Synthesis and antibacterial activity of C-7 acylhydrazone derivatives of dehydroabietic acid

Article abstract of DOI:10.3184/174751918X15337207982686

Seven new C-7 acylhydrazone derivatives of dehydroabietic acid were synthesised from dehydroabietic acid through benzylic oxidation, condensation with hydrazine hydrate, followed by nucleophilic substitution reactions with a variety of substituted aromatic acids. The structures of the synthesised compounds were characterised by IR, ¹H NMR and MS. The antibacterial activities of the synthesised compounds were evaluated by the disk diffusion method. Antibacterial activity studies showed that C-7 acylhydrazone derivatives of dehydroabietic acid exhibited inhibitory activities against Escherichia coli, Staphylococcus aureus and Bacillus subtilis. Among the seven compounds, dehydroabietic acid p-fluorobenzoyl hydrazone showed the strongest inhibitory activity against B. subtilis and S. aureus.

Full text of DOI:10.3184/174751918X15337207982686

JOURNAL OF CHEMICAL RESEARCH 2018
VOL. 42 AUGUST, 405–407
RESEARCH PAPER 405
Synthesis and antibacterial activity of C-7 acylhydrazone derivatives of
dehydroabietic acid
a
b
Zhi Zhou * and Tingting Zhou
a
School of Life and Health Science, Kaili University, Kaili, Guizhou 556011, P.R. China
Clinical Laboratory, Yuping Dong Autonomous County People’s Hospital, Yuping, Guizhou 556011, P.R. China
b
Seven new C-7 acylhydrazone derivatives of dehydroabietic acid were synthesised from dehydroabietic acid through benzylic oxidation,
condensation with hydrazine hydrate, followed by nucleophilic substitution reactions with a variety of substituted aromatic acids. The
1
structures of the synthesised compounds were characterised by IR, H NMR and MS. The antibacterial activities of the synthesised
compounds were evaluated by the disk diffusion method. Antibacterial activity studies showed that C-7 acylhydrazone derivatives of
dehydroabietic acid exhibited inhibitory activities against Escherichia coli, Staphylococcus aureus and Bacillus subtilis. Among the seven
compounds, dehydroabietic acid p-fluorobenzoyl hydrazone showed the strongest inhibitory activity against B. subtilis and S. aureus.
Keywords: dehydroabietic acid, acylhydrazone, synthesis, antibacterial activity
Dehydroabietic acid 1, which possesses an aromatic diterpene
structure with three rings and three chiral carbon atoms,
can be extracted from commercial disproportionated rosin.
Dehydroabietic acid and its derivatives have attracted
considerable interest due to their potential biological activities,
with hydrazine hydrate, followed by nucleophilic substitution
reactions with a variety of substituted aromatic acids. The
antibacterial activities of the target compounds were then tested.
Results and discussion
1
,2
3
4–6
7
including antimicrobial, antiviral, antitumour, antiulcer and
The general procedure for the synthesis of C-7 acylhydrazone
derivatives of dehydroabietic acid (4a–g) is shown in Scheme 1.
Dehydroabietic acid 1, the starting material, was oxidised
with t-BuOOH to give compound 2. The traditional methods for
C-7 benzylic oxidations of dehydroabietic acid have involved
the use of very large excesses of chromium(VI) reagents, such
8
anti-inflammatory activity. Reports of the biological activity of
dehydroabietic acid and its derivatives prompted us to search
9
for new rosin acid derivatives. Li et al. utilised transformation
of the carboxyl group to synthesise dehydroabietic acid-based
acylhydrazone derivatives, many of which showed moderate to
high levels of anticancer activity, and some displayed similar
potent inhibitory activities comparable to commercial anticancer
11–14
as CrO and Na CrO ,
in a mixed solvent of Ac O/AcOH.
