Synthesis and antifungal activity of aspirin derivatives

Article abstract of DOI:10.14233/ajchem.2014.16535

Using aspirin as a lead compound, a series of its derivatives (compounds 1-7) were designed and synthesized. Their activity of antipathogenic fungi of plants has been evaluated in the laboratory. The results showed that these compounds had good antifungal activity against Sclerotinia sclerotiorum, Helminthosprium maydis, Botrytis cinerea and Rhizoctonia solani. Among them, the inhibition of growth for compounds 1 and 2 against Helminthosprium maydis reached 92.5 and 91.6% at a concentration of 100 mg L^-1, respectively, which was superior to carbendazim.

Full text of DOI:10.14233/ajchem.2014.16535

Asian Journal of Chemistry; Vol. 26, No. 21 (2014), 7157-7159
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.16535
Synthesis and Antifungal Activity of Aspirin Derivatives
1
1
1
2
1
1
1
1,*
SUMEI GAO , ZHIHONG XU , XUESONG WANG , HUI FENG , LING WANG , YUANJIANG ZHAO , YUE WANG and XIAORONG TANG
1School of Physics and Chemistry, Xihua University, Chengdu 610039, P.R. China
2School of Bioengineering, Xihua University, Chengdu 610039, P.R. China
*Corresponding authors: E-mail: tangxiaorong0901@163.com
Received: 16 October 2013;
Accepted: 14 March 2014;
Published online: 30 September 2014;
AJC-16092
Using aspirin as a lead compound, a series of its derivatives (compounds 1-7) were designed and synthesized. Their activity of anti-
pathogenic fungi of plants has been evaluated in the laboratory. The results showed that these compounds had good antifungal activity
against Sclerotinia sclerotiorum, Helminthosprium maydis, Botrytis cinerea and Rhizoctonia solani. Among them, the inhibition of
growth for compounds 1 and 2 against Helminthosprium maydis reached 92.5 and 91.6 % at a concentration of 100 mg L-1, respectively,
which was superior to carbendazim.
Keywords: Aspirin derivatives, Antifungal activity.
Academy of Agricultural Sciences. They were preserved at
4 °C.All chemicals and solvents were purchased from commer-
cial sources unless specified otherwise. IR spectra were
recorded on a Thermofisher Nicolet-6700 spectrophotometer.
1H NMR spectra were taken on a Varian Unity Inova-400
instrument using deuteron-chloroform as the solvent.
Synthesis of target compounds: The target compounds
were synthesized in accordance with the reaction shown in
Fig. 1. Aniline or its derivatives (0.01 mol) and pyridine (0.01
mol) were dissolved in CH2Cl2 (15 mL). The mixture was
stirred and heated to 35-45 °C. 2-(Chlorocarbonyl)phenyl
acetate (0.01 mol) with CH2Cl2 (15 mL) was slowly added to
the above mixture under stirring until the reaction was
complete. The precipitate was filtered and washed with stilled
water. The pure compounds were obtained by re-crystallization
in anhydrous ethanol.
INTRODUCTION
Sclerotinia sclerotiorum, Helminthosprium maydis, Botrytis
cinerea and Rhizoctonia solani are harmful pathogenic fungi
of crops or vegetables1-4. Over the past decades, synthetic fungi-
cides including carbendazim have been used to prevent them.
However, in recent years, they have developed resistance to
the fungicides5-9. Moreover, their scope of resistance continues
to expand and has already included many new fungicides10-12
.
Therefore, new fungicides are continually required.
It is well-known that since aspirin (acetylsalicylic acid)
was first marketed in 1899, it has been widely used for the
treatment of pains, fever and colds13-16. Therefore, in the present
study, aspirin derivatives were synthesized based on aspirin.
In the meantime, their antifungal activity has been evaluated
in the laboratory to find new fungicides with high efficacy
and low toxicity.
Compound 1 (C15H13O3N): Light yellow powder; yield:
75 %; m.p. 152-153 °C; IR (KBr, νmax, cm-1): 3243, 3191, 3131,
3072, 3040, 1760, 1649, 1597, 1542, 1494, 1451, 1370, 1327,
EXPERIMENTAL
1
Sclerotinia sclerotiorum, Helminthosprium maydis, Botrytis
cinerea and Rhizoctonia solani were obtained from the Chinese
1300, 1195, 1156, 1097, 758, 748, 709, 596; H NMR (400
MHz, CDCl3) δ (ppm): 8.08 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H),
O
O
H
C–N
C–Cl
Pyridine/CH2Cl2
R
H2N
R
+
∆
OCOCH3
OCOCH3
1: R=H; 2: R=Cl; 3: R=Br; 4: R= -NO2; 5: R= -CH3; 6: R= -OCH3; 7: R= -COCH3
Fig. 1. Synthetic method of target compounds 1-7

7158 Gao et al.
Asian J. Chem.
7.60 (d, J = 8.0 Hz, 2H), 7.49-7.53 (m, 1H), 7.33-7.38 (m,
3H), 7.13-7.17 (m, 2H), 2.32 (s, 3H).
7.85 (m, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.51-7.56 (m, 1H),
7.34-7.38 (m, 1H), 7.17 (d, J = 8.0 Hz, 1H), 2.58 (s, 3H), 2.33
(s, 3H).
Compound 2 (C15H12O3NCl):White needle crystal; yield:
40 %; m.p. 133-134 °C; IR (KBr, νmax, cm-1): 3487, 3285, 3190,
3111, 3048, 1755, 1656, 1608, 1595, 1533, 1493, 1447, 1396,
Assay of antifungal activity: The antifungal activity of
the synthesized compounds against Sclerotinia sclerotiorum,
Helminthosprium maydis, Botrytis cinerea and Rhizoctonia
solani were determined using the plate growth rate method17.
The synthesized compounds and carbendazim (purity
90 %) were dissolved in dimethyl sulfoxide, respectively. The
two solutions were diluted into five different concentrations
with distilled water, respectively. They were added to the sterile
culture medium (PDA) at 45 °C, mixed to homogeneity and
transferred to sterile Petri dishes to solidify. A mycelium agar
disc (5 mm in diameter) of the target fungi was placed in the
center of PDA plates. They were incubated at 28 °C in the
dark until the target fungi used as controls covered the surface
of these plates. Control groups were treated with the corres-
ponding solutions without the synthesized compounds or
carbendazim. The experiment for each concentration was
replicated three times. The diameter of the fungi in the cultures
was measured and the inhibition of growth was calculated
according to the formula of Abbott.
1
1317, 1207, 1172, 830, 751, 701, 589; H NMR (400 MHz,
CDCl3) δ (ppm): 8.10 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.49-
7.55 (m, 3H), 7.30-7.36 (m, 3H), 7.14 (d, J = 8.4 Hz, 1H),
2.31 (s, 3H).
Compound 3 (C15H12O3NBr): Light yellow needle crystal;
yield: 82 %; m.p. 138-139 °C; IR (KBr, νmax, cm-1): 3485, 3281,
3183, 3105, 3042, 1755, 1656, 1597, 1607, 1587, 1526, 1490,
1446, 1391, 1317, 1208, 1173, 826, 750, 700, 589; 1H NMR
(400 MHz, CDCl3) δ (ppm): 8.15 (s, 1H), 7.77 (d, J = 7.6 Hz,
1H), 7.42-7.52 (m, 5H), 7.32 (t, J = 7.6 Hz, 1H), 7.13 (d, J =
8.0 Hz, 1H), 2.30 (s, 3H).
Compound 4 (C15H12O5N2): Golden yellow crystal; yield:
54 %; m.p. 90-91 °C; IR (KBr, νmax, cm-1): 3315, 3123, 3068,
3030, 1775, 1675, 1604, 1585, 1501, 1451, 1370, 1298, 1176,
1146, 1121, 812, 744, 693, 592; 1H NMR (400 MHz, CDCl3)
δ (ppm): 11.10 (s, 1H), 8.91 (d, J = 8.4 Hz, 1H), 8.24 (d, J =
8.4 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H),
7.58 (t, J = 7.6 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.21-7.26 (m,
2H), 2.36 (s, 3H).
RESULTS AND DISCUSSION
Compound 5 (C16H15O3N): Light yellow crystal; yield:
85 %; m.p. 139-140 °C; (KBr, νmax, cm-1): 3494, 3280, 3193,
3122, 3060, 2921, 1756, 1654, 1606, 1533, 1513, 1446, 1382,
All the synthesized derivatives of aspirin were screened
for their activity against Sclerotinia sclerotiorum, Helmintho-
sprium maydis, Botrytis cinerea and Rhizoctonia solani. The
results are presented in Table-1. Most of them were active
against the four different pathogenic fungi at a concentration
of 100 mg L-1. The inhibition rate of compounds 1 and 2 against
Helminthosprium maydis reached 92.5 and 91.6 %, respec-
tively, which was higher than carbendazim. The inhibition rate
of compound 3 against Botrytis cinerea reached 90.6 %, which
was close to carbendazim.
1
1220, 1206, 812, 762, 701; H NMR (400 MHz, CDCl3) δ
(ppm): 7.98 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.47-7.53 (m,
3H), 7.35 (t, J = 7.4 Hz, 1H), 7.16 (t, J = 7.2 Hz, 3H), 2.34
(s, 3H), 2.32 (s, 3H).
Compound 6 (C16H15O4N): Light purple solid; yield:
77 %; m.p. 119-120 °C; IR (KBr, νmax, cm-1): 3341, 3246,
3123, 3044, 3009, 2937, 2839, 1760, 1643, 1608, 1599, 1513,
1445, 1371, 1301, 1219, 1198, 816, 759, 634; 1H NMR (400
MHz, CDCl3) δ (ppm): 7.94 (s, 1H), 7.83 (d, J = 8.0 Hz,
1H), 7.49-7.52 (m, 3H), 7.35 (t, J = 7.2 Hz, 1H), 7.15 (d, J =
8.0 Hz, 1H), 6.90 (d, J = 9.2 Hz, 2H), 3.81 (s, 3H), 2.33 (s,
3H).
A series of derivatives of aspirin have been successfully
synthesized and tested for their antifungal activity against
Sclerotinia sclerotiorum, Helminthosprium maydis, Botrytis
cinerea and Rhizoctonia solani. The preliminary results
suggested that the design and synthesis of these compounds
may be conducive to the antifungal activity of derivatives of
aspirin. They are also promising and beneficial to further
studies in developing new and more effective fungicides in
the agricultural chemistry field. However, there is more work
Compound 7 (C17H15O4N): Orange yellow crystal; yield:
35 %; m.p. 160-161 °C; (KBr, νmax, cm-1): 3502, 3330, 3184,
3104, 3000, 1772, 1682, 1601, 1586, 1522, 1447, 1366, 1314,
1
1218, 1196, 1180, 820, 759, 698, 595; H NMR (400 MHz,
CDCl3) δ (ppm): 8.37 (s, 1H), 7.97 (d, J = 8.8 Hz, 2H), 7.82-
TABLE-1
ANTIFUNGAL ACTIVITY OF COMPOUNDS 1-7 AGAINST Sclerotinia sclerotiorum,
Helminthosprium maydis, Botrytis cinerea AND Rhizoctonia solani AT 100 mg L–1
Inhibition of growth (%)∗
Compound
R
Sclerotinia sclerotiorum
Helminthosprium maydis
Botrytis cinerea
72.0
Rhizoctonia solani
1
H
4-Cl
87.5
93.7
87.7
50.6
91.1
91.1
71.7
100
92.5
91.6
72.7
67.8
78.5
70.4
79.4
87.5
88.7
63.8
61.3
67.7
48.9
46.2
37.1
100
2
88.8
3
4-Br
90.6
4
4-NO2
4-CH3
4-OCH3
4-COCH3
–
66.4
5
68.2
6
60.8
7
77.2
Carbendazim
91.3
∗Based on the mean of triplicates

Vol. 26, No. 21 (2014)
Synthesis and Antifungal Activity of Aspirin Derivatives 7159
2. Z.Q. Shi, M.G. Zhou and Z.Y. Ye, J. Jiangsu Agric., 16, 212 (2000).
3. W. Li, Y.J. Zhou and H.G. Chen, Chin. J. Oil Crop Sci., 29, 63 (2007).
4. K.Y. Liu and F.X. Chen, Anhui Agric. Sci., 35, 756 (2007).
5. Y.X. Qi, F.X. Chen and K.J. Ding, Pesticides, 8, 567 (2006).
6. A. Have, R. Berloo, P. Lindhout and J.A.L. Kan, Eur. J. Plant Pathol.,
117, 153 (2007).
to be done.A number of derivatives of aspirin should be further
synthesized for screening and surveying quantitative structure-
activity relationships so as to find novel fungicides with high
effect and low toxicity. Meanwhile, the mode of action of
compounds 1 and 2 and their safety to humans and non-target
organisms also need to be investigated.
7. S.I. Ignatova, N.S. Gorshkova and T.A. Tereshonkova, Acta Physiol.
Plant., 22, 326 (2000).
8. H. Egashira, A. Kuwashima, H. Ishiguro, