Design, synthesis and antifungal activity of carbazole derivatives

Article abstract of DOI:10.1016/j.cclet.2013.10.022

The incidence of invasive fungal infections is increasing rapidly. Clinically available antifungal agents suffer from limited efficacy and severe resistance. There is an urgent need to discover antifungal lead compounds with novel chemical scaffold. On the basis of our previously identified tetrahydrocarbazole antifungal leads, the structure-activity relationship was further explored by modifying the scaffold and the side chains. Several targeted compounds showed potent activity against Candida species. Particularly, compound 13i showed better antifungal activity than the lead compound, which can be used as a good starting point for further optimization.

Full text of DOI:10.1016/j.cclet.2013.10.022

Chinese Chemical Letters 25 (2014) 229–233
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Design, synthesis and antifungal activity of carbazole derivatives
Shi-Ping Zhu 1, Wen-Ya Wang 1, Kun Fang, Zheng-Gang Li, Guo-Qiang Dong,
*
*
Zhen-Yuan Miao, Jian-Zhong Yao, Wan-Nian Zhang , Chun-Quan Sheng
School of Pharmacy, Second Military Medical University, Shanghai 200433, China
A R T I C L E I N F O
A B S T R A C T
Article history:
The incidence of invasive fungal infections is increasing rapidly. Clinically available antifungal agents
suffer from limited efficacy and severe resistance. There is an urgent need to discover antifungal lead
compounds with novel chemical scaffold. On the basis of our previously identified tetrahydrocarbazole
antifungal leads, the structure–activity relationship was further explored by modifying the scaffold and
the side chains. Several targeted compounds showed potent activity against Candida species.
Particularly, compound 13i showed better antifungal activity than the lead compound, which can be
used as a good starting point for further optimization.
Received 29 August 2013
Received in revised form 26 September 2013
Accepted 9 October 2013
Available online 21 November 2013
Keywords:
Carbazole
ß 2013 Wan-Nian Zhang and Chun-Quan Sheng. Published by Elsevier B.V. on behalf of Chinese Chemical
Society. All rights reserved.
Antifungal activity
Structure–activity relationship
1. Introduction
antifungal drug discovery [10–23], the structure–activity relation-
ship (SAR) of the tetrahydrocarbazole lead was extended and
There is an urgent need for novel antifungal agents because the
incidence of invasive fungal infections (IFIs) has been increasing
dramatically [1,2]. Immunocompromised hosts, such as patients
undergoing anticancer chemotherapy or organ transplants and
patients with AIDS, are vulnerable populations for IFIs and the
associated mortality is very high [3]. Candida albicans is the most
common cause of IFIs, which ranks the third to fourth among the
bloodstream infections in the United States [2]. However, effective
and safe antifungal agents that can be used for life-threatening
fungal infections are very limited. Clinically, four classes of
antifungal agents (Fig. 1), namely amphotericin B [4], azoles (e.g.
fluconazole and itraconazole) [5], echinocandins (e.g. caspofungin
and micafungin) [6] and 5-fluorocytosine, are available for the
treatment of IFIs. Unfortunately, they have had only limited
success in reducing the high mortality rate of IFIs. Moreover, severe
resistance of antifungal drugs is also becoming a serious problem
[7]. Therefore, there is a pressing need to develop novel antifungal
agents with new chemical scaffold and fungal-specific mecha-
nisms [8].
several targeted compounds showed potent activity against
Candida species.
2. Experimental
All starting materials were commercially available and
analytically pure. 1H NMR spectra were recorded on a BRUKER
AVANCE 500 spectrometer (Bruker Company, Germany), using
TMS as an internal standard and CDCl3 as solvents. Chemical shifts
(d values) and coupling constants (J values) are given in ppm and
Hz, respectively. TLC analysis was carried out on silica gel plates
GF254 (Qindao Haiyang Chemical, China).
Synthetic routes of the targeted compounds are outlined in
Schemes 1–2. According to the procedure of Fisher indole
synthesis, 3,4-dihydronaphthalen-1(2H)-one (2) was condensed
with phenylhydrazine hydrochloride in EtOH to give the annulated
benzocarbazole 3 [24]. Then, it was alkylated by 1,3-dibromopro-
pane using KOH as a base. Notably, two products, namely
substituted compound 4 and eliminated compound 5, were
obtained in this reaction. A reaction of intermediate 4 with benzyl
amine in the presence of K2CO3 and DMF gave the targeted
compound 6. Using acridone and carbazole as the starting material,
targeted compounds 9 and 13a–j were prepared using a similar
procedure in moderate to good yields. Intermediate 14 was
obtained by substituting carbazole 10 with 3-bromoprop-1-yne
[25], which was subsequently reacted with (azidomethyl)benzene
(16) using the classical conditions of the click reaction to afford the
targeted compound 17.
In our previous studies, tetrahydrocarbazole derivatives (Fig. 1)
were identified as antifungal leads [9], which provide a good
starting point for structural optimization. Continuing our efforts in
*
Corresponding authors.
E-mail addresses: zhangwnk@hotmail.com (W.-N. Zhang),
shengcq@hotmail.com (C.-Q. Sheng).
1
These two authors contributed equally to this article.
1001-8417/$ – see front matter ß 2013 Wan-Nian Zhang and Chun-Quan Sheng. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.10.022

230
S.-P. Zhu et al. / Chinese Chemical Letters 25 (2014) 229–233
OH
Ar-H), 6.16–6.21 (m, 1H, allyl-2-CH), 5.21 (d, 1H, J = 10.5 Hz, allyl-3-
Ha), 5.03 (s, 2H, allyl-CH2), 4.87 (d, 1H, J = 17.0 Hz, allyl-3-Hb), 2.90–
2.94 (m, 2H, CH2CH2), 2.83–2.87 (m, 2H, CH2CH2).
OH
O
O
OH
OH
N
N
N
N
F
HO
O
OH OH
OH OH
N
N
H
O
2.2. Synthesis of 3-(5H-benzo[a]carbazol-11(6H)-yl)-N-
O
O
NH2
benzylpropan-1-amine (6)
OH
F
Amphotericin B
Fluconazole
OH
To a solution of intermediate 4 (0.34 g, 1 mmol, 1 equiv.) and
phenylmethanamine (0.86 g, 8 mmol, 8 equiv.) in DMF (10 mL)
was added K2CO3 (0.28 g, 2 mmol, 2 equiv.) and the mixture was
allowed to stir at 80 8C for 4 h. Then, the reaction mixture was
diluted with diethyl ether (25 mL) and washed with water
(10 mL Â 3). The organic layer was separated, dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by
silica gel column chromatography (hexane/EtOAc, 40:1, v/v) to
give the targeted compound 6 as a pale yellow solid (0.06 g, 16.4%
H2N
OH
NH
NH
OH
O
O
N
H
H
N
N
H2NH2CH2C
HO
O
HN
O
OH
NH
O
CH3
OH
Caspofungin
N
O
N
yield). 1H NMR (500 Hz, CDCl3):
d 7.12–7.68 (m, 13H, Ar-H), 4.55 (t,
H
N
HO
2H, J = 7.5 Hz, NCH2CH2CH2NH), 3.76 (s, 2H, phenyl-CH2), 2.90–
3.01 (m, 4H, carbazole-3,4-CH2), 2.70 (t, 2H, J = 6.8 Hz,
NCH2CH2CH2NH), 2.07–2.19 (m, 2H, NCH2CH2CH2NH); MS (ESI)
m/z: 367 (M+1).
The synthetic methods for the targeted compounds 8–13 were
similar to the above procedure.
CH3
Lead compound (1)
O
HO
OH
Fig. 1. Chemical structures of representative antifungal agents and the lead
compound 1.
2.1. Synthesis of 1-(3-bromopropyl)-6,11-dihydro-5H-
10-(3-Bromopropyl)acridin-9(10H)-one (8): Yellow solid (1.01 g,
32.0% yield). 1H NMR (500 Hz, CDCl3):
d 7.32–8.37 (m, 8H, Ar-H),
benzo[a]carbazole (4)
4.81 (t, 2H, J = 7.8 Hz, NCH2CH2CH2Br), 3.86 (t, 2H, J = 6.0 Hz,
NCH2CH2CH2Br), 2.63–2.69 (m, 3H, NCH2CH2CH2Br).
10-(3-(Benzylamino)propyl)acridin-9(10H)-one (9): Yellow solid
(0.23 g, 67.6% yield). 1H NMR (500 Hz, CDCl3):
d 7.32–8.37 (m, 13H,
To a solution of intermediate 3 (2.19 g, 0.01 mol) and 1,3-
dibromopropane (8.08 g, 0.04 mol, 4 equiv.) in DMSO (50 mL) was
added KOH (2.24 g, 0.04 mol, 4 equiv.) and the mixture was allow
to stir at ambient temperature for 3 h. Then, the reaction mixture
was diluted with water (50 mL) and extracted with diethyl ether
(50 mL Â 3). The combined organic layer was washed with brine
(100 mL), dried over anhydrous MgSO4, filtered, and concentrated
in vacuo. The residue was purified by silica gel column
chromatography (hexane/EtOAc, 40:1, v/v) to give compound 4
Ar-H), 4.57 (t, 2H, J = 7.7 Hz, NCH2CH2CH2NH), 3.75 (s, 2H, phenyl-
CH2), 2.72 (t, 2H, J = 6.3 Hz, NCH2CH2CH2Br), 1.95–1.99 (m, 2H,
NCH2CH2CH2NH); MS (ESI) m/z: 343 (M+1).
9-Allyl-9H-carbazole (11): White solid (0.67 g, 32.4% yield). 1H
NMR (500 Hz, CDCl3): d 7.18–8.17 (m, 8H, Ar-H), 5.91–6.01 (m, 1H,
allyl-2-CH), 5.10 (dd, 1H, J1 = 10.1 Hz, J2 = 1.4 Hz, allyl-3-Ha), 5.04
(d, 2H, J = 5.1 Hz, allyl-CH2), 4.96 (dd, 1H, J1 = 17.1 Hz, J2 = 1.5 Hz,
allyl-3-Hb).
as a white solid (1.31 g, 38.5% yield). 1H NMR (500 Hz, CDCl3):
d
7.13–7.59 (m, 8H, Ar-H), 4.59–4.63 (m, 2H, NCH2CH2CH2Br), 3.40
(t, 2H, J = 6.2 Hz, NCH2CH2CH2Br), 2.95–2.99 (m, 2H, carbazole-3-
CH2), 2.88–2.92 (m, 2H, carbazole-4-CH2), 2.40–2.45 (m, 2H,
NCH2CH2CH2Br).
9-(3-Bromopropyl)-9H-carbazole (12): White solid (1.26 g, 43.7%
yield). 1H NMR (500 Hz, CDCl3):
d 7.23–8.13 (m, 8H, Ar-H), 4.52 (t,
2H, J = 6.5 Hz, NCH2CH2CH2Br), 3.40 (t, 2H, J = 6.3 Hz,
NCH2CH2CH2Br), 2.41–2.50 (m, 2H, NCH2CH2CH2Br).
N-Benzyl-3-(9H-carbazol-9-yl)propan-1-amine (13a): White
solid (0.15 g, 48.4% yield). 1H NMR (500 Hz, CDCl3):
d 7.17–8.15
Compound 5 (11-allyl-6,11-dihydro-5H-benzo[a]carbazole) was
the by-product in the synthesis of intermediate 4. White solid
(0.70 g, 27.0% yield). 1H NMR (500 Hz, CDCl3):
d
7.05–7.57 (m, 8H,
Br
H
N
O
H
N
N
b
c
a
N
4
+
3
2
6
N
5
H
N
Br
H
N
b
N
N
c
O
O
O
9
7
8
Scheme 1. Synthetic route of compounds 4–9. Reagents and conditions: (a) phenylhydrazine hydrochloride, EtOH, reflux, 4 h, 69.1%; (b) 1,3-dibromopropane, KOH, DMSO,
r.t., 3 h, 27.0%–38.5%; (c) benzyl amine, K2CO3, DMF, 80 8C, 4 h, 16.4%–67.6%.

S.-P. Zhu et al. / Chinese Chemical Letters 25 (2014) 229–233
231
Br
H
N
R
H
N
N
N
N
a
b
+
10
11
12
13a-j
13a R = H
13f R = 2-Cl
13g R = 3-Cl
13h R = 4-CH
13b R = 4-F
13c R = 3-F
13d R = 2-F
13e R = 4-Cl
C
CH
3
H
13i R = 4-OCH
3
N
N
13j R = 2,4-2Cl
c
N
N
10
14
N
e
N
Br
CH N
2
3
d
17
15
16
Scheme 2. Synthetic route of compounds 11–17. Reagents and conditions: (a) 1,3-dibromopropane, KOH, DMSO, r.t., 3 h, 32.4%–43.7%; (b) benzyl amine, K2CO3, DMF, 80 8C,
4 h, 16.4%–67.6%; (c) 3-bromoprop-1-yne, KOH, r.t., 4 h, 82.4%; (d) sodium azide, DMSO, r.t., 12 h, 100%; (e) VcNa, CuSO4, DMSO/H2O, r.t., 24 h, 89.6%.
(m, 13H, Ar-H), 4.46 (t, 2H, J = 6.9 Hz, NCH2CH2CH2NH), 3.65 (s, 2H,
phenyl-CH2), 3.29 (br, 2H, NCH2CH2CH2NH), 1.91–1.95 (m, 2H,
NCH2CH2CH2NH); MS (ESI) m/z: 315 (M+1).
3-(9H-Carbazol-9-yl)-N-(4-methoxybenzyl)propan-1-amine
(13i): 1H NMR (500 Hz, CDCl3):
6.84–8.15 (m, 12H, Ar-H), 4.45 (t,
2H, J = 6.9 Hz, NCH2CH2CH2NH), 3.72 (s, 3H, OCH3), 3.56 (s, 2H,
phenyl-CH2), 2.48 (t, 2H, J = 6.9 Hz, NCH2CH2CH2NH), 1.89–1.92
(m, 2H, NCH2CH2CH2NH); MS (ESI) m/z: 345 (M+1).
d
3-(9H-Carbazol-9-yl)-N-(4-fluorobenzyl)propan-1-amine (13b):
1H NMR (500 Hz, CDCl3):
d 7.09–8.15 (m, 12H, Ar-H), 4.45 (t,
2H, J = 6.9 Hz, NCH2CH2CH2NH), 3.61 (s, 2H, phenyl-CH2), 2.48 (t,
2H, J = 6.5 Hz, NCH2CH2CH2NH), 2.26 (br, 1H, NH), 1.88–1.94 (m,
2H, NCH2CH2CH2NH); MS (ESI) m/z: 333 (M+1).
3-(9H-Carbazol-9-yl)-N-(2,4-dichlorobenzyl)propan-1-amine
(13j): 1H NMR (500 Hz, CDCl3):
d 7.71–8.71 (m, 11H, Ar-H), 5.02 (t,
2H, J = 6.6 Hz, NCH2CH2CH2NH), 4.26 (s, 2H, phenyl-CH2), 3.06 (br,
2H, NCH2CH2CH2NH), 2.46–2.51 (m, 2H, NCH2CH2CH2NH); MS
(ESI) m/z: 384 (M+1).
3-(9H-Carbazol-9-yl)-N-(3-fluorobenzyl)propan-1-amine (13c):
1H NMR (500 Hz, CDCl3):
d 7.13–8.15 (m, 12H, Ar-H), 4.46 (t,
2H, J = 6.9 Hz, NCH2CH2CH2NH), 3.65 (s, 2H, phenyl-CH2), 2.49 (br,
2H, NCH2CH2CH2NH), 2.30 (br, 1H, NH), 1.90–1.93 (m, 2H,
NCH2CH2CH2NH); MS (ESI) m/z: 333 (M+1).
2.3. Synthesis of 9-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-9H-
carbazole (17)
3-(9H-Carbazol-9-yl)-N-(2-fluorobenzyl)propan-1-amine (13d):
1H NMR (500 Hz, CDCl3):
2H, J = 6.9 Hz, NCH2CH2CH2NH), 3.68 (s, 2H, phenyl-CH2), 2.51 (br,
2H, NCH2CH2CH2NH), 2.26 (br, 1H, NH), 1.89–1.95 (m, 2H,
NCH2CH2CH2NH); MS (ESI) m/z: 333 (M+1).
3-(9H-Carbazol-9-yl)-N-(4-chlorobenzyl)propan-1-amine (13e):
1H NMR (500 Hz, CDCl3):
2H, J = 6.9 Hz, NCH2CH2CH2NH), 3.62 (s, 2H, phenyl-CH2), 2.49 (br,
2H, NCH2CH2CH2NH), 1.90–1.93 (m, 2H, NCH2CH2CH2NH); MS
(ESI) m/z: 349 (M+1).
d
7.11–8.15 (m, 12H, Ar-H), 4.46 (t,
A suspension of (bromomethyl)benzene (0.86 g, 5.0 mmol,
5 equiv.) and NaN3 (0.36 g, 5.5 mmol, 5.5 equiv.) in DMSO (25 mL)
was allowed to stir overnight. Then, intermediate 14 (0.20 g,
1.0 mmol, 1 equiv.), an aqueous solution of sodium ascorbate
(0.01 mol/L, 10 mL, 0.1 equiv) and a copper sulfate solution
(0.005 mol/L, 2 mL, 0.01 equiv) were added under a nitrogen
atmosphere and was allowed to stir at ambient temperature for
24 h. The reaction mixture was diluted with water (20 mL) and
extracted with EtOAc (20 mL Â 3). The combined organic layer was
washed with brine (30 mL), dried over anhydrous MgSO4, filtered,
and concentrated in vacuo. The residue was purified by silica gel
column chromatography (hexane/EtOAc, 4:1, v/v) to give the
targeted compound 17 as a white solid (0.60 g, 89.6% yield). 1H-
d 7.17–8.15 (m, 12H, Ar-H), 4.45 (t,
3-(9H-Carbazol-9-yl)-N-(2-chlorobenzyl)propan-1-amine (13f):
1H NMR (500 Hz, CDCl3):
d
7.17–8.15 (m, 12H, Ar-H), 4.46 (t,
2H, J = 6.9 Hz, NCH2CH2CH2NH), 3.74 (s, 2H, phenyl-CH2), 2.54 (t,
2H, J = 7.2 Hz, NCH2CH2CH2NH), 1.90–1.93 (m, 2H,
NCH2CH2CH2NH); MS (ESI) m/z: 349 (M+1).
3-(9H-Carbazol-9-yl)-N-(3-chlorobenzyl)propan-1-amine (13g):
1H NMR (500 Hz, CDCl3):
7.17–8.15 (m, 12H, Ar-H), 4.47 (t,
NMR (500 Hz, CDCl3):
d 7.18–8.15 (m, 14H, Ar-H), 5.66 (s, 2H,
phenyl-CH2), 5.49 (s, 2H, carbazole-CH2). MS (ESI) m/z: 339 (M+1).
d
2H, J = 6.9 Hz, NCH2CH2CH2NH), 3.65 (s, 2H, phenyl-CH2), 2.49 (br,
2H, NCH2CH2CH2NH), 1.89–1.95 (m, 2H, NCH2CH2CH2NH); MS
(ESI) m/z: 349 (M+1).
2.4. In vitro antifungal activity assays
The in vitro antifungal activity was measured by means of the
MIC using the serial dilution method in 96-well microtest plates.
Test fungal strains were obtained from the ATCC or were clinical
isolates. The MIC determination was performed according to the
National Committee for Clinical Laboratory Standards (NCCLS)
recommendations using RPMI 1640 (Sigma) buffered with MOPS
3-(9H-Carbazol-9-yl)-N-(4-methylbenzyl)propan-1-amine (13h):
1H NMR (500 Hz, CDCl3):
d 7.08–8.15 (m, 12H, Ar-H), 4.45 (t, 2H,
J = 6.9 Hz, NCH2CH2CH2NH), 3.58 (s, 2H, phenyl-CH2), 2.48 (br, 2H,
NCH2CH2CH2NH), 2.27 (s, 3H, CH3), 1.89–1.92 (m, 2H,
NCH2CH2CH2NH); MS (ESI) m/z: 329 (M+1).

232
S.-P. Zhu et al. / Chinese Chemical Letters 25 (2014) 229–233
Table 1
(3-morpholinopropanesulfonic acid, 0.165 mol/L, Sigma) as the
test medium. The MIC value was defined as the lowest
concentration of test compounds that resulted in a culture with
turbidity less than or equal to 80% inhibition when compared to the
growth of the control. Test compounds were dissolved in DMSO
serially diluted in growth medium. Plates were incubated without
shaking at 35 8C. Optical density (OD) was measured at 630 nm and
the background OD was subtracted from each well. Growth MIC
was determined at 24 h for Candida species. Each experiment was
performed in triplicate.
In vitro antifungal activities of the carbazole derivatives (MIC80, mg/mL).
Compounds
Candida albicans
Candida parapsilosis
Candida glabrata
1
16
>64
>64
64
32
>64
>64
64
16
>64
>64
32
5
6
9
11
>64
16
>64
8
>64
8
13a
13b
13c
13d
13e
13f
64
32
8
>64
>64
>64
>64
>64
32
64
16
64
32
64
16
>64
>64
16
>64
64
3. Results and discussion
13g
13h
13i
8
The design rationale for the targeted compounds is depicted in
Fig. 2. The tetrahydrocarbazole scaffold was replaced by benzo-
carbazole, acridone and carbazole, respectively. Two kinds of side
chain, namely benzylaminopropyl and benzyltriazolmethyl, were
also investigated. In vitro antifungal activity of the targeted
compounds was expressed as the minimal inhibitory concentra-
tion (MIC) that achieved 80% inhibition of the tested fungi. Three
kinds of pathogenic fungi, namely Candida albicans, Candida
parapsilosis and Candida glabrata, were chosen for assaying because
Candidosis is the leading cause of the IFIs. Fluconazole was used as a
positive control.
Initially, we aimed to investigate the influence of the
tetrahydrocarbazole scaffold on the antifungal activity. When
the tetrahydrocarbazole core was annulated with a phenyl group,
the resulting compound 6 was found to be inactive. If the
tetrahydrocarbazole scaffold was replaced by the acridone, the
antifungal activity of compound 9 decreased (MIC range: 16–
16
8
4
13j
>64
>64
1
>64
>64
1
>64
>64
0.5
17
Fluconazole
(MIC = 8
mg/mL). In order to investigate the importance the
terminal benzyl group, two by-products from the elimination
reaction, 5 and 11, were also subjected to antifungal assaying.
Unfortunately, they are totally inactive, indicating that the
terminal benzyl group was essential for the antifungal activity.
Moreover, 1,2,3-triazole was also designed as a linker in the side
chain. However, the loss of the antifungal activity was observed for
compound 17, highlighting the importance of the benzylamino-
propyl side chain. Notably, these carbazole derivatives were
designed from N-myristoyltransferase (NMT) inhibitors [9], the
determination of their NMT inhibitory activity would be helpful to
clarify the mode of action and provide important information for
further structural optimization.
32
mg/mL). Interestingly, the aromatization of the tetrahydrocar-
bazole core to carbazole led to an increase of the antifungal
activity. Compound 13a showed potent activity against Candida
albicans, Candida parapsilosis, Candida glabrata with MIC values of
4. Conclusion
16
mg/mL, 16 mg/mL and 8 mg/mL, respectively. The results
indicated that the scaffold of this series of compounds played an
important role for the antifungal activity.
In summary, a series of novel carbazole derivatives were
designed and synthesized as antifungal lead compounds. The SARs
revealed that the carbazole scaffold was better than tetrahydro-
carbazole and the benzylaminopropyl side chain was important for
the antifungal activity. The introduction of 4-methoxyl substituent
slightly improved the antifungal activity. Compound 13i showed
better antifungal activity than the lead compound 1. Although it
was still less active than fluconazole, it can be used as a good
starting point for further optimization.
Then, various substitutions were introduced on the terminal
phenyl group (compounds 13a–j in Table 1). When position 4 of
the phenyl group was substituted with a fluorine (compound 13b)
or chlorine (compound 13e) atom, their antifungal activity
generally decreased. Moving the fluorine or chlorine substituent
to position 2 or 3 resulted in further decrease of the antifungal
activity. The results revealed that halogen substitutions on the
phenyl group were not favorable for the antifungal activity. On the
other hand, the introduction of 4-methyl and 4-methoxyl group on
compound 13a led to comparable or improved antifungal activity.
Acknowledgments
Particularly, compound 13i (MIC = 4
inhibitory activity against Candida glabrata than compound 13a
mg/mL) showed better
This work was supported in part by the National Natural
Science Foundation of China (No. 81222044), the 863 Hi-Tech
Program of China (No. 2012AA020302), Shanghai Rising-Star
Program (No. 12QH1402600), and Shanghai Municipal Health
Bureau (No. XYQ2011038).
H
N
H
N
N
References
H
N
N
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O
N
H
R
N
N
N
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