00 (6.98) (d, J = 8.0 Hz, 1H, H-12), 7.14–7.19 (m, 3H, H-11,
H-2 and H-6), 7.62 (7.77) (d, J = 7.0 Hz, 2H, H-3 and H-5), 8.15 (7.82) (s, 1H, N=CH), 8.76 (9.21)
(s, 1H, CONH). 13C-NMR (CDCl3): 16.4 (15.8), 18.6 (18.4), 21.2 (21.1), 21.4 (21.5), 23.9 (23.8)
(C-18 and C-19), 25.2 (25.0), 29.7 (29.8), 33.4 (33.2), 37.0 (36.9), 37.1 (37.2), 37.8 (37.7), 45.3 (45.2),
47.2 (46.8), 123.8 (123.7) (C-12), 124.0 (123.9) (C-11), 126.9 (126.8) (C-14), 127.6 (127.7) (C-2 and
C-6), 129.3 (129.4) (C-3 and C-5), 131.0 (130.9) (C-1), 134.6 (134.5) (C-8), 140.6 (140.5) (C-4),
145.8 (145.7) (C-13), 146.8 (146.6) (C-7), 148.0 (148.4) (C=N), 174.4 (175.1) (C=O). MS (ESI) m/z
417 ([M+H]+). Anal. Calcd for C28H36N2O: C, 80.72; H, 8.71, N, 6.72; found C, 80.96; H, 8.62;
N, 6.51.
Dehydroabietic acid 2-[(4-fluorophenyl)methylene]hydrazide (4c). White powder; yield 74%; m.p.
205–207 C; IR (KBr, υ, cm1): 3255, 2957, 2930, 2869, 1651, 1604, 1508, 1340, 1234, 835. 1H-NMR
(CDCl3): 1.22 (1.21) (d, J = 7.0 Hz, 6H, H-18 and H-19), 1.25 (1.24) (s, 3H, CH3, H-16), 1.39 (1.34) (s,
3H, CH3, H-15), 1.51–1.90 (m, 7H, H-2, H-3, Ha-4 and H-10), 2.26 (2.19) (d, J = 12.1 Hz, 1H, H-6),
2.34 (2.30) (d, J = 12.9 Hz, 1H, He-4), 2.75–2.96 (m, 3H, H-9 and H-17), 6.87 (6.82) (s, 1H, H-14),

Molecules 2012, 17
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7.00 (6.95) (d, J = 8.0 Hz, 1H, H-12), 7.16 (7.08) (d, J = 8.0 Hz, 1H, H-11), 7.07 (7.21) (dd, J = 8.3,
8.1 Hz, 2H, H-3 and H-5), 7.71 (7.91) (dd, J = 8.3, 5.4 Hz, 2H, H-2 and H-6), 8.22 (8.05) (s, 1H,
N=CH), 8.80 (9.28) (s, 1H, CONH). 13C-NMR (CDCl3): 16.4 (15.8), 18.6 (18.4), 21.3 (21.2), 23.9
(23.8) (C-18 and C-19), 25.2 (25.1), 29.7 (29.8), 33.4 (33.2), 37.0 (36.9), 37.1 (37.2), 37.8 (37.7), 45.3
(45.2), 47.3 (46.8), 115.6 (115.8) (2JC-F = 21.2 Hz, C-3 and C-5), 123.8 (123.7) (C-12), 124.0 (123.9)
(C-11), 126.8 (126.7) (C-14), 129.3 (129.4) (3JC-F = 7.5 Hz, C-2 and C-6), 130.1 (130.0) (4JC-F = 2.5
Hz, C-1), 134.5 (134.4) (C-8), 145.8 (145.7) (C-13), 146.6 (146.5) (C-7), 146.9 (147.4) (C=N), 164.9
(162.9) (1JC-F = 241.9 Hz, C-4), 174.4 (174.8) (C=O). MS (ESI) m/z 421 ([M+H]+). Anal. Calcd for
C27H33FN2O: C, 77.11; H, 7.91; N, 6.66; found C, 77.02; H, 8.06; N, 6.46.
Dehydroabietic acid 2-[(4-chlorophenyl)methylene]hydrazide (4d). White powder; yield 70%; m.p.
