Synthesis and Antibacterial Activity of Calycanthaceous Alkaloid Derivatives

Article abstract of DOI:10.1007/s10600-018-2274-6

A series of 45 calycanthaceous alkaloid derivatives with the tetrahydropyrroloindole core structure was synthesized from tryptophan in good yields. The synthesized compounds were evaluated against five strains of bacteria (Bacillus cereus, Bacillus subtilis, Staphylococcus aureus, Escherichia coil, Ralstonia solanacearum, and Pseudomonas aeruginosa). The bioassays indicated that among the synthesized compounds, compounds b3 and b4 exhibited a high degree of activity towards Gram positive B. subtilis. Compounds a14 and a18 displayed a high degree of activity towards R. solanacearum. These results will pave the way for further design, structural modification, and development of calycanthaceous alkaloids as antibacterial agents.

Full text of DOI:10.1007/s10600-018-2274-6

DOI 10.1007/s10600-018-2274-6
Chemistry of Natural Compounds, Vol. 54, No. 1, January, 2018
SYNTHESIS AND ANTIBACTERIAL ACTIVITY
OF CALYCANTHACEOUS ALKALOID DERIVATIVES
1,2,3*
1
1
Shaojun Zheng,
Yongdong Gu, Rui Zhu,
3
2*
3*
Longbo Li, Hongjin Bai, and Jiwen Zhang
A series of 45 calycanthaceous alkaloid derivatives with the tetrahydropyrroloindole core structure was
synthesized from tryptophan in good yields. The synthesized compounds were evaluated against five strains
of bacteria (Bacillus cereus, Bacillus subtilis, Staphylococcus aureus, Escherichia coil, Ralstonia
solanacearum, and Pseudomonas aeruginosa). The bioassays indicated that among the synthesized compounds,
compounds b3 and b4 exhibited a high degree of activity towards Gram positive B. subtilis. Compounds a14
and a18 displayed a high degree of activity towards R. solanacearum. These results will pave the way for
further design, structural modification, and development of calycanthaceous alkaloids as antibacterial agents.
Keywords: calycanthaceous alkaloids, synthesis, antibacterial activity, agrochemicals, tryptophan.
Plant diseases are caused partly by bacterial pathogens, leading to severe losses to agriculture worldwide. Many of
the currently available antibacterial agents have several drawbacks, such as drug-related toxicity, severe drug resistance, and
serious drug interactions [1]. Therefore, there is a growing need to develop new antibacterial agents to effectively control
those agricultural diseases. Calycanthaceous alkaloids [2–5], which contain (+)-calycanthine (1), (–)-folicanthine (2),
(–)-chimonanthine (3), and (–)-calycanthidine (4), are an important class of alkaloid that can be isolated from roots, leaves,
flowers, and fruits of Chimonanthus praecox [6]. These compounds possess a unique chiral, dimeric core structure and are
distributed mainly in China, North America, and Australia [7, 8]. Calycanthaceous alkaloids have demonstrated important
biological activities such as anticonvulsant, antifungal, antiviral, antibacterial, antitumor, and melanogenesis inhibitory properties
[9–13]. Because of their broad spectrum of biological properties, a number of studies aimed at the synthesis and antimicrobial
activity of calycanthaceous alkaloids have been reported [13–20]. However, little attention has been paid to the structural
optimization of the tetrahydropyrroloindole core structure of calycanthaceous alkaloids for their antibacterial activities. Therefore,
we envisioned that the structural optimization might be a lead for the discovery of novel agricultural bactericide.
Herein, a series of analogs of calycanthaceous alkaloids was synthesized using tryptophan as starting material via an
efficient method. Their antibacterial effects were investigated. To the best of our knowledge, the antibacterial activities of the
synthetic derivatives are reported for the first time.
R
1
H
Me
N
Me
N
H
N
N
N
N
N
N
H
Me
Me
R
2
1
2 - 4
1) School of Environmental and Chemical Engineering, Jiangsu University of Science and Technology, 212003,
Zhenjiang, Jiangsu, P. R. China, e-mail: sz281cam@just.edu.cn; 2) Key Laboratory of Protection & Utilization of Biological
Resources in Tarim Basin of Xinjiang Production and Construction Corps/College of Life Sciences, Tarim University, 843300,
Alar Xinjiang, P. R. China, e-mail:bhj67@163.com; 3) Key Laboratory of Botanical Pesticide R & D in Shaanxi Province,
712100, Yangling, Shaanxi Province, P. R. China, e-mail: nwzjw@nwsuaf.edu.cn. Published in Khimiya Prirodnykh Soedinenii,
No. 1, January–February, 2018, pp. 110–112. Original article submitted April 21, 2016.
0009-3130/18/5401-0127 02018 Springer Science+Business Media, LLC
127

