The synthesis and antistaphylococcal activity of dehydroabietic acid derivatives: Modifications at C-12

Article abstract of DOI:10.1016/j.bmcl.2016.10.018

A series of 12-oxime and O-oxime ether derivatives of dehydroabietic acid were synthesized and investigated for the antibacterial activity against Staphylococcus aureus Newman strain and five multidrug-resistant strains (NRS-1, NRS-70, NRS-100, NRS-108, a

Full text of DOI:10.1016/j.bmcl.2016.10.018

Bioorganic & Medicinal Chemistry Letters 26 (2016) 5492–5496
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The synthesis and antistaphylococcal activity of dehydroabietic acid
derivatives: Modifications at C-12
Ming-Liang Liu , Xue-Ying Pan b,d, Teng Yang c,d, Wen-Ming Zhang , Tian-Qi Wang , He-Yun Wang ,
a
a
a
a
a
d,
⇑
a,d,
⇑
Hai-Xia Lin , Cai-Guang Yang , Yong-Mei Cui
a
Department of Chemistry, Innovative Drug Research Center, College of Sciences, Shanghai University, Shanghai 200444, China
Nano Science and Technology Institute, University of Science and Technology of China, Suzhou 215123, China
Center for Research and Development of Fine Chemicals, Guizhou University, Guiyang 550025, China
b
c
d
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 July 2016
Revised 27 September 2016
Accepted 7 October 2016
Available online 12 October 2016
A series of 12-oxime and O-oxime ether derivatives of dehydroabietic acid were synthesized and
investigated for the antibacterial activity against Staphylococcus aureus Newman strain and five
multidrug-resistant strains (NRS-1, NRS-70, NRS-100, NRS-108, and NRS-271). The aromatic oximate
derivative 11a showed the highest activity with MIC of 0.39–0.78
note, compounds 10b, 11 and 14 showed the most potent antibacterial activity against five multidrug-
resistant S. aureus with MIC values of 1.25–3.13 g/mL. These results offered useful information for
lg/mL against S. aureus Newman. Of
l
Keywords:
further strategic optimization in search of the antibacterial candidates against infection of
multidrug-resistant Gram-positive bacteria.
Antistaphylococcal
Multidrug-resistant
Synthesis
Ó 2016 Elsevier Ltd. All rights reserved.
Oxime
Dehydroabietic acid
Hospital acquired infections with multidrug-resistant bacteria
represent a global public health threat. In particular, methicillin-
resistant Staphylococcus aureus (MRSA) acquired resistance against
many different antibiotics, including b-lactam, cephalosporin, fluo-
roquinolone, aminoglycoside, tetracycline, macrolide, trimetho-
prim-sulfamethoxazole, and vancomycin.1 The current situation
has stimulated an urgent need to develop more effective
antistaphylococcal agents with novel chemical structures and
mechanisms. Natural products (NPs) are biologically validated
starting points for drug discovery and have played a dominant role
OH
12
1
2
1
2
OH
1
9
0
C
1
9
1
9
14
1
8
14
14
A
B
10
8
10
5
8
5
5
4
7
6
4
4
H
H
H
CO
2
H
abietane skeleton
totarol
ferruginol
dehydroabietic acid,1
Figure 1.
2
antiviral, antimicrobial, anti-inflammatory, and BK channel-
in drug discovery efforts for treatment of human diseases. The abi-
etanes are diterpenoids possessing an ABC ring system and have
1
2–17
opening activities.
Interestingly, DHAA and its derivatives
inhibited the formation of bacterial biofilm during infections
of S. aureus, which demonstrated its ability not only to prevent
bacterial colonization, but also to inhibit existing biofilms.1
These findings indicate the potential usage of the DHAA analogues
as novel biological probes and pharmaceutical agents. In addition
to the several series of DHAA derivatives that displayed potent
antimicrobial activities 0–22, there are still interesting
modifications to be exploited, especially for antibiotic-resistant
Gram-positive bacteria.
demonstrated to show a broad range of biological properties partic-
ularly antibacterial activity.3–6 For example, the well-known natural
8,19
diterpenoids totarol and ferruginol (Fig. 1) and related NPs, as well
as tricyclic diterpene analogues have shown antibacterial activity
against Gram-positive bacteria7 and in particular MRSA.
–9
10,11
Dehydroabietic acid (DHAA, 1) is an abietane diterpene that can
be readily obtained by disproportionation of rosin or abietic acid.
DHAA and its derivatives have been reported to possess a broad
spectrum of biological properties such as antiulcer, antitumor,
2
Oximes and derivatives are found in a variety of drugs on the
market, including fluvoxamine (antidepressant), oxiconazole
⇑
Corresponding authors.
E-mail addresses: yangcg@simm.ac.cn (C.-G. Yang), ymcui@t.shu.edu.cn
(
(
antifungal), and antibacterial drugs gemifloxacin and cefetamet
Fig. 2). In our continued efforts against S. aureus infection,
23
(
Y.-M. Cui).
http://dx.doi.org/10.1016/j.bmcl.2016.10.018
960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
0