3
2
4
2
This has led to considerable amounts of toxic effluents and low
yields (56.7%). When dehydroabietic acid was treated with an
10
drugs. Gu et al. synthesised a series of dehydroabietic acid
acylhydrazone derivatives by means of carboxyl halogenation,
reaction with hydrazine hydrate to generate an acylhydrazine,
followed by condensation with a variety of substituted aromatic
aldehydes, some of which exhibited pronounced antimicrobial
activity. The majority of studies on acylhydrazone derivatives
of dehydroabietic acid have focused on the carboxyl group,
and acylhydrazone derivatives at other centres have seldom
been reported. In this paper, we report the synthesis of seven
new C-7 acylhydrazone derivatives of dehydroabietic acid from
dehydroabietic acid through benzylic oxidation, condensation
excess of t-BuOOH (8 equiv.) as an oxidant and CrO /pyridine
3
mixture as a catalyst in CH Cl the yields of compound 2
2
2
increased significantly (70.5%). Subsequently, the reactions of
compound 2 with hydrazine hydrate yielded the corresponding
7-oxodehydroabietic acid hydrazone 3.
Dehydroabietic acid acylhydrazone derivatives 4a–g were
prepared by the following procedure. First, substituted aromatic
acids were reacted with thionyl chloride (SOCl ) in dry toluene
2
for 30 min at room temperature. The products were dissolved in
dry CH Cl and cooled to 0 °C, a solution of compound 3 and
2
2
Scheme 1 Synthesis of C-7 acylhydrazone derivatives of dehydroabietic acid (4a–g).
*
Correspondent. E-mail: zhou86zhi@163.com

4
06 JOURNAL OF CHEMICAL RESEARCH 2018
Table 1 Antimicrobial activities of the tested compounds (units: diameter of inhibition zone/cm)
Compound no.
4a
4b
4c
4d
4e
4f
4g
Ciprofloxacin
2.93
Escherichia coli
Staphylococcus aureus
Bacillus subtilis
0.78
0.86
0.95
0.85
1.02
0.83
1.21
1.34
1.40
1.26
1.45
1.68
1.18
1.24
1.29
1.03
0.94
1.07
1.23
1.42
1.39
3.01
3.39
pyridine in dry CH Cl was added, and the mixture was then
stirred for 2 h at room temperature.
J = 2.0 Hz, 1H), 7.41 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 7.29 (d, J = 8.0 Hz,
1H), 2.92 (septet, J = 7.0 Hz, 1H), 2.75 (dd, J = 13.9 Hz, 13.9 Hz,
2
2
1
H), 2.70 (d, J = 13.9 Hz, 1H), 2.49 (d, J = 13.9 Hz, 1H), 2.36 (br d,
J = 13.0 Hz, 1H), 2.90–1.39 (m, 3H), 1.35 (s, 3H), 1.26 (s, 3H), 1.24 (d,
J = 7.0 Hz, 6H); TOF MS m/z: 314.2 [M ]; Anal. calcd for C H O
3
Antibacterial activity
The results for the antimicrobial activities of acylhydrazone
derivatives of dehydroabietic acid are listed in Table 1.
As shown in Table 1, all of the compounds 4a–g that were
tested showed some inhibitory activity against three bacterial
strains. Dehydroabietic acid p-nitrobenzoyl hydrazone 4c,
dehydroabietic acid p-fluorobenzoyl hydrazone 4d and
dehydroabietic acid p-chlorobenzoyl hydrazone 4g exhibited
considerably higher inhibitory activity against two bacterial
strains, including Bacillus subtilis and Staphylococcus
aureus. Among the seven compounds, dehydroabietic acid
p-fluorobenzoyl hydrazone showed the strongest inhibitory
activity against B. subtilis and S. aureus, the diameters of
antibacterial rings reaching 1.68 and 1.45 cm, respectively.
+
2
0
26
(314.42): C, 76.40; H, 8.33; found: C, 76.51; H, 8.58%.