137–139 C; IR (KBr, υ, cm1): 3243, 2957, 2929, 2869, 1651, 1597, 1538, 1490, 1361, 1254, 1089,
822. 1H-NMR (CDCl3): 1.22 (1.21) (d, J = 7.0 Hz, 6H, H-18 and H-19), 1.25 (1.24) (s, 3H, CH3, H-16),
1.39 (1.36) (s, 3H, CH3, H-15), 1.50–1.89 (m, 7H, H-2, H-3, Ha-4 and H-10), 2.26 (2.10) (d, J = 12.1 Hz,
1H, H-6), 2.34 (2.26) (d, J = 12.9 Hz, 1H, He-4), 2.79–2.92 (m, 3H, H-9 and H-17), 6.87 (6.81) (s, 1H,
H-14), 7.00 (6.95) (d, J = 7.9 Hz, 1H, H-12), 7.16 (7.07) (d, J = 7.9 Hz, 1H, H-11), 7.35 (7.52) (d,
J = 8.2 Hz, 2H, H-3 and H-5), 7.65 (7.82) (d, J = 7.8 Hz, 2H, H-2 and H-6), 8.21 (7.96) (s, 1H,
N=CH), 8.84 (9.37) (s, 1H, CONH). 13C-NMR (CDCl3): 16.3 (15.8), 18.5 (18.4), 21.3 (21.2), 23.9
(23.8) (C-18 and C-19), 25.2 (25.1), 29.7 (29.8), 33.4 (33.2), 37.0 (36.9), 37.1 (37.2), 37.8 (37.7), 45.3
(45.2), 47.3 (47.0), 123.8 (123.7) (C-12), 124.0 (123.9) (C-11), 126.8 (126.7) (C-14), 128.6 (128.7)
(C-3 and C-5), 128.8 (129.0) (C-2 and C-6), 132.3 (132.2) (C-1), 134.5 (134.4) (C-8), 136.1 (136.0)
(C-4), 145.7 (145.6) (C-13), 146.6 (146.5) (C-7), 146.7 (146.9) (C=N), 175.0 (175.6) (C=O). MS (ESI)
m/z 437 ([M+H]+). Anal. Calcd for C27H33ClN2O: C, 74.20; H, 7.61, N, 6.41; found C, 74.51; H, 7.36;
N, 6.17.
Dehydroabietic acid 2-[(4-bromophenyl)methylene]hydrazide (4e). White powder; yield 65%; m.p.
115–117 C; IR (KBr, υ, cm1): 3270, 2958, 2929, 2869, 1651, 1606, 1538, 1486, 1382, 1253, 1069,
820. 1H-NMR (CDCl3): 1.22 (1.21) (d, J = 7.0 Hz, 6H, H-18 and H-19), 1.25 (1.23) (s, 3H, CH3, H-16),
1.39 (1.34) (s, 3H, CH3, H-15), 1.50–1.92 (m, 7H, H-2, H-3, Ha-4 and H-10), 2.25 (2.19) (d, J = 12.1 Hz,
1H, H-6), 2.34 (2.31) (d, J = 13.0 Hz, 1H, He-4), 2.73–2.95 (m, 3H, H-9 and H-17), 6.87 (6.82) (s, 1H,
H-14), 6.99 (6.94) (d, J = 8.2 Hz, 1H, H-12), 7.16 (6.07) (d, J = 8.3 Hz, 1H, H-11), 7.51 (7.69) (d,
J = 8.2 Hz, 2H, H-3 and H-5), 7.58 (7.75) (d, J = 8.0 Hz, 2H, H-2 and H-6), 8.21 (8.02) (s, 1H,
N=CH), 8.83 (9.41) (s, 1H, CONH). 13C-NMR (CDCl3): 16.4 (15.8), 18.6 (18.4), 21.3 (21.2), 23.9
(23.8) (C-18 and C-19), 25.2 (25.1), 29.7 (29.8), 33.4 (33.2), 37.0 (36.9), 37.1 (37.2), 37.8 (37.3), 45.3
(45.2), 47.3 (46.9), 123.9 (123.8) (C-12), 124.1 (124.0) (C-11), 124.5 (124.2) (C-4), 126.8 (126.7)
(C-14), 128.8 (128.4) (C-2 and C-6), 131.8 (131.6) (C-3 and C-5), 132.8 (132.4) (C-1), 134.5
(134.4) (C-8), 145.7 (145.6) (C-13), 146.6 (146.5) (C-7), 146.7 (147.1) (C=N), 174.5 (174.9) (C=O).
MS (ESI) m/z 481, 483 ([M+H]+). Anal. Calcd for C27H33BrN2O: C, 67.35; H, 6.91, N, 5.82; found C,
67.12; H, 6.84; N, 5.96.
Dehydroabietic acid 2-[(4-methoxylphenyl)methylene]hydrazide (4f). White powder; yield 89%; m.p.
130–132 C; IR (KBr, υ, cm1): 3242, 2957, 2930, 2868, 1646, 1606, 1510, 1463, 1381, 1252, 1169,

Molecules 2012, 17
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1033, 830. 1H-NMR (CDCl3): 1.22 (1.21) (d, J = 7.0 Hz, 6H, H-18 and H-19), 1.25 (1.24) (s, 3H, CH3,
H-16), 1.39 (1.34) (s, 3H, CH3, H-15), 1.50–1.95 (m, 7H, H-2, H-3, Ha-4 and H-10), 2.26 (2.18) (d,
J = 11.5 Hz, 1H, H-6), 2.33 (2.29) (d, J = 12.8 Hz, 1H, He-4), 2.78–2.96 (m, 3H, H-9 and H-17), 3.83
(3.89) (s, 3H, OCH3), 6.87 (6.88) (s, 1H, H-14), 6.90 (6.92) (d, J = 8.5 Hz, 2H, H-3 and H-5), 7.00
(7.05) (d, J = 7.0 Hz, 1H, H-12), 7.16 (7.14) (d, J = 7.0 Hz, 1H, H-11), 7.67 (7.79) (d, J = 7.8 Hz, 2H,
H-2 and H-6), 8.12 (7.84) (s, 1H, N=CH), 8.83 (9.12) (s, 1H, CONH). 13C-NMR (CDCl3): 16.4 (15.8),
18.5 (18.4), 21.3 (21.2), 23.9 (23.8) (C-18 and C-19), 25.2 (25.1), 29.7 (29.8), 33.4 (33.2), 37.0 (36.9),
37.1 (37.2), 37.8 (37.7), 45.3 (45.2), 47.4 (47.1), 55.8 (55.6) (OCH3), 114.8 (114.7) (C-3 and C-5),
123.8 (123.7) (C-12), 124.0 (123.9) (C-11), 126.8 (126.7) (C-14), 128.0 (127.6) (C-1), 131.0 (130.8)
(C-2 and C-6), 134.6 (134.4) (C-8), 144.1 (144.5) (C=N), 145.8 (145.7) (C-13), 146.6 (146.5) (C-7),
161.2 (160.9) (C-4), 175.7 (176.1) (C=O). MS (ESI) m/z 433 ([M+H]+). Anal. Calcd for C28H36N2O2:
C, 77.74; H, 8.39, N, 6.48; found C, 77.42; H, 8.11; N, 6.68.
Dehydroabietic acid 2-[(2-hydroxyphenyl)methylene]hydrazide (4g). White powder; yield 73%; m.p.
153–155 C; IR (KBr, υ, cm1): 3273, 2956, 2928, 2866, 1654, 1609, 1540, 1498, 1458, 1382, 1128,
820. 1H-NMR (CDCl3): 1.21 (1.20) (d, J = 7.0 Hz, 6H, H-18 and H-19), 1.26 (1.24) (s, 3H, CH3, H-16),
1.39 (1.36) (s, 3H, CH3, H-15), 1.50–1.88 (m, 7H, H-2, H-3, Ha-4 and H-10), 2.25 (2.17) (d, J = 11.7 Hz,
1H, H-6), 2.34 (2.29) (d, J = 12.9 Hz, 1H, He-4), 2.77–2.95 (m, 3H, H-9 and H-17), 6.85 (6.80) (s, 1H,
H-14), 6.96 (7.04) (d, J = 8.2 Hz, 1H, H-3), 7.00 (6.95) (d, J = 8.0 Hz, 1H, H-12), 7.08–7.19 (m, 2H,
H-11 and H-5), 7.52–7.67 (m, 2H, H-4 and H-6), 8.19 (7.83) (s, 1H, N=CH), 8.84 (9.36) (s, 1H,
13
CONH), 9.91 (10.17) (s, 1H, 2-OH). C-NMR (CDCl3): 16.3 (15.8), 18.5 (18.3), 21.4 (21.2), 23.8
(23.7) (C-18 and C-19), 25.1 (25.0), 29.7 (29.8), 33.3 (33.2), 37.0 (36.9), 37.1 (37.2), 37.8 (37.7), 45.4
(45.1), 47.3 (47.1), 116.9 (116.8) (C-3), 119.8 (119.6) (C-5), 120.1 (119.9) (C-1), 123.9 (123.8)
(C-12), 124.1 (124.0) (C-11), 126.8 (126.7) (C-14), 131.2 (130.9) (C-6), 131.6 (131.3) (C-4), 134.6
(134.5) (C-8), 145.8 (145.7) (C-13), 146.6 (146.5) (C-7), 146.8 (147.3) (C=N), 157.2 (156.9) (C-2),
175.3 (175.8) (C=O). MS (ESI) m/z 419 ([M+H]+). Anal. Calcd for C27H34N2O2: C, 77.48; H, 8.19, N,
6.69; found C, 77.69; H, 8.37; N, 6.52.
Dehydroabietic acid 2-[(3-hydroxyphenyl)methylene]hydrazide (4h). White powder; yield 86%; m.p.
135–137 C; IR (KBr, υ, cm1): 3276, 2957, 2930, 2869, 1652, 1602, 1539, 1455, 1382, 1362, 1230,
821. 1H-NMR (CDCl3): 1.21 (1.20) (d, J = 7.1 Hz, 6H, H-18 and H-19), 1.24 (1.23) (s, 3H, CH3, H-16),
1.37 (1.33) (s, 3H, CH3, H-15), 1.51–1.95 (m, 7H, H-2, H-3, Ha-4 and H-10), 2.26 (2.18) (d,
J = 11.5 Hz, 1H, H-6), 2.32 (2.21) (d, J = 12.3 Hz, 1H, He-4), 2.78–2.92 (m, 3H, H-9 and H-17), 6.84
(6.80) (s, 1H, H-14), 6.88 (6.90) (d, J = 7.9 Hz, 1H, H-4), 6.91–7.04 (m, 2H, H-12 and H-5),
7.13–7.18 (m, 2H, H-11and H-6), 7.29 (7.39) (s, 1H, H-2), 8.01 (7.73) (s, 1H, N=CH), 8.71 (9.09) (s,
1H, CONH), 9.37 (9.72) (s, 1H, 3-OH). 13C-NMR (CDCl3): 16.3 (15.8), 18.5 (18.4), 21.3 (21.2), 23.9
(23.8) (C-18 and C-19), 25.2 (25.1), 29.7 (29.8), 33.4 (33.2), 37.0 (36.9), 37.1 (37.2), 37.8 (37.7), 45.4
(45.2), 47.3 (47.1), 114.5 (114.2) (C-2), 118.2 (118.1) (C-4), 121.8 (121.6) (C-6), 123.8 (123.7)
(C-12), 124.0 (123.9) (C-11), 126.8 (126.7) (C-14), 130.6 (130.5) (C-5), 134.5 (134.3) (C-8), 138.7
(138.5) (C-1), 145.7 (145.6) (C-13), 146.6 (146.5) (C-7), 146.9 (147.2) (C=N), 158.6 (158.4) (C-3),
175.5 (176.0) (C=O). MS (ESI) m/z 419 ([M+H]+). Anal. Calcd for C27H34N2O2: C, 77.48; H, 8.19, N,
6.69; found C, 77.70; H, 8.01; N, 6.45.