M.-L. Liu et al. / Bioorg. Med. Chem. Lett. 26 (2016) 5492–5496
5493
OR2
N
Table 1
O
N
OMe
R
1
Preliminary MIC measurements for aliphatic oximate derivatives against S. aureus
Newman
N
COOH
H
1
2
N
S
S
OR2
N
MeO
H
N
O
O
N
O
Me
R1
N
2
H N
N
O
4
2
H
CO
2
H
O
O
Gemifloxacin
Cefetamet
5
-15c
COOH
Figure 2.
Compound
R1
R2
MIC (lg/mL)
OH
N
Vancomycin
Tetracycline
DHAA (1)
5
—
—
—
CH
—
—
—
H
0.78–1.56
<0.2
12.5–20
>50
R1
O
R1
3
a
b
5a
CH
CH
3
30–40
>50
5b
3
COOMe
COOMe
a-k
R1
COOMe
4a-k
5
c
CH
3
>50
2
3
6
6
H
CH
3
>50
>50
>50
c
a
3
a, 4a,5
Me
Et
6b
OH
N
3
b, 4b, 6
R1
6c
20–25
3c, 4c,7
3
d, 4d, 8
6d
7
>50
3
e, 4e, 9
f, 4f, 10
H
40–50
40–50
10–12.5
7a
CH
3
3
7b
COOH
3
F C
5-15
7c
15–20
>50
3
g, 4g, 11
d
7d
CF
3
3
h, 4h, 12
OR
2
8
H
>50
N
R1
3
i, 4i, 13
j, 4j, 14
k, 4k, 15
CF
Cl
8a
CH3
30–40
10–12.5
10–12.5
3
Cl
8
8
b
c
3
3
S
COOH
a-15c
8
9
d
>50
5
R2 = CH
,
3
H
12.5–25
>50
1
9a
9b
CH3
Scheme 1. Reagents and conditions: (a) R COCl, AlCl
6–99%; (b) NH OH–HCl, Py, EtOH, reflux, 4 h, 51–86%; (c) KOBu , DMSO, rt, 2 h,
3–91% (d) R Br or R I, NaI, KOH, EtOH, 40–70 °C, 6 h, 44–95%.
3
, CCl
4
, À20 °C, overnight,
t
5
7
2
2
2
12.5–25
>50
9c
herein, we report the synthesis of a series of new 12-oxime or
oxime ether derivatives 5–15c starting from DHAA. The in vitro
antibacterial activities were evaluated against S. aureus Newman
strain and five multidrug-resistant S. aureus in order to define
the influence of structural features on the aromatic ring upon
antibacterial potency of these diterpenes.
stereo-configuration of which was determined by X-ray analysis24
and its derivatives 5a–c were isolated as E isomers. All remaining
oximes 6–15c were used in the pharmacological tests as mixtures
of E and Z isomers.
The in vitro antimicrobial activities of all the synthesized DHAA
derivatives were evaluated for Gram-positive bacteria, S. aureus
Newman, and five multidrug-resistant S. aureus including NRS-1
,
The synthetic procedures for the target compounds are outlined
in Scheme 1. Friedel–Crafts acylation of dehydroabietic acid
methyl ester (2) with various acyl chloride in the presence of AlCl
in CCl
yields. Treatment of 3a–k with hydroxylamine hydrochloride in
3
(
resistant to aminoglycosides and tetracycline), NRS-70 (resistant
4
at À20 °C afforded the 12-keto derivatives 3a–k in 56–99%
to erythromycin), NRS-100 (resistant to oxacillin and tetracycline),
NRS-108 (resistant to gentamicin), and NRS-271 (linezolid resis-
tant, containing phage type E-MRSA 15). All target compounds
EtOH under reflux afforded the corresponding oximes 4a–k in
t
5
1–86% yields. Then esterolysis of 4a–k by KOBu in DMSO
were evaluated at the concentrations ranging from 0.39
lg/mL to
afforded 5–15 in 73–91% yields. The target oxime ether derivatives
a–15c (Tables 1 and 2) were correspondingly prepared by
50 l
g/mL and assessed in terms of minimum inhibitory concentra-
5
tions (MICs), which are defined as the lowest concentrations of
compound at which microbial growth was inhibited. Vancomycin
and tetracycline were included as positive controls. Experiments
were performed in triplicate for each condition. The antibacterial
data are shown in Tables 1 and 2.
O-Alkylation of 5–15 with various alkyl or aryl halides. Almost all
the oximes 4a–k obtained in the coupling reactions were mixtures
of E and Z isomers and, in most cases, not resolved in the two
components when their separation proved to be impossible by
crystallization or flash chromatography. Compound 5, the