Preparation of 7-oxodehydroabietic acid hydrazone (3)
Compound 2 (10 g, 31.80 mmol) was dissolved in ethanol (160 mL)
and the mixture was stirred and heated to reflux. Next, 98% hydrazine
hydrate (2.08 g, 41.34 mmol) was added dropwise and the mixture was
stirred and heated at reflux for 1 h. The solvent was evaporated under
reduced pressure and the residue was recrystallised from ethanol to
give compound 3: Light yellow solid; yield: 85.5%; m.p. 164–166 °C;
−1
FTIR (KBr, νmax/cm ): 3358, 3243 (NH), 2954, 2925, 2863 (CHalkyl),
1
1
721 (C=O), 1657 (C=N), 1608, 1501, 1453 (C=Carom); H NMR
(
500 MHz, CDCl ): δ (ppm) 7.56 (d, J = 2.0 Hz, 1H), 7.27 (dd, J
3
= 8.0 Hz, 2.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 5.34 (br s, 2H), 2.87
septet, J = 7.0 Hz, 1H), 2.72 (dd, J = 13.8 Hz, 13.8 Hz, 1H), 2.67 (d,
(
Conclusion
J = 13.8 Hz, 1H), 2.45 (d, J = 13.8 Hz, 1H), 2.35 (br d, J = 13.0 Hz, 1H),
We have prepared a series of C-7 acylhydrazone derivatives
of dehydroabietic acid by benzylic oxidation, condensation
with hydrazine hydrate, followed by nucleophilic substitution
reactions with a variety of substituted aromatic acids. Their
antibacterial activities against E. coli, S. aureus and B. subtilis
were evaluated by the disk diffusion method. The results
showed that C-7 acylhydrazone derivatives of dehydroabietic
acid possessed good antibacterial activities, among which
dehydroabietic acid p-fluorobenzoyl hydrazone showed the
highest activity against B. subtilis and S. aureus.
2.89–1.37 (m, 3H), 1.34 (s, 3H), 1.25 (s, 3H), 1.23 (d, J = 7.0 Hz, 6H);
+
TOF MS m/z: 330.2 [M+H] ; Anal. calcd for C20
H
N
O
(329.46): C,
29
2
2
72.91; H, 8.87; N, 8.50; found: C, 72.76; H, 8.83; N, 8.39%.
Preparation of dehydroabietic acid acylhydrazone derivatives (4a–g)
Thionyl chloride (2.34 g, 19.71 mmol) was added slowly with stirring to a
solution of p-methoxybenzoic acid (2.00 g, 13.14 mmol) in dry toluene
(
20 mL) at 0 °C. The mixture was then stirred at 23 °C for 30 min.
After cooling, the solvent and excess SOCl were removed in vacuo
2
to yield p-methoxybenzoyl chloride as a colourless oily product. This
was then dissolved in dry CH Cl (10 mL) and cooled to 0 °C, then a
2
2
solution of compound 3 (2.16 g, 6.57 mmol) and pyridine (1.56 g,
9.71 mmol) in dry CH Cl (30 mL) was added dropwise with stirring.
Experimental
1
2
2
All chemicals and solvents were obtained from commercial sources
and were used as received or dried according to standard procedures.
Column chromatography was performed on silica gel (ZCXII,
The mixture was stirred for 2 h at room temperature and the precipitate
that formed was collected by filtration and washed with CH Cl2
2
(10 mL) and acetone (10 mL). The solid was then added to cold water
(20 mL) and stirred for 1 h, then filtered, washed with distilled water
(3 × 10 mL) and recrystallised from ethanol to give compound 4a:
100~200 mesh). Chemical reactions were monitored by thin-layer
chromatography (TLC) using pre-coated silica gel GF254 plates.
Melting points were determined on an RY-1G melting point apparatus
−1
White solid; yield: 54.5%; m.p. 183–185 °C; FTIR (KBr, νmax/cm ):
1
and are uncorrected. H NMR spectra were recorded on a Bruker
3241 (NH), 2955, 2926, 2863 (CHalkyl), 1725 (C=O), 1646 (C=N),
1
Avance AV-500 spectrometer at 500 MHz. Chemical shifts are
reported in δ (parts per million) relative to tetramethylsilane (TMS)
and coupling constants (J) are given in hertz (Hz). Infrared spectra
were recorded using KBr pellets on a Nicolet 360 FT-IR spectrometer.
ESI mass spectra were obtained on an Agilent 1100 Capillary
LC/Micromass Q-TOF micromass spectrometer. Microanalytical data
were obtained on an Elementar Vario EL III elemental analyser.