TABLE 1. Antibacterial Actitity of Calycanthaceous Alkaloid Derivatives (Diameter of Inhibition zone, mm)
Compound
Compound
B. subtilis
R. solanacearum
B. subtilis
R. solanacearum
–
–
11.5 (+++)
13.0 (++)
–
–
–
–
8.5 (+++)
8.5 (++)
7.0 (++)
9.5 (+++)
15.7 (+++)
a14
a18
b3
b4
b8
b12
b13
15.0 (+++)
15.5 (+++)
–
–
–
b14
b20
Ampicillin
9.5 (+)
25.9 (+++)
______
The diameters of inhibition zone of all the above are means of three replicates, acetone as the blank control, ampicillin sodium
as the positive control; “–” means no inhibition effect, “+” means eyeable, “++” means clear, “+++” means transparent. B. cereus,
S. aureus, P. aeruginosa, E. coli – no inhibition effect.
COOH
H
CO Me
2
H
CO Me
2
H
NHCO Me
2
NH
NH
2
2
a
b
N
H
N
H
N
H
7
5
6
c
MeO C
2
MeO C
2
H
MeO C
2
H
H
H
H
H
N
CO Me
2
N
N
CO Me
2
N
H
CO Me
2
H
N
N
H
R
1
R
1
b1 - b21
8
a1 - a24
O
O
O
O
S
O
O
O
O
F
F
CH
3
R
R
R =
1
O
F
a21
a22
a1 - a11
a12 - a19
a20
a23
a24
a1: R = CH ; a2: R = C H ; a3: R = C H ; a4: R = C H : a5: R = (CH ) CH; a6: R = C H ; a7: R = C H ; a8: C H
3
2
5
3
5
3
7
3 2
4
9
5
11
6
13
a9: R = C H ; a10: R = C H ; a11: R = OCH ; a12: R = 3-Cl; a13: R = 4-Cl; a14: R = 3-CH ; a15: R = 4-CH
7
15
12 25
3
3
3
a16: R = 2-F; a17: R = 4-F; a18: R = 4-NO ; a19: R = H
2
R = CH (b1); CH CH (b2); CH (CH ) (b3); CH (CH ) (b4); (CH ) CH (b5); CH =CHCH (b6); CH (CH ) (b7)
1
3
3
2
3
2 3
3
2 4
3 2
2
2
3
2 7
CH (CH ) (b8)
3
2 11
R =
1
R
b9
b11 - b21
b10
b11: R = 4-Cl; b12: R = 3-F; b13: R = 4-F; b14: R = 2,4-F; b15: R = 2-CH
3
b16: R = 3-CH ; R = 4-CH ; b18: R = 3-CF ; b19: R = 2,6-F; b20: R = 4-F; b21: 2,4,6-F
3
3
3
a. SOCl , MeOH; b. ClCOOMe, Py; c. H PO
4
2
3
Scheme 1
The synthetic route of the title compounds is outlined in Scheme 1. The derivatives of calycanthaceous alkaloids were
synthesized using tryptophan as the starting material via acylation or alkylation at the 8-N position. Acylation resulted in 24
derivatives. Alkylation resulted in unexpected ring opening of the calycanthaceous alkaloid core structure at the C–N bond; 21
tryptophan methyl ester derivatives were synthesized.
Antibacterial Acitivity. The biological activities of these compounds towards five strains of bacteria were evaluated.
The in vitro antibacterial results of the calycanthaceous alkaloid analogues are listed in Table 1. Disk diffusion antibiotic
testing was utilized, with ampicillin sodium as a positive control, to evaluate the biological activities of the 45 synthesized
calycanthaceous alkaloid analogues against B. cereus, S. aureus, B. subtilis, P. aeruginosa, E. coli, and R. solanacearum.
128

