Synthesis and antibacterial activity of pyridinium-tailored aromatic amphiphiles

Article abstract of DOI:10.1016/j.bmcl.2016.01.053

In this Letter, the antibacterial activities of pyridinium-tailored aromatic amphiphiles were evaluated by turbidimeter tests in vitro. The bioassays revealed that most of the target compounds exhibit appreciable inhibition activities against the plant pathogenic bacteria Xanthomonas oryzae pv. oryzae, Ralstonia solanacearum, and Xanthomonas axonopodis pv. citri. The half-maximal effective concentrations (EC₅₀) of 2-NP-10, 9-AP-10, and 9-AP-7 against these three bacteria were relatively high, which may be ascribed to the favourable hydrophobicity/hydrophilicity balance in these compounds. Our results suggest that pyridinium-tailored aromatic amphiphiles are promising bactericide candidates against plant bacterial diseases.

Full text of DOI:10.1016/j.bmcl.2016.01.053

Bioorganic & Medicinal Chemistry Letters 26 (2016) 1136–1139
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antibacterial activity of pyridinium-tailored aromatic
amphiphiles
Peiyi Wang , Manni Gao , Lei Zhou , Zhibing Wu , Deyu Hu , Jun Hu , Song Yang a,
a,y
a,y
a
a
a
b,
⇑
⇑
a
State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of
Education, Center for R&D of Fine Chemicals of Guizhou University, Guiyang 550025, China
State Key Lab of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter, the antibacterial activities of pyridinium-tailored aromatic amphiphiles were evaluated by
turbidimeter tests in vitro. The bioassays revealed that most of the target compounds exhibit appreciable
inhibition activities against the plant pathogenic bacteria Xanthomonas oryzae pv. oryzae, Ralstonia sola-
nacearum, and Xanthomonas axonopodis pv. citri. The half-maximal effective concentrations (EC50) of 2-
NP-10, 9-AP-10, and 9-AP-7 against these three bacteria were relatively high, which may be ascribed
to the favourable hydrophobicity/hydrophilicity balance in these compounds. Our results suggest that
pyridinium-tailored aromatic amphiphiles are promising bactericide candidates against plant bacterial
diseases.
Received 12 August 2015
Revised 2 January 2016
Accepted 19 January 2016
Available online 19 January 2016
Keywords:
Anthracene
Pyridinium
Amphiphile
Synthesis
Ó 2016 Elsevier Ltd. All rights reserved.
Antibacterial
Plant bacterial diseases have attracted the significant attention
in the past decades because of the serious threats they pose to agri-
bacterial leaf blight at a high concentration of 200 l
g/mL.11 There-
fore, exploring and developing new highly efficient bactericides to
prevent and control plant bacterial diseases remains a considerable
challenge.
1
–6
cultural production.
Rice bacterial leaf blight, tobacco bacterial
wilt, and citrus bacterial canker are the three major diseases
caused by the Gram-negative bacteria Xanthomonas oryzae pv. ory-
zae (Xoo), Ralstonia solanacearum (R. solanacearum), and Xan-
thomonas axonopodis pv. citri (Xac), respectively.7 Rice bacterial
Amphiphiles containing hydrophobic and hydrophilic portions
can mimic membrane properties and exhibit excellent biocidal
activities toward bacteria and fungi by disrupting their innate
,8
1
5–22
leaf blight is a vascular disease that occurs at all growth stages of
defense system in microorganisms.
Among them, pyri-
rice, generally resulting in production losses of up to 10%.9
–11
With
dinium-functionalized amphiphiles containing the flat pyridinium
cations exert significant antibacterial activities, since their positive
charges can facilitate interactions with anionic cell components,
typical symptoms of yellowing and wilting of tobacco leaves,
tobacco bacterial wilt is always obtained through soil-borne patho-
7
,12
23–28
gens; this disease causes significant economic losses each year.
thus enhancing the affinity toward biological membranes.
Citrus bacterial canker, an extremely persistent disease, can cause
lesions on the leaves, stems, and fruit of citrus trees, thereby lead-
For example, Sen and co-workers investigated the antibacterial
activity of amphiphilic pyridinium-methacrylate copolymers, and
found that polymers with positive charges and hydrophobic tails
on spatially separated centres exhibited higher membrane-dis-
rupting ability against Gram-negative (Escherichia coli) and
13,14
ing to a significant loss in agricultural output every year.
To
date, a number of commercial bactericides have been developed
to address these diseases; however, these agents cannot achieve
the desired effect because of their poor efficiency, high phytotoxi-
city, or bactericide resistance. For example, bismerthiazol, one of
the bactericides most widely used to control rice bacterial leaf
blight, has led to the appearance of bismerthiazol-resistant strains
2
9
Gram-positive (Bacillus subtilis) bacteria. Bhattacharya and co-
workers reported that triple pyridinium-beard amphiphile
a
showed impressive antibacterial activity against both Gram-posi-
tive and -negative bacteria by disrupting the bacterial mem-
9
30
of Xoo in Anhui Province, China. The registered bactericide thiodi-
brane.
Obviously, pyridinium-tailored amphiphiles are
azole copper only shows a control efficiency of 37.49% against rice
promising candidates in the development of novel highly efficient
bactericides against plant bacterial diseases. The membrane-dis-
rupting activity of amphiphiles depends on their positive charge
as well as the overall hydrophobicity/hydrophilicity balance.3
Inspired by these previous reports, we propose that appreciable
⇑
Corresponding authors.
E-mail addresses: jhu@ciac.ac.cn (J. Hu), jhzx.msm@gmail.com (S. Yang).
These two authors contribute equally to this work.
1–33
y
http://dx.doi.org/10.1016/j.bmcl.2016.01.053
960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
0

P. Wang et al. / Bioorg. Med. Chem. Lett. 26 (2016) 1136–1139
1137
O
O
i: SOCl
ii: R
2
, reflux, 5 h
Br
Br
10
(a)
(b)
HO
R
O
O
Br
1
0
N
OH, Et N, CH Cl , r.t, 4 h
3
2 2
N
0
0 oC, 6 h, 34%
O
5
1
9
-AQ10
Br
O
N
N
R
O
R =
O
0 oC, 6 h
10
yield: 67%-75%
N
O
5
Br
10
O
N
0
Br
1
-BP-10
2-NP-10
1-PP-10
DMF, 70 oC, 24 h, 52%
O
1
9
-ABr-10
9
-AA-10
(c)
HN
O
2
-AP-10
9-AP-10
N
0
NaOH, DMF, r. t., 24 h, 59%
O
1
Scheme 1. Synthetic route of 1-BP-10, 2-NP-10, 2-AP-10, 9-AP-10, and 1-PP-10.
9-AD-10
Scheme 2. Synthetic route of 9-AQ-10, 9-AA-10, and 9-AD-10.
bioactivity can be achieved by manipulating the ratio between the
hydrophobic and hydrophilic components of amphiphiles. In this
study, we synthesized a series of amphiphilic pyridinium-tailored
amphiphiles and investigated their antibacterial activities against
Xoo, R. solanacearum, and Xac. Within these amphiphilic molecules,
hydrophobic tails with various aromatic areas were linked to the
hydrophilic cations by different alkyl chains.
The synthesis routes of 1-[11-benzyloxy-11-oxoundecyl] pyri-
dinium bromide (1-BP-10), 1-[11-(2-naphthalenylmethoxy)-11-
oxoundecyl]pyridinium bromide (2-NP-10), 1-[11-(2-anthracenyl
methoxy)-11-oxoundecyl]pyridinium bromide (2-AP-10), 1-[11-
O
O
9-anthracenylmethanol
CO , THF, r.t, 3 h
Br
Br
Br
K
2
3
O
Br
n
O
i: SOCl , reflux, 5 h;
2
HO
n
ii: 9-anthracenylmethanol,
Et N, CH Cl , r.t, 4 h
3 2 2
n = 1, 3, 5, 7, 15
n = 3, 5, 7, 15
(
9-anthracenyl methoxy)-11-oxoundecyl] pyridinium bromide (9-
AP-10), and 1-[11-(1-pyrenylmethoxy)-11-oxoundecyl] pyri-
O
Br
dinium bromide (1-PP-10) are shown in Scheme 1.3
4,35
11-bro-
N
0 oC, 6 h
N
O
5
n
moundecanoic acid was treated with aromatic methyl alcohol to
afford bromide-tailored intermediates that were subsequently
reacted with pyridine at 50 °C to obtain the target molecules 1-
BP-10, 2-NP-10, 2-AP-10, 9-AP-10, and 1-PP-10. All of the struc-
tures were characterised by 1H NMR, C NMR, MS, and HRMS
9
-AP-n n = 1, 3, 5, 7, 15
yield: 34%-81%
Scheme 3. Synthetic route of 9-AP-n.
13
(
for detailed information, see the Supplementary data).
The turbidimeter test36 was performed to evaluate the antibac-
10, featuring smaller or larger aromatic areas than naphthalene
and anthracene, resulted in a decreased bioactivity toward R. sola-
nacearum and Xac, although the EC50 value of 1-PP-10 against Xoo
terial activities of 1-BP-10, 2-NP-10, 2-AP-10, 9-AP-10, and 1-PP-
0 against Xoo, R. solanacearum, and Xac in vitro. The commercial
agricultural antibacterial bismerthiazol (CK ) was selected as the
positive control for Xoo, while thiodiazole copper (CK ) was
selected as controls for R. solanacearum and Xac. As shown in
Table 1, 1-BP-10, 2-NP-10, 9-AP-10, and 1-PP-10 showed better
bioactivities against these three bacteria than either CK or CK .
1 2
The half-maximal effective concentrations (EC50) of 2-NP-10
against Xoo, R. solanacearum, and Xac are 9.8 ± 0.8, 23.1 ± 4.0, and
1
is 4.6 ± 1.6 lg/mL. This result indicates that even slight changes in
1
the ratio between hydrophobic and hydrophilic parts will affect
their bioactivities. The activity of 9-AP-10 against these bacteria
is much better than that of its regioisomer 2-AP-10, although both
compounds have the same hydrophobic and hydrophilic ratios.
Given the anisotropic feature of the anthracene ring, the alkyl
chain of 9-AP-10 orients in a nearly perpendicular direction rela-
tive to the anthracene plane, similar to a ‘shaver’-like molecular
configuration. By contrast, 2-AP-10 orients in a direction parallel
to the anthracene ring, as shown in our previous work (Fig. S0).34
2
8
.6 ± 0.4
lg/mL, respectively; 9-AP-10 showed better bioactivity
than 2-NP-10 against Xoo and Xac, with EC50 values of 5.3 ± 0.7
and 6.3 ± 0.5 lg/mL, respectively. Conversely, 1-BP-10 and 1-PP-
Table 1
Antibacterial activity of 1-BP-10, 2-NP-10, 2-AP-10, 9-AP-10, 1-PP-10, 9-AQ-10, 9-AA-10, 9-ABr-10, and 9-AD-10 against Xoo, R. solanacearum, and Xac in vitro. The average EC50
values were statistically estimated by probit analysis with the probit package of the SPSS 17.0 software and consequently give an equation (Regression equation)
Compounds
Xoo
R. solanacearum
Xac
Regression equation
r
EC50
(l
g/mL)
Regression equation
r
EC50
(l
g/mL)
Regression equation
r
EC50 (lg/mL)
1-BP-10
2-NP-10
2-AP-10
9-AP-10
1-PP-10
9-AQ-10
9-AA-10
9-ABr-10
9-AD-10
y = 3.831xꢀ0.338
y = 3.746x+1.289
y = 2.186x+2.214
y = 3.289x+2.605
y = 2.836x+3.126
y = 3.458x+1.731
y = 4.941x+1.868
/
0.96
0.98
0.96
0.93
0.99
0.95
0.97
/
24.7 ± 1.5
9.8 ± 0.8
18.8 ± 2.6
5.3 ± 0.7
4.6 ± 1.6
8.8 ± 2.1
4.3 ± 0.7
>100
y = 2.567x+0.710
y = 1.885x+2.429
/
y = 1.005x+3.496
y = 0.759x+3.764
y = 1.207x+3.501
y = 1.755x+2.838
0.95
0.98
/
0.97
0.98
0.92
0.99
/
46.9 ± 4.2
23.1 ± 4.0
>160
31.3 ± 8.2
42.4 ± 2.7
17.4 ± 3.4
17.1 ± 3.0
>100
y = 3.454x+0.141
y = 2.789x+2.390
y = 2.083x+0.852
y = 2.745x+2.805
y = 1.244x+2.875
y = 0.918x+4.372
y = 2.729x+2.996
/
0.98
0.91
0.99
0.96
1.00
0.96
0.98
/
25.5 ± 1.4
8.6 ± 0.4
98.1 ± 21.0
6.3 ± 0.5
51.0 ± 7.4
4.8 ± 0.9
5.4 ± 0.7
>100
/
/
/
/
>100
/
>100
/
/
>100
CK
CK
1
y = 1.499x+2.052
/
0.98
/
92.6 + 2.1
/
/
/
/
/
/
/
2
y = 1.031x+2.942
0.99
216.7 ± 5.1
y = 2.153x+0.938
0.98
77.0 ± 2.0

1
138
P. Wang et al. / Bioorg. Med. Chem. Lett. 26 (2016) 1136–1139
Table 2
Antibacterial activity of 9-AP-n (n = 1, 3, 5, 7, 10, 15) against Xoo, R. solanacearum, and Xac in vitro
Compounds
Xoo
R. solanacearum
Xac
Regression equation
r
EC50
(l
g/mL)
Regression equation
r
EC50
(l
g/mL)
Regression equation
r
EC50 (lg/mL)
9
9
9
9
9
9
-AP-1
-AP-3
-AP-5
-AP-7
-AP-10
-AP-15
y = 1.963x+0.757
y = 6.364xꢀ5.914
y = 8.214xꢀ6.937
y = 3.001x+2.234
y = 3.289x+2.605
y = 2.298x+0.624
y = 1.499x+2.052
/
0.97
1.00
1.00
0.96
0.93
0.96
0.98
/
144.9 ± 8.3
51.9 ± 3.2
28.4 ± 3.1
8.3 ± 1.2
5.3 ± 0.7
80.1 ± 8.9
92.6 + 2.1
/
/
/
>160
y = 0.632x+4.313
y = 1.046x+4.151
y = 5.926xꢀ1.255
y = 6.094x+0.746
y = 2.745x+2.805
/
0.98
0.99
0.91
1.00
0.96
/
12.2 ± 6.0
6.5 ± 2.8
11.4 ± 1.1
5.0 ± 0.2
6.3 ± 0.5
>100
y = 1.354x+3.231
y = 1.082x+3.631
y = 1.022x+3.629
y = 1.005x+3.496
/
0.99
0.99
0.94
0.97
/
20.2 ± 3.2
18.4 ± 4.8
21.9 ± 6.3
31.3 ± 8.2
>160
CK
CK
1
/
/
/
/
/
/
2
y = 1.031x+2.942
0.99
216.7 ± 5.1
y = 2.153x+0.938
0.98
77.0 ± 2.0
Thus, the difference in bioactivities between these two regioiso-
mers is attributed to the ‘shaver’-like molecular configuration of
by a turbidimeter test. After optimising the aromatic areas, substi-
tuted positions, cation types, and alkyl length of these pyridinium-
tailed aromatic amphilphiles, the bioassay showed that 2-NP-10,
9-AP-10, and 9-AP-7 exhibited excellent comprehensive bioactiv-
ity against these three bacteria because of the appropriate balance
between hydrophobicity and hydrophilicity in these molecules.
This finding verifies that pyridinium-tailored aromatic amphi-
philes are promising bactericide candidates for treating plant bac-
terial diseases.
9
-AP-10, which may be stuck in the bacterial membrane due to
the steric hindrance, and consequently disrupt the functions of
bacterial membrane. Based on the above results, 9-AP-10 was
selected as the lead compound for further structure optimisation.
To investigate the effect of cation types toward bioactivity, the
quinolinium-tailored anthracene 9-AQ-10 and the ammonium-tai-
lored anthracene 9-AA-10 were synthesized.34 As shown in
Scheme 2, the intermediate (9-anthracenylmethyl-11-bromounde-
canoate) was treated with quinoline (or triethylamine) to afford 9-
AQ-10 (or 9-AA-10); the bioactivities of these compounds were
examined under the same conditions (Table 1).
Acknowledgments
We acknowledge the financial support of the National Natural
Science Foundation of China (21372052, 21202025), Key Technolo-
gies R&D Program (2014BAD23B01), Guizhou Province S&T Pro-
gram ([2012]6012 and [2011]3016), and the Graduate Student
Innovation Foundation of Guizhou University (2014077,
2014078), Scientific Research Foundation for the Introduced
Talents of Guizhou University ([2015]34). J.H. is thankful for the
support of the State Key Laboratory of Polymer Physics and Chem-
istry, CIAC, and Scientific Research Foundation for the Returned
Overseas Chinese Scholars, State Education Ministry.
Results revealed that both 9-AQ-10 and 9-AA-10 exhibit bioac-
tivities similar to that of 9-AP-10 against the three bacteria with
EC50 values of 8.8 ± 2.1, 17.4 ± 3.4, 4.8 ± 0.9
lg/mL (9-AQ-10), and
4
.3 ± 0.7, 17.1 ± 3.0, 5.4 ± 0.7 g/mL (9-AA-10), respectively. In
l
order to investigate the effect of positive charge, another two pre-
cursors of the amphiphiles (9-ABr-10 and 9-AD-10) were synthe-
sized and their antibacterial activities were evaluated. Their high
EC50 (>100
charge.
lg/mL) strongly verified the crucial role of the positive
In addition, another five pyridinium-tailed anthracenes with dif-
ferent alkyl lengths were synthesized to investigate how linker
length affects bioactivity. The synthesis of the pyridinium-tailored
anthracene 9-AP-n is shown in Scheme 3.37 Briefly, 9-anthracenyl-
methanol was treated with bromoacetyl bromide or bromo-car-
boxylic acids to obtain bromide-modified intermediates with
different alkyl lengths, which were then reacted with pyridine at
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2016.01.053.
5
0 °C to afford the target compound 9-AP-n (n = 1, 3, 5, 7, 15). All
References and notes
1
13
of the structures were characterised by H NMR, C NMR, MS, and
HRMS (for detailed information, see the Supplementary data).
The antibacterial activity of 9-AP-n against Xoo, R. solanacearum,
and Xac was examined using the turbidimeter test under the same
conditions. Except for 9-AP-1, as shown in Table 2, 9-AP-n exhib-
1.
2.
3.
4.
Zou, L. F.; Wang, X. P.; Xiang, Y.; Zhang, B.; Li, Y. R.; Xiao, Y. L.; Wang, J. S.;
Walmsley, A. R.; Chen, G. Y. Appl. Environ. Microbiol. 2006, 72, 6212.
Gottig, N.; Garavaglia, B. S.; Garofalo, C. G.; Orellano, E. G.; Ottado, J. PLoS One
2009, 4, 4358.
Li, Z.; Wu, S.; Bai, X.; Liu, Y.; Lu, J.; Liu, Y.; Xiao, B.; Lu, X.; Fan, L. J. Bacteriol.