5
494
M.-L. Liu et al. / Bioorg. Med. Chem. Lett. 26 (2016) 5492–5496
Table 2
MICs of synthetic aromatic oximate derivatives against the growth of strains of S. aureus Newman, NRS-1, NRS-70, NRS-100, NRS-108, and NRS-271
OR2
N
R1
COOH
Compound
R1
R2
MIC (lg/mL)
Newman
NRS-1
NRS-70
NRS-100
NRS-108
NRS-271
Vancomycin
Tetracycline
DHAA (1)
—
—
—
—
—
—
—
—
0.78–1.56
<0.2
12.5–20
10–12.5
1.56–3.13
>25
12.5–25
—
0.2–0.39
<0.20
12.5–25
—
0.39–0.78
<0.20
12.5–25
—
0.39–0.78
<0.20
12.5–25
—
0.39–0.78
<0.20
12.5–25
—
1
0
1
0a
CH
3
5.0
—
—
—
—
—
1
1
1
0b
0c
0d
1.25–2.5
2.5
2.5–3.13
6.25–12.5
—
1.25–1.56
1.56–2.5
—
1.56–2.5
3.13
1.56–2.5
3.13–6.25
—
1.56–2.5
3.13–6.25
—
>50
—
1
1
1
1
1
H
1.56–3.13
0.39–0.78
0.78–1.56
1.56–3.13
1.56–3.13
3.13–6.25
12.5–25
>25
1.56–3.13
1.56–3.13
1.56–3.13
>25
1.56–3.13
3.13–6.25
6.25–12.5
>25
1.56–3.13
6.25–12.5
6.25–12.5
>25
1.56–3.13
1.56–3.13
>50
F
F
F
F
3
3
3
3
C
C
C
C
1a
1b
1c
CH
3
>25
CF
CF
CF
CF
3
3
3
3
1
1
1
1
2
H
1.56–3.13
1.56–3.13
>50
3.13–6.25
>25
1.56–3.13
>25
3.13–6.25
>25
3.13–6.25
>25
3.13–6.25
>25
2a
2b
2c
CH
3
—
—
—
—
—
1.56–3.13
>25
>25
>25
>25
>25
1
1
1
1
3
H
>50
>50
>50
>50
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
CF
CF
CF
CF
3
3
3
3
3a
3b
3c
CH
3
Cl
Cl
Cl
Cl
1
1
1
1
4
H
1.56–3.13
1.56–3.13
1.56–3.13
1.56–3.13
3.13
>25
>25
>25
1.56–3.13
1.56–3.13
1.56–3.13
1.56–3.13
3.13
1.56–3.13
>25
1.56–3.13
>25
Cl
Cl
Cl
Cl
4a
4b
4c
CH
3
>25
12.5–25
12.5–25
12.5
>25
12.5
12.5–25

M.-L. Liu et al. / Bioorg. Med. Chem. Lett. 26 (2016) 5492–5496
5495
Table 2 (continued)
Compound
R1
R2
MIC (lg/mL)
Newman
6.25–12.5
6.25–12.5
25–50
NRS-1
NRS-70
NRS-100
NRS-108
NRS-271
S
S
S
S
1
1
1
1
5
H
—
—
—
—
—
—
—
—
—
—
—
—
—
5a
5b
5c
CH
3
—
—
1.56–3.13
>25
3.13–6.25
>25
>25
>25
As shown in Table 1, DHAA exhibited moderate antibacterial
activity against Newman with MIC in the range of 12.5–20 g/
mL. Most of the aliphatic oximate derivatives 5–9c showed weak
activities at 50 g/mL against S. aureus Newman. Introduction of
a small saturated substituent such as methyl, small unsaturated
substituents or benzyl group (compounds 5a–c, 6a–d, 7a–d, 8a–
d) slightly impacted antistaphylococcal activity when compared
to the corresponding O-unsubstituted oximes (5, 6, 7, 8). Among
these derivatives, only the butyraldehyde oxime analogues 7b,
S. aureus Newman. Similarly, for the 2,4-dichloro series of com-
pounds, alkylation of the oxime group (14a–c) decreased the activ-
ity except for NRS-70 strain. The SARs of these compounds suggest
the importance of the hydroxyloxime group in ring C, especially for
the activity against multidrug-resistant S. aureus.
In conclusion, we have described here the design, synthesis, and
the evaluation of antibacterial activity against S. aureus of novel
derivatives of dehydroabietic acid with modifications at C12 posi-
tion. Analysis of SARs indicates that the 12-oxime structure pro-
vides good opportunity for designing novel antimicrobial agents
against multidrug-resistant S. aureus. The aromatic oximate deriva-
l
l
8
b–c exhibited comparable activity (10–12.5
lg/mL) with DHAA.
We also made a series of aromatic oximate derivatives 10–15c.
The activities of these compounds are dependent on the positions
and properties of the substituents (Table 2). 12-((Hydroxyimino)
tive 11a showed the highest activity with MIC of 0.39–0.78 lg/mL
against S. aureus Newman, while compounds 10b, 11, and 14
(
phenyl)methyl)-dehydroabietic acid 10 exhibited comparable
showed the most potent antibacterial activity with MIC values of
activity (10–12.5 g/mL) with DHAA. Introduction of small unsat-
l
1.25–3.13 lg/mL against five multidrug-resistant S. aureus
urated substituents to the oxime functionality (compounds 10b
and 10c) increased the activity significantly, with MICs in the range
of 1.25–2.5 lg/mL. However, introduction of a phenyl-substituted
carbon chain such as benzyl group decreased the activity, for
example the inactive compound 10d. In the series of oxime deriva-
tives 11, 12, and 13, ortho- or meta-substitution of an electron-
withdrawing trifluoromethyl group on the aromatic ring increased
the activity, and compounds 11 and 12 showed MICs values of
(NRS-1, NRS-70, NRS-100, NRS-108 and NRS-271). The results
highlight these new oxime and oxime ether derivatives as
potential leads for further investigation of new antimicrobial
agents. Further SAR study in depth of the active scaffolds and the
mechanism are yet to be investigated.
Acknowledgments
1
.56–3.13
oxime ether derivatives 13a–c exhibited no in vitro activity against
any of the Gram-positive strains at 50 g/mL. For the o-CF series
l
g/mL. On the contrary, the para-CF
3
isomer 13 and its
This work is financially supported by National Natural Science
Foundation of China (81202402, 21272154, and 8161101140)
and the State Key Laboratory of Drug Research (SIMM1601KF-11).
l
3
of compounds, introduction of a small saturated substituent such
as methyl (11a) or small unsaturated substituents (11b, 11c)
retained or increased the activities as compared with the
O-unsubstituted oxime 11. Compound 11a showed the highest
activity among the synthesized compounds with MIC value of
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2016.10.
0
3
.39–0.78 lg/mL. However, for the m-CF series of compounds,
0
18.
introduction of a small unsaturated allyl substituent (12b) resulted
in a loss in activity. The 2,4-dichloro oxime derivative 14 and its
oxime ether derivatives 14a–c exhibited similar activity with MICs
References and notes
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