1603, 1510, 1461 (C=Carom); H NMR (500 MHz, CDCl
3
): δ (ppm)
11.08 (s, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.82 (d, J = 2.0 Hz, 1H), 7.22 (dd,
J = 8.0 Hz, 2.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.5 Hz,
2
H), 3.79 (s, 3H), 2.97 (dd, J = 17.6 Hz, 12.8 Hz, 1H), 2.87 (septet,
J = 7.0 Hz, 1H), 2.68–2.49 (m, 2H), 2.45 (d, J = 11.9 Hz, 1H), 2.38 (br
d, J = 11.8 Hz, 1H), 2.19–1.98 (m, 2H), 1.65–1.58 (m, 1H), 1.56 (s, 3H),
+
1
.27 (d, J = 6.8 Hz, 6H), 1.22 (s, 3H); TOF MS m/z: 463.2 [M+H] ;
Anal. calcd for C H N O (462.58): C, 72.70; H, 7.41; N, 6.06; found:
2
8
34
2
4
Preparation of 7-oxodehydroabietic acid (2)
C, 72.57; H, 7.36; N, 5.95%.
A suspension of CrO (74 mg, 0.74 mmol) in CH Cl (120 mL) was
Compounds 4b–g were prepared by the same procedure as used for
the synthesis of compound 4a.
3
2
2
treated with 65% t-BuOOH (19 mL, 118.4 mmol) and pyridine
0.12 mL, 1.48 mmol). The mixture was stirred for 3 min at room
(
Compound 4b: White solid; yield: 57.4%; m.p. 174–176 °C; FTIR
−1
temperature. Dehydroabietic acid 1 (4.45 g, 14.8 mmol) was added
and stirring continued for 24 h at room temperature, The resulting
solution was then washed successively with saturated solutions of
Na S O (2 × 40 mL) and brine (40 mL), dried over anhydrous MgSO
4
(KBr, νmax/cm ): 3271 (NH), 2956, 2862 (CHalkyl), 1722 (C=O),
1
1651 (C=N), 1602, 1531, 1453 (C=Carom); H NMR (500 MHz, CDCl ):
3
δ (ppm) 11.35 (s, 1H), 10.85 (s, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.80 (d,
J = 2.0 Hz, 1H), 7.21 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 7.27 (d, J = 8.0 Hz,
1H), 7.12 (d, J = 8.5 Hz, 2H), 2.95 (dd, J = 17.6 Hz, 12.8 Hz, 1H), 2.89
(septet, J = 7.0 Hz, 1H), 2.71–2.50 (m, 2H), 2.42 (d, J = 11.9 Hz, 1H),
2.37 (br d, J = 11.8 Hz, 1H), 2.17–1.95 (m, 2H), 1.62–1.57 (m, 1H),
1.53 (s, 3H), 1.29 (d, J = 6.8 Hz, 6H), 1.23 (s, 3H); TOF MS m/z: 449.2
2
2
3
and filtered. The solvent was evaporated under reduced pressure,
and the residue was purified by column chromatography on silica gel
(
chloroform/ethylacetate, 10:1) to give compound 2: Light yellow
15
solid; yield: 70.5%; m.p. 158–160 °C (lit. 160–161.5 °C); FTIR
(
1
−1
+
KBr, νmax/cm ): 2955, 2929, 2868 (CHalkyl), 1722, 1693 (C=O), 1604,
[M+H] ; Anal. calcd for C H N O (448.55): C, 72.30; H, 7.19; N,
27
32
2
4
1
497, 1458 (C=Carom); H NMR (500 MHz, CDCl ): δ (ppm) 7.87 (d,
6.25; found: C, 72.25; H, 7.16; N, 6.19%.