2011, 193, 6088.
1
ited better antibacterial activities against Xoo than CK . The EC50
Zou, L.; Li, Y.; Chen, G. Agric. Sci. China 2011, 10, 1139.
value decreased with the increase in the length of the alkyl chains
and reached a minimum when n was 10. When n was 15, antibac-
terial activity increased to 80.1 ± 8.9 lg/mL (16-fold higher com-
pared with that of 9-AP-10). These results revealed that a suitable
5. Gottwald, T. R.; Sun, X.; Riley, T.; Graham, J. H.; Ferrandino, F.; Taylor, E. L.
Phytopathology 2002, 92, 361.
6.
de Oliveira, A. G.; Murate, L. S.; Spago, F. R.; Lopes, L. D.; Beranger, J. P. D.;
Martin, J. A. B. S.; Nogueira, M. A.; de Mello, J. C. P.; Andrade, C. G. T. D.;
Andrade, G. Biol. Control 2011, 56, 125.
7.
He, K.; Yang, S. Y.; Li, H.; Wang, H.; Li, Z. L. Eur. J. Plant Pathol. 2014, 140, 665.
hydrophobicity/hydrophilicity balance was achieved by 9-AP-10
2
4–27
8. Niño-Liu, D. O.; Ronald, P. C.; Bogdanove, A. J. Mol. Plant Pathol. 2006, 7, 303.
against Xoo.
antibacterial activities against R. solanacearum than CK
EC50 values ranging from 18.4 g/mL to 21.9 g/mL The EC50 values
of 9-AP-1, 9-AP-3, 9-AP-5, and 9-AP-7 against Xac were 12.2 ± 6.0,
.5 ± 2.8, 11.4 ± 1.1, and 5.0 ± 0.2 g/mL, respectively, all of which
were lower than that of CK . 9-AP-7 and 9-AP-10 exhibited the best
9-AP-3, 9-AP-5, and 9-AP-7 showed better
9.
Chen, Y.; Yang, X.; Gu, C. Y.; Zhang, A. F.; Zhang, Y.; Wang, W. X.; Gao, T. C.; Yao,
2
, with
J.; Yuan, S. K. Ann. Appl. Biol. 2015, 166, 129.
10. Li, P.; Shi, L.; Yang, X.; Yang, L.; Chen, X.; Wu, F.; Shi, Q.; Xu, W. M.; He, M.; Hu,
l
l
D. Y.; Song, B. A. Bioorg. Med. Chem. Lett. 2014, 24, 1677.
11. Li, P.; Shi, L.; Gao, M.; Yang, X.; Xue, W.; Jin, L. H.; Hu, D. Y.; Song, B. A. Bioorg.
6
l
Med. Chem. Lett. 2015, 25, 481.
12. Wei, Z.; Huang, J. F.; Tan, S. Y.; Mei, X. L.; Shen, Q. R.; Xu, Y. C. Biol. Control 2013,
5, 278.
2
6
antibacterial activity against Xoo, R. solanacearum, and Xac, thereby
suggesting that a favourable overall hydrophobicity/ hydrophilicity
balance was attained when n is 7 or 10.
In summary, a series of pyridinium-tailored aromatic amphi-
philes were synthesized, and their antibacterial activities against
pathogens Xoo, R. solanacearum, and Xac in vitro were evaluated
1
3. Piazza, A.; Zimaro, T.; Garavaglia, B. S.; Ficarra, F. A.; Thomas, L.; Marondedze,
C.; Feil, R.; Lunn, J. E.; Gehring, C.; Ottado, J.; Gottig, N. J. Exp. Bot. 2015, 66,
2795.
14. Shirai, A.; Sumitomo, T.; Kurimoto, M.; Maseda, H.; Kourai, H. Biocontrol Sci.
2009, 14, 13.
15. Singh, S.; Bhadani, A.; Kataria, H.; Kaur, G.; Kamboj, R. Ind. Eng. Chem. Res. 2009,
48, 1673.

P. Wang et al. / Bioorg. Med. Chem. Lett. 26 (2016) 1136–1139
1139
1
6. Ventura, S. P. M.; Gurbisz, M.; Ghavre, M.; Ferreira, F. M. M.; Goncalves, F.;
Beadham, I.; Quilty, B.; Coutinho, J. A. P.; Gathergood, N. ACS Sustainable Chem.
Eng. 2013, 1, 393.
27. Sundararaman, M.; Kumar, R. R.; Venkatesan, P.; Ilangovan, A. J. Med. Microbiol.
2013, 62, 241.
28. Kahriman, N.; Yayli, B.; Aktas, A.; Iskefiyeli, Z.; Beris, F. S.; Yayli, N. Eur. J. Med.
Chem. 2013, 69, 348.
29. Sambhy, V.; Peterson, B. R.; Sen, A. Angew. Chem., Int. Ed. 2008, 47, 1250.
30. Haldar, J.; Kondaiah, P.; Bhattacharya, S. J. Med. Chem. 2005, 48, 3823.
31. Tew, G. N.; Liu, D.; Chen, B.; Doerksen, R. J.; Kaplan, J.; Carroll, P. J.; Klein, M. L.;
DeGrado, W. F. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 5110.
32. Kuroda, K.; DeGrado, W. F. J. Am. Chem. Soc. 2005, 127, 4128.
33. Ilker, M. F.; Nüsslein, K.; Tew, G. N.; Coughlin, E. B. J. Am. Chem. Soc. 2004, 126,
15870.
1
1
7. Pernak, J.; Rogoza, J.; Mirska, I. Eur. J. Med. Chem. 2001, 36, 313.
8. Caruso, E.; Banfi, S.; Barbieri, P.; Leva, B.; Orlandi, V. T. J. Photochem. Photobiol. B
2
012, 114, 44.
1
9. Patel, A. A.; Lad, H. B.; Pandya, K. R.; Patel, C. V.; Brahmbhatt, D. I. Med. Chem.
Res. 2013, 22, 4745.
2
2
0. Bharate, S. B.; Thompson, C. M. Chem. Biol. Drug Des. 2010, 76, 546.
1. Cole, M. R.; Li, M.; El-Zahab, B.; Janes, M. E.; Hayes, D.; Warner, I. M. Chem. Biol.
Drug Des. 2011, 78, 33.
2
2
2. Zasloff, M. Nature 2002, 415, 389.
3. Wang, L. Y.; Qin, H. L.; Wang, L.; Huo, S. C.; Zhao, B.; Song, B.; Yan, T. J. Chem.
Res. 2013, 37, 205.
34. Hu, J.; Wang, P.; Lin, Y.; Zhang, J.; Smith, M.; Pellechia, P. J.; Yang, S.; Song, B.;
Wang, Q. Chem. Eur. J. 2014, 20, 7603.
35. Wang, P.; Lin, Y.; Smith, M.; Feng, S.; Song, B.; Yang, S.; Hu, J. Chem. Commun.
2014, 50, 11950.
2
4. Brahmachari, S.; Debnath, S.; Dutta, S.; Das, P. K. Beilstein J. Org. Chem. 2010, 6,
8
59.
36. Wang, X.; Yin, J.; Shi, L.; Zhang, G.; Song, B. Eur. J. Med. Chem. 2014, 77, 65.
37. Wang, P.; Hu, J.; Lin, Y.; Smith, M.; Yang, S.; Song, B.; Wang, Q. Tetrahedron
2014, 70, 6651.
2
2
5. Debnath, S.; Shome, A.; Das, D.; Das, P. K. J. Phys. Chem. B 2010, 114, 4407.
6. Chanawanno, K.; Chantrapromma, S.; Anantapong, T.; Kanjana-Opas, A.; Fun,
H. K. Eur. J. Med. Chem. 2010, 45, 4199.