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Dehydroabietic acid 2-[(4-hydroxyphenyl)methylene]hydrazide (4i). White powder; yield 79%; m.p.
297–298 C; IR (KBr, υ, cm1): 3279, 2958, 2932, 2866, 1653, 1612, 1536, 1452, 1380, 1367, 1227,
830. 1H-NMR (CDCl3): 1.22 (1.21) (d, J = 7.1 Hz, 6H, H-18 and H-19), 1.25 (1.24) (s, 3H, CH3, H-16),
1.38 (1.34) (s, 3H, CH3, H-15), 1.52–1.89 (m, 7H, H-2, H-3, Ha-4 and H-10), 2.26 (2.19) (d, J = 11.2 Hz,
1H, H-6), 2.36 (2.32) (d, J = 12.8 Hz, 1H, He-4), 2.80–2.98 (m, 3H, H-9 and H-17), 6.87 (6.81) (s, 1H,
H-14), 6.95 (7.05) (d, J = 8.1 Hz, 2H, H-3 and H-5), 6.99 (6.94) (d, J = 8.2 Hz, 1H, H-12), 7.16 (7.08)
(d, J = 8.0 Hz, 1H, H-11), 7.63 (7.79) (d, J = 8.3 Hz, 2H, H-2 and H-6), 8.12 (7.88) (s, 1H, N=CH),
13
8.79 (9.12) (s, 1H, CONH), 9.87 (9.58) (s, 1H, 4-OH). C-NMR (CDCl3): 16.3 (15.8), 18.5 (18.4),
21.3 (21.2), 23.9 (23.8) (C-18 and C-19), 25.2 (25.1), 29.7 (29.8), 33.3 (33.2), 37.0 (36.9), 37.1 (37.2),
37.8 (37.7), 45.3 (45.2), 47.3 (46.9), 116.2 (116.0) (C-3 and C-5), 123.8 (123.7) (C-12), 124.0 (123.9)
(C-11), 126.1 (126.0) (C-1), 126.8 (126.7) (C-14), 130.6 (130.4) (C-2 and C-6), 134.5 (134.3) (C-8),
144.8 (145.2) (C=N), 145.7 (145.6) (C-13), 146.7 (146.5) (C-7), 160.8 (160.5) (C-4), 175.1 (175.6)
(C=O). MS (ESI) m/z 419 ([M+H]+). Anal. Calcd for C27H34N2O2: C, 77.48; H, 8.19, N, 6.69; found C,
77.31; H, 8.36; N, 6.82.
Dehydroabietic acid 2-[(4-hydroxy-3-methoxylphenyl)methylene]hydrazide (4j). White powder; yield
92%; m.p. 138–140 C; IR (KBr, υ, cm1): 3252, 2958, 2930, 2875, 1651, 1600, 1538, 1455, 1384,
1270, 1052, 820, 742. 1H-NMR (CDCl3): 1.22 (1.21) (d, J = 6.8 Hz, 6H, H-18 and H-19), 1.25 (1.24)
(s, 3H, CH3, H-16), 1.39 (1.34) (s, 3H, CH3, H-15), 1.53–1.95 (m, 7H, H-2, H-3, Ha-4 and H-10), 2.27
(2.18) (d, J = 10.4 Hz, 1H, H-6), 2.34 (2.30) (d, J = 12.8 Hz, 1H, He-4), 2.80–2.92 (m, 3H, H-9 and
H-17), 3.93 (3.99) (s, 3H, OCH3), 5.89 (brs, 1H, OH), 6.86 (6.80) (s, 1H, H-14), 6.89 (7.04) (d, J = 8.1 Hz,
1H, H-5), 6.98 (7.12) (d, J = 8.4 Hz, 1H, H-6), 7.00 (6.95) (d, J = 8.2 Hz, 1H, H-12), 7.17 (7.06) (d,
J = 8.2 Hz, 1H, H-11), 7.50 (7.42) (s, 1H, H-2), 8.05 (7.71) (s, 1H, N=CH), 8.76 (9.08) (s, 1H,
13
CONH). C-NMR (CDCl3): 16.3 (15.9), 18.6 (18.5), 21.2(21.1), 23.9 (23.8) (C-18 and C-19), 25.1
(25.0), 29.7 (29.8), 33.4 (33.2), 37.0 (36.9), 37.1 (37.2), 37.8 (37.4), 45.3 (45.2), 47.1 (46.7), 56.1
(56.0) (OCH3), 107.7 (107.6) (C-2), 114.0 (114.2) (C-5), 123.5 (123.4) (C-6), 123.8 (123.7) (C-12),
124.0 (123.9) (C-11), 126.1 (126.2) (C-1), 126.8 (126.7) (C-14), 134.6 (134.4) (C-8), 145.7 (145.6)
(C-13), 146.8 (146.7) (C-7), 147.2 (147.5) (C=N), 148.2 (148.0) (C-3), 148.3 (148.4) (C-4), 174.7
(175.2) (C=O). MS (ESI) m/z 449 ([M+H]+). Anal. Calcd for C28H36N2O3: C, 74.97; H, 8.09, N, 6.24;
found C, 74.73; H, 7.96; N, 6.45.