3

JOURNAL OF CHEMICAL RESEARCH 2018 407
Compound 4c: Light yellow solid; yield: 60.7%; m.p. 195–197 °C;
FTIR (KBr, νmax/cm ): 3254 (NH), 2967, 2925, 2846 (CHalkyl),
Antibacterial activity studies
−1
The antibacterial activities of the synthesised compounds were
evaluated against three test bacteria: Escherichia coli, Staphylococcus
aureus and Bacillus subtilis. The antimicrobial screening of the
prepared compounds was performed according to the disk diffusion
1
1
1
721 (C=O),
1649 (C=N),
1602 (C=Carom),
1528
(NO ),
2
1
471 (C=Carom), 1351 (NO ); H NMR (500 MHz, CDCl ): δ (ppm)
1.59 (s, 1H), 8.32 (d, J = 8.5 Hz, 2H), 8.12 (d, J = 8.5 Hz, 2H), 7.83 (d,
2
3
J = 2.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.23 (dd, J = 8.0 Hz, 2.0 Hz,
H), 2.95 (dd, J = 17.6 Hz, 12.8 Hz, 1H), 2.88 (septet, J = 7.0 Hz, 1H),
.73–2.52 (m, 2H), 2.45 (d, J = 11.9 Hz, 1H), 2.39 (br d, J = 11.8 Hz,
16
method. Filter paper disks of 7 mm diameter were sterilised by
1
2
1
autoclaving for 15 min at 121°C. Compounds 4a–g were dissolved in
dimethylformamide (DMF) to give a 30 mg mL solution, and the
−1
H), 2.18–1.94 (m, 2H), 1.64–1.58 (m, 1H), 1.54 (s, 3H), 1.30 (d,
sterile disks were impregnated with the prepared solution for 10 min.
Agar plates were surface inoculated uniformly from the broth culture
of the tested microorganisms. The impregnated disks were placed
on the medium, suitably spaced apart, and the plates were incubated
at 5 °C for 1 h to permit good diffusion and then transferred to an
incubator at 35 °C for 48 h to grow the bacteria, which were then
examined for the inhibition zones resulting from the action of the
prepared compounds on the microorganisms. The zone of inhibition
was measured in cm and compared with the reference standard,
ciprofloxacin.
+
J = 6.8 Hz, 6H), 1.24 (s, 3H); TOF MS m/z: 478.2 [M+H] ; Anal. calcd
for C H N O (477.55): C, 67.91; H, 6.54; N, 8.80; found: C, 67.87; H,
2
7
31
3
5
6
.58; N, 8.71%.
Compound 4d: White solid; yield: 58.3%; m.p. 181–183 °C; FTIR
−1
(
1
(
7
KBr, νmax/cm ): 3256 (NH), 2953, 2930, 2869 (CHalkyl), 1727 (C=O),
1
651 (C=N), 1604, 1508 (C=Carom); H NMR (500 MHz, CDCl ): δ
3
ppm) 11.50 (s, 1H), 8.30 (d, J = 8.5 Hz, 2H), 8.07 (d, J = 8.5 Hz, 2H),
.78 (d, J = 2.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.21 (dd, J = 8.0 Hz,
.0 Hz, 1H), 2.91 (dd, J = 17.6 Hz, 12.8 Hz, 1H), 2.84 (septet,
J = 7.0 Hz, 1H), 2.76–2.54 (m, 2H), 2.46 (d, J = 11.9 Hz, 1H), 2.35 (br
2
d, J = 11.8 Hz, 1H), 2.25–1.96 (m, 2H), 1.69–1.60 (m, 1H), 1.53 (s, 3H),
Acknowledgement
+
1.29 (d, J = 6.8 Hz, 6H), 1.23 (s, 3H); TOF MS m/z: 451.2 [M+H] ;
This study was supported by the Qiandongnan Science and
Technology Planning Project (QDNco-J word (2015) 002).
Anal. calcd for C H FN O (450.55): C, 71.98; H, 6.94; N, 6.22;
2
7
31
2
3
found: C, 71.92; H, 6.92; N, 6.18%.
Compound 4e: White solid; yield: 55.2%; m.p. 187–189 °C; FTIR
−1
Received 15 May 2018; accepted 22 July 2018
Paper 1805431
https://doi.org/10.3184/174751918X15337207982686
Published online: 17 August 2018
(
1
(
7
KBr, νmax/cm ): 3268 (NH), 2943, 2927, 2861 (CHalkyl), 1719 (C=O),
1
643 (C=N), 1603, 1512 (C=Carom); H NMR (500 MHz, CDCl ): δ
3
ppm) 11.57 (s, 1H), 8.14 (d, J = 7.8 Hz, 2H), 7.87 (d, J = 8.4 Hz, 2H),
.81 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.20 (dd, J = 8.0 Hz,
2
.0 Hz, 1H), 2.89 (dd, J = 17.6 Hz, 12.8 Hz, 1H), 2.83 (septet,
References
J = 7.0 Hz, 1H), 2.74–2.55 (m, 2H), 2.47 (d, J = 11.9 Hz, 1H), 2.37 (br
d, J = 11.8 Hz, 1H), 2.30–1.98 (m, 2H), 1.71–1.64 (m, 1H), 1.54 (s, 3H),
1
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+
1.29 (d, J = 6.8 Hz, 6H), 1.22 (s, 3H); TOF MS m/z: 501.2 [M+H] ;
2
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found: C, 67.13; H, 6.22; N, 5.54%.
2
8
31
3
2
3
Compound 4f: White solid; yield: 60.3%; m.p. 178–180 °C; FTIR
3
4
5
6
7
8
9
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(
1
KBr, νmax/cm ): 3265 (NH), 2958, 2929, 2837 (CHalkyl), 1715 (C=O),
1
653 (C=N), 1607, 1536, 1481 (C=Carom); H NMR (500 MHz, CDCl ):
3
δ (ppm) 10.97 (s, 1H), 8.24 (d, J = 8.5 Hz, 2H), 8.01 (d, J = 8.4 Hz, 2H),
7.79 (d, J = 2.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.18 (dd, J = 8.0 Hz,
2
.0 Hz, 1H), 2.87 (dd, J = 17.5 Hz, 12.6 Hz, 1H), 2.82 (septet,
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d, J = 11.3 Hz, 1H), 2.28–2.01 (m, 2H), 1.70–1.64 (m, 1H), 1.52 (s,
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3H), 1.27 (d, J = 6.7 Hz, 6H), 1.23 (s, 3H); TOF MS m/z: 511.1, 513.1
+
[
M+H] ; Anal. calcd for C H BrN O (511.45): C, 63.41; H, 6.11; N,
27 31 2 3
5.48; found: C, 63.37; H, 6.18; N, 5.35%.
Compound 4g: Light yellow solid; yield: 56.9%; m.p. 174–176 °C;
10
−1
FTIR (KBr, νmax/cm ): 3242 (NH), 2971, 2934, 2865 (CHalkyl),
1
1726 (C=O), 1650 (C=N), 1598, 1539, 1491 (C=Carom); H NMR
11
W.G. Salmond, M.A. Bartra and J.L. Havens, J. Org. Chem., 1978, 43, 2057.
(
500 MHz, CDCl ): δ (ppm) 11.29 (s, 1H), 8.29 (d, J = 8.5 Hz, 2H),
12 Y. Matsushita, Y. Iwakiri, S. Yoshida, K. Sugamoto and T. Matsui,
3
8
1
1
.15 (d, J = 8.5 Hz, 2H), 7.84 (d, J = 2.0 Hz, 1H), 7.24 (d, J = 8.0 Hz,
H), 7.21 (dd, J = 7.9 Hz, 2.0 Hz, 1H), 2.81 (dd, J = 17.6 Hz, 12.5 Hz,
H), 2.78 (septet, J = 6.9 Hz, 1H), 2.83–2.64 (m, 2H), 2.38 (d,
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14
J = 11.5 Hz, 1H), 2.34 (br d, J = 11.3 Hz, 1H), 2.30–2.18 (m, 2H),
.78–1.67 (m, 1H), 1.51 (s, 3H), 1.26 (d, J = 6.5 Hz, 6H), 1.21 (s, 3H);
1
1
+
TOF MS m/z: 467.2, 469.2 [M+H] ; Anal. calcd for C H ClN O
16 H.H. Fahmy, A. El-Masry and S.H. Ali Abdelwhed, Arch. Pharm. Res.,
2001, 24, 27.
2
7
31
2
3
(467.00): C, 69.44; H, 6.69; N, 6.00; found: C, 69.37; H, 6.75; N, 5.94%.