In the bioassays of the compounds tested, compounds b3 and b4 exhibited a high degree of activity towards Gram positive
B. subtilis; Compounds a14 and a18 dispalyed a high degree of activity towards R. solanacearum.
In conclusion, 45 calycanthaceous alkaloid derivatives with the tetrahydropyrroloindole core structure were synthesized
by modification at the 8-N position and evaluated for their antibacterial activity against five strains of bacteria (B. cereus,
B. subtilis, S. aureus, E. coil, R. solanacearum, and P. aeruginosa). The bioassays indicated that among the synthesized
compounds, compounds b3 and b4 exhibited a high degree of activity towards Gram positive B. subtilis. Compounds a14 and
a18 displayed a high degree of activity towards R. solanacearum. These results will pave the way for further design, structural
modification, and development of calycanthaceous alkaloids as antibacterial agents.
EXPERIMENTAL
General. All reagents and solvents were of reagent grade or purified according to standard methods before use.
Analytical thin-layer chromatography (TLC) was performed with silica gel plates using silica gel 60 GF (Qingdao Haiyang
254
Chemical Co., Ltd.). Melting points were measured on an electrothermal digital apparatus made in Beijing and were uncorrected.
1
13
The H NMR (500 MHz) and C NMR (125 MHz) were obtained on a Bruker AM-500 FT-NMR spectrometer with CDCl as
3
the solvent and TMS as the internal standard. MS were recorded under ESI conditions using a Thermo LCQ Fleet instrument.
Optical rotation was measured by a Rudolph Autopol II polarimeter. The title compounds were synthesized under nitrogen
atmosphere.
Synthesis. The general synthetic methods for compounds a1–a24 and b1–b21 are depicted in Scheme 1 [21, 22].
Biological Assay. The antibacterial activity of calycanthaceous alkaloid analogues was measured according to a
previously reported method [22].
Filter PaperAssay. The antibacterial activities of compounds against five strains of bacteria (B. cereus, B. subtilis,
S. aureus, E. coil, R. solanacearum, and P. aeruginosa) were evaluated by the filter paper assay. The standard bacterial strains
were obtained from the College of Plant Protection, Northwest A & F University. Ampicillin (Sigma, Shanghai, China) was
used as a positive control. Beef extract peptone agar was used as the assay medium. The medium was mixed with a suspension
containing the bacterial pathogen. Next, the mixture was poured onto 9 cm Petri dishes. The tested compounds were dissolved
in acetone at the concentration of 2000 ppm. The filter papers (6 mm in diameter) were impregnated with 5 ꢀL/disc of each
compound, then completely dried and placed on the inoculated agar. The inoculated plates were incubated at 37ꢁC for 24 h.
Antibacterial activity was evaluated by measuring the zone of inhibition against the test organism. Experiments were run in
triplicate.
ACKNOWLEDGMENT
This work was supported by the National Natural Science Foundation of China (31360079, 21372185, and 21502073),
the Natural Key Research and Development Program of China (No. 2017YFD0200506), the Natural Science Foundation of
Jiangsu Province (Grants No. BK 20150465), and the Marine Equipment and Technology Institute of Jiangsu University of
Scince and Technology.
REFERENCES
1.
L. Lin, N. Mulholland, Q. Y. Wu, D. Beattie, S. W. Huang, D. Irwin, J. Clough, Y. C. Gu, and G. F. Yang,
J. Agric. Food. Chem., 60, 4480 (2012).
2.
3.
4.
5.
6.
7.
J. W. Zhang, Z. Hu, S. K. Li, and W. J. Wu, Int. J. Mol. Sci., 12, 9596 (2011).
L. Xiang, K. Zhao, and L. Chen, Plant Physiol. Biochem., 48, 845 (2010).
J. W. Zhang, S. K. Li, Z. Q. Ji, Z. N. Hu, and W. J. Wu, Chem. Nat. Compd., 45, 507 (2009).
Z. M. Yang, Z. Q. Ji, Q. F. Ye, and W. J. Wu, J. Labelled Compd. Radiopharm., 51, 109 (2008).
Y. Liu, Y. Liu, H. Xiao, R. Gao, and X. Tian, Pestic. Biochem. Physiol., 91, 116 (2008).
B. Kozomara, B. Vinterhalter, L. Radojevic, and D. Vinterhalter, In vitro Cell. Dev. Biol.: Plant, 44, 142 (2008).
129

8.
9.
10.
11.
12.
13.
B. K. Xiao and Y. M. Liu, Res. Pract. Chin. Med., 17 (2003).
J. S. Lv, L. L. Zhang, X. Z. Chu, and J. F. Zhou, Nat. Prod. Res., 26, 1363 (2012).
S. H. Zhang, Y. Wei, J. L. Liu, H. M. Yu, J. H. Yin, H. Y. Pan, and T. C. Baldwin, Biol. Plant., 55, 141 (2011).
R. Y. Gui, W. W. Liang, S. X. Yang, L. Llu, and J. C. Qin, Asian J. Chem., 26, 4445 (2014).
J. W. Zhang, J. M. Gao, T. Xu, X. C. Zhang, Y. T. Ma, S. Jarussophon, and Y. Konishi, Chem. Biodiv., 6, 838 (2009).
T. Araki, Y. Manabe, K. Fujioka, H. Yokoe, M. Kanematsu, M. Yoshida, and K. Shishido, Tetrahedron Lett., 54,
1012 (2013).
14.
15.
16.
17.
18.
19.
20.
21.
22.
J. B. Xu and K. J. Cheng, Molecules, 20, 6715 (2015).
P. Ruiz-Sanchis, S. A. Savina, F. Albericio, and M. Alvarez, Chem. Eur. J., 17, 1388 (2011).
Y. X. Li, H. X. Wang, S. Ali, X. F. Xia, and Y. M. Liang, Chem. Commun., 48, 2343 (2012).
Y. Peng, L. Luo, C. S. Yan, J. J. Zhang, and Y. W. Wang, J. Org. Chem., 78, 10960 (2013).
J. Kim and M. Movassaghi, Acc. Chem. Res., 48, 1159 (2015).
J. A. May and B. Stoltz, Tetrahedron, 62, 5262 (2006).
M. Ding, K. J. Liang, R. Pan, H. B. Zhang, and C. B. Xia, J. Org. Chem., 80, 10309 (2015).
S. Zheng, L. B. Li, Y. Wang, R. Zhu, H. J. Bai, and J. W. Zhang, Nat. Prod. Commun., 11, 1429 (2016).
W. J. Zhang, S. P. Wei, J. W. Zhang, and W. J. Wu, Molecules, 18, 2763 (2013).
130