Dehydroabietic acid 2-[(4-nitrophenyl)methylene]hydrazide (4k). Yellow powder; yield 71%; m.p.
148–150 C; IR (KBr, υ, cm1): 3255, 2956, 2927, 2869, 1657, 1602, 1523, 1473, 1382, 1249, 1172,
830. 1H-NMR (CDCl3): 1.22 (1.21) (d, J = 6.8 Hz, 6H, H-18 and H-19), 1.26 (1.24) (s, 3H, CH3, H-16),
1.41 (1.38) (s, 3H, CH3, H-15), 1.50–1.91 (m, 7H, H-2, H-3, Ha-4 and H-10), 2.24 (2.17) (d, J = 11.6 Hz,
1H, H-6), 2.35 (2.30) (d, J = 13.2 Hz, 1H, He-4), 2.75–2.96 (m, 3H, H-9 and H-17), 6.88 (6.82) (s, 1H,
H-14), 7.01 (6.95) (d, J = 8.1 Hz, 1H, H-12), 7.17 (7.07) (d, J = 8.1 Hz, 1H, H-11), 7.87 (8.07) (d,
J = 8.5 Hz, 2H, H-3 and H-5), 8.23 (8.39) (d, J = 8.5, 2H, H-2 and H-6), 8.44 (8.32) (s, 1H, N=CH),
9.31 (9.87) (s, 1H, CONH). 13C-NMR (CDCl3): 16.3 (15.8), 18.5 (18.4), 21.3 (21.2), 23.9 (23.8) (C-18
and C-19), 25.1 (25.0), 29.7 (29.8), 33.4 (33.2), 37.0 (36.8), 37.1 (37.2), 37.8 (37.7), 45.4 (45.3), 47.5
(46.9), 123.8 (123.6) (C-2 and C-6), 123.9 (123.7) (C-12), 124.0 (124.1) (C-11), 126.8 (126.7) (C-14),
127.9 (127.8) (C-3 and C-5), 134.3 (134.4) (C-8), 140.0 (140.1) (C-1), 145.0 (145.5) (C=N), 145.9

Molecules 2012, 17
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(145.8) (C-13), 146.6 (146.5) (C-7), 148.5 (148.6) (C-4), 174.6 (175.4) (C=O). MS (ESI) m/z 448
([M+H]+). Anal. Calcd for C27H33N3O3: C, 72.46; H, 7.43, N, 9.39; found C, 72.79; H, 7.18; N, 9.12.
Dehydroabietic acid 2-[(4-chloro-3-nitrophenyl)methylene]hydrazide (4l). Yellow crystals; yield 73%;
m.p. 248–250 C; IR (KBr, υ, cm1): 3232, 2957, 2923, 2869, 1658, 1605, 1537, 1473, 1383, 1350,
1246, 1128, 822. 1H-NMR (CDCl3): 1.22 (1.21) (d, J = 7.1 Hz, 6H, H-18 and H-19), 1.25 (1.24) (s, 3H,
CH33, H-16), 1.40 (1.36) (s, 3H, CH3, H-15), 1.52–1.90 (m, 7H, H-2, H-3, Ha-4 and H-10), 2.24 (2.10)
(d, J = 12.0 Hz, 1H, H-6), 2.35 (2.28) (d, J = 13.0 Hz, 1H, He-4), 2.72–2.95 (m, 3H, H-9 and H-17),
6.87 (6.81) (s, 1H, H-14), 7.00 (6.94) (d, J = 7.9 Hz, 1H, H-12), 7.17 (7.07) (d, J = 8.2 Hz, 1H, H-11),
7.55 (7.76) (d, J = 8.4 Hz, 1H, H-5), 7.89 (8.03) (d, J = 8.1 Hz, 1H, H-6), 8.13 (8.36) (s, 1H, H-2),
13
8.44 (8.27) (s, 1H, N=CH), 9.82 (10.18) (s, 1H, CONH). C-NMR (CDCl3): 16.4 (15.8), 18.6 (18.4),
21.2 (21.1), 23.9 (23.8) (C-18 and C-19), 25.2 (25.1), 29.7 (29.8), 33.4 (33.2), 37.0 (36.9), 37.1 (37.2),
37.8 (37.4), 45.3 (45.2), 47.2 (46.8), 123.5 (123.2) (C-2), 123.8 (123.7) (C-12), 124.0 (123.9) (C-11),
126.3 (125.9) (C-1), 126.8 (126.7) (C-14), 129.2 (129.0) (C-5), 131.9 (131.5) (C-6), 134.4 (134.2)
(C-4), 134.6 (134.5) (C-8), 145.7 (145.6) (C-13), 146.6 (146.5) (C-7), 146.8 (147.2) (C=N), 147.9
(147.7) (C-3), 174.3 (174.7) (C=O). MS (ESI) m/z 482 ([M+H]+). Anal. Calcd for C27H32ClN3O3: C,
67.28; H, 6.69, N, 8.72; found C, 67.43; H, 6.91; N, 8.51.
Dehydroabietic acid 2-[(2-hydroxy-5-nitrophenyl)methylene]hydrazide (4m). Yellow powder; yield
68%; m.p. 158–160 C; IR (KBr, υ, cm1): 3269, 2959, 2928, 2869, 1655, 1610, 1513, 1478, 1383,
1340, 1247, 1174, 822. 1H-NMR (CDCl3): 1.22 (1.21) (d, J = 6.8 Hz, 6H, H-18 and H-19), 1.25 (1.24)
(s, 3H, CH3, H-16), 1.41 (1.35) (s, 3H, CH3, H-15), 1.50–1.92 (m, 7H, H-2, H-3, Ha-4 and H-10), 2.18
(2.10) (d, J = 11.8 Hz, 1H, H-6), 2.36 (2.24) (d, J = 13.0 Hz, 1H, He-4), 2.80–2.92 (m, 3H, H-9 and
H-17), 6.87 (6.82) (s, 1H, H-14), 7.01 (6.95) (d, J = 7.8 Hz, 1H, H-12), 7.06 (7.10) (d, J = 8.9 Hz, 1H,
H-3), 7.16 (7.08) (d, J = 8.2 Hz, 1H, H-11), 8.15 (8.04) (s, 1H, H-6), 8.17 (8.09) (d, J = 8.0 Hz, 1H,
H-4), 8.51 (8.48) (s, 1H, N=CH), 9.03 (9.76) (s, 1H, CONH), 10.02 (s, 1H, 2-OH). 13C-NMR
(CDCl3): 16.2 (15.8), 18.4 (18.3), 21.3 (21.2), 23.9 (23.8) (C-18 and C-19), 25.1 (25.0), 29.6 (29.7),
33.3 (33.2), 37.0 (36.9), 37.1 (37.2), 37.7 (37.6), 45.4 (45.2), 47.3 (47.1), 117.5 (117.4) (C-3), 117.8
(117.9) (C-1), 123.7 (123.6) (C-12), 123.9 (123.8) (C-11), 126.4 (126.3) (C-6), 126.7 (126.6) (C-14),
126.8 (127.0) (C-4), 134.2 (134.1) (C-8), 140.0 (139.9) (C-5), 145.8 (145.7) (C-13), 146.5 (146.3)
(C-7), 147.7 (148.1) (C=N), 163.7 (163.8) (C-2), 175.3 (175.8) (C=O). MS (ESI) m/z 464 ([M+H]+).
Anal. Calcd for C27H33N3O4: C, 69.95; H, 7.18, N, 9.06; found C, 69.78; H, 7.26; N, 8.92.
Dehydroabietic acid 2-[(5-chloro-2-hydroxyphenyl)methylene]hydrazide (4n). White powder; yield
73%; m.p. 133–134 C; IR (KBr, υ, cm1): 3269, 2957, 2930, 2869, 1650, 1611, 1530, 1478, 1383,
1345, 1272, 952, 821. 1H-NMR (CDCl3): 1.22 (1.21) (d, J = 6.8 Hz, 6H, H-18 and H-19), 1.25 (1.24)
(s, 3H, CH3, H-16), 1.40 (1.36) (s, 3H, CH3, H-15), 1.48–1.90 (m, 7H, H-2, H-3, Ha-4 and H-10), 2.17
(2.08) (d, J = 11.8 Hz, 1H, H-6), 2.35 (2.30) (d, J = 12.9 Hz, 1H, He-4), 2.72–2.95 (m, 3H, H-9 and
H-17), 6.88 (6.81) (s, 1H, H-14), 6.93 (6.96) (d, J = 8.8 Hz, 1H, H-3), 7.01 (7.07) (d, J = 8.0 Hz, 1H,
H-12), 7.14–7.25 (m, 3H, H-11, H-4 and H-6), 8.37 (8.18) (s, 1H, N=CH), 8.83 (8.68) (s, 1H, 2-OH),
9.84 (10.13) (s, 1H, CONH). 13C-NMR (CDCl3): 16.3 (15.8), 18.5 (18.4), 21.3 (21.2), 23.9 (23.8)
(C-18 and C-19), 25.1 (25.0), 29.6 (29.8), 33.4 (33.2), 37.0 (36.9), 37.1 (37.2), 37.8 (37.7), 45.5 (45.3),

Molecules 2012, 17
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47.3 (46.9), 118.6 (118.5) (C-3), 118.7 (118.8) (C-1), 123.7 (123.6) (C-5), 123.9 (123.8) (C-12),
124.0 (124.1) (C-11), 126.9 (126.8) (C-14), 129.7 (129.6) (C-6), 131.3 (131.1) (C-4), 134.4 (134.5)
(C-8), 145.9 (145.8) (C-13), 146.6 (146.5) (C-7), 148.9 (149.2) (C=N), 157.0 (157.1) (C-2), 174.7
(175.2) (C=O). MS (ESI) m/z 453 ([M+H]+). Anal. Calcd for C27H33ClN2O2: C, 71.58; H, 7.34, N, 6.18;
found C, 71.79; H, 7.51; N, 6.02.
Dehydroabietic acid 2-[(furan-2-yl)methylene]hydrazide (4o). White powder; yield 77%; m.p.
127–129 C; IR (KBr, υ, cm1): 3247, 2957, 2929, 2868, 1652, 1610, 1532, 1474, 1387, 1248, 1134,
952, 820, 742. 1H-NMR (CDCl3): 1.21 (1.20) (d, J = 7.0 Hz, 6H, H-18 and H-19), 1.26 (1.24) (s, 3H,
CH3, H-16), 1.45 (1.38) (s, 3H, CH3, H-15), 1.48–1.90 (m, 7H, H-2, H-3, Ha-4 and H-10), 2.23 (2.16)
(d, J = 11.9 Hz, 1H, H-6), 2.33 (2.29) (d, J = 12.0 Hz, 1H, He-4), 2.75–2.95 (m, 3H, H-9 and H-17),
6.60 (6.48) (dd, J = 3.6, 1.8 Hz, 1H, H-4), 6.86 (6.81) (s, 1H, H-14), 6.73 (6.58) (dd, J = 3.6, 0.8 Hz,
1H, H-3), 6.99 (6.94) (d, J = 8.0 Hz, 1H, H-12), 7.16 (7.06) (d, J = 8.1 Hz, 1H, H-11), 7.58 (7.52) (dd,
J = 1.8, 0.8 Hz, 1H, H-5), 8.45 (7.89) (s, 1H, N=CH), 9.67 (10.11) (s, 1H, CONH). 13C-NMR (CDCl3):
16.4 (15.8), 18.5 (18.4), 21.4 (21.2), 23.9 (23.8) (C-18 and C-19), 25.2 (25.1), 29.7 (29.8), 33.4 (33.2),
37.0 (36.9), 37.1 (37.2), 37.8 (37.7), 45.5 (45.3), 47.3 (46.8), 112.7 (112.5) (C-3), 113.4 (113.2) (C-4),
123.7 (123.6) (C-12), 123.9 (123.8) (C-11), 126.8 (126.7) (C-14), 134.2 (134.1) (C-8), 137.2 (137.6)
(C=N), 145.4 (145.2) (C-5), 145.8 (145.7) (C-13), 146.6 (146.5) (C-7), 149.0 (149.6) (C-2), 175.3
(175.9) (C=O). MS (ESI) m/z 393 ([M+H]+). Anal. Calcd for C25H32N2O2: C, 76.49; H, 8.22, N, 7.14;
found C, 76.33; H, 8.05; N, 7.36.
Dehydroabietic acid 2-[(5-nitrofuran-2-yl)methylene]hydrazide (4p). White powder; yield 77%; m.p.
127–129 C; IR (KBr, υ, cm1): 3256, 2959, 2932, 2866, 1651, 1607, 1522, 1465, 1382, 1241, 1136,
823, 755; 1H-NMR (CDCl3): 1.21 (1.20) (d, J = 6.8 Hz, 6H, H-18 and H-19), 1.25 (1.24) (s, 3H, CH3,
H-16), 1.42 (1.36) (s, 3H, CH3, H-15), 1.46–1.92 (m, 7H, H-2, H-3, Ha-4 and H-10), 2.21 (2.15) (d,
J = 11.7 Hz, 1H, H-6), 2.32 (2.28) (d, J = 12.6 Hz, 1H, He-4), 2.78–2.90 (m, 3H, H-9 and H-17), 6.86
(6.80) (s, 1H, H-14), 7.00 (6.94) (d, J = 8.1 Hz, 1H, H-12), 7.28 (7.42) (d, J = 3.8 Hz, 1H, H-3), 7.17
(7.05) (d, J = 8.1 Hz, 1H, H-11), 7.72 (7.85) (d, J = 3.8 Hz, 1H, H-4), 8.39 (8.11) (s, 1H, N=CH), 9.51
(9.85) (s, 1H, CONH). 13C-NMR (CDCl3): 16.3 (15.8), 18.5 (18.4), 21.3 (21.2), 23.9 (23.8) (C-18 and
C-19), 25.2 (25.1), 29.7 (29.8), 33.4 (33.2), 37.0 (36.9), 37.1 (37.2), 37.7 (37.6), 45.4 (45.3), 47.3
(47.0), 114.6 (114.5) (C-3), 115.1 (115.0) (C-4), 123.8 (123.7) (C-12), 124.0 (123.8) (C-11), 126.8
(126.7) (C-14), 134.3 (134.2) (C-8), 137.8 (138.2) (C=N), 145.8 (145.7) (C-13), 146.6 (146.5) (C-7),
151.5 (151.2) (C-5), 152.0 (151.8) (C-2), 175.1 (175.6) (C=O). MS (ESI) m/z 438 ([M+H]+). Anal.
Calcd for C25H31N3O4: C, 68.63; H, 7.14, N, 9.60; found C, 68.48; H, 7.21; N, 9.45.
Dehydroabietic acid 2-[(pyridin-2-yl)methylene]hydrazide (4q). White powder; yield 74%; m.p.
238–240 C; IR (KBr, υ, cm1): 3260, 2957, 2930, 2869, 1652, 1611, 1528, 1470, 1382, 1271, 1132,
820, 776; 1H-NMR (CDCl3): 1.22 (1.21) (d, J = 7.0 Hz, 6H, H-18 and H-19), 1.25 (1.24) (s, 3H, CH3,
H-16), 1.41 (1.36) (s, 3H, CH3, H-15), 1.48–1.95 (m, 7H, H-2, H-3, Ha-4 and H-10), 2.22 (2.16) (d,
J = 11.6 Hz, 1H, H-6), 2.36 (2.29) (d, J = 13.0 Hz, 1H, He-4), 2.75–2.90 (m, 3H, H-9 and H-17), 6.87
(6.82) (s, 1H, H-14), 6.99 (6.95) (d, J = 8.0 Hz, 1H, H-12), 7.16 (7.06) (d, J = 8.1 Hz, 1H, H-11), 7.46
(7.31) (dd, J = 7.8, 4.5 Hz, 1H, H-5), 7.87 (7.66) (t, J = 7.6 Hz, 1H, H-4), 8.23 (8.38) (d, J = 7.6 Hz,

Molecules 2012, 17
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1H, H-3), 8.54 (8.65) (d, J = 4.5 Hz, 1H, H-6), 8.58 (8.42) (s, 1H, N=CH), 9.16 (9.58) (s, 1H, CONH).
13C-NMR (CDCl3): 16.3 (15.8), 18.6 (18.4), 21.3 (21.2), 23.9 (23.8) (C-18 and C-19), 25.2 (25.1), 29.7
(29.8), 33.4 (33.2), 37.0 (36.9), 37.1 (37.2), 37.8 (37.7), 45.4 (45.2), 47.3 (47.1), 120.2 (119.8) (C-3),
123.9 (123.8) (C-12), 124.1 (124.0) (C-11), 124.6 (124.5) (C-5), 126.8 (126.7) (C-14), 134.6 (134.5)
(C-8), 137.5 (137.3) (C-4), 145.8 (145.7) (C-13), 146.2 (146.4) (C=N), 146.6 (146.5) (C-7), 149.8
(149.5) (C-6), 153.7 (153.8) (C-2), 175.7 (176.0) (C=O). MS (ESI) m/z 404 ([M+H]+). Anal. Calcd
for C26H33N3O: C, 77.38; H, 8.24, N, 10.41; found C, 77.48; H, 8.11; N, 10.32.
3.4. Antibacterial Studies
The antibacterial activities of the newly synthesized compounds 4a–q were evaluated against
four test bacteria: Bacillus subtilis CGMCC1.3343, Escherichia coli CGMCC1.3373, Pseudomonas
fluorescens CGMCC1.1802 and Staphylococcus aureus CGMCC1.2465. The four bacteria were
obtained from China General Microbiological Culture Collection Center (CGMCC), China. The
antibacterial activity was assessed in terms of minimum inhibitory concentrations (MICs) by a
modified microdilution method [22]. Compounds were dissolved in DMSO and serial double dilutions
of each compound (50 μL) were prepared in 96 well micro-trays. The same amount of test
microorganism suspension in Martin’s broth (~105 colony forming unit (CFU)/mL) was added to each
well to give final concentrations ranging from 250 to 0.45 μg/mL. Amikacin sulfate was co-assayed as
positive control, and DMSO was used as negative control. After incubation at 37 C for 24 h, the trays
were examined for the growth for the test microorganisms. The MIC was defined as the lowest
concentrations of compound at which there was no visual turbidity due to microbial growth. All assays
were performed in duplicate.
4. Conclusions
In this study, a series of new N-acylhydrazone derivatives 4a–q of dehydroabietic acid were
synthesized and characterized in approach of new antibacterial agents. All the compounds were
evaluated for their in vitro antibacterial activities against four bacteria. The MIC results indicated that
the activities of the investigated compounds were influenced by the physicochemical properties of the
substituent at hydrazone moiety. Compounds with fluoro, chloro and nitro substituents exhibited
pronounced antibacterial activities, among which the nitrofuranyl derivative 4p showed strongest
activity against two Gram-positive bacteria. The results highlight these new N-acylhydrazone
derivatives as potential leads for the further investigation on new antibacterial drug candidates.
Acknowledgements
The authors are grateful to the National Natural Science Foundation of China for financial support
(Project: 31000273 and 30972316). This work was also supported by a project funded by the Priority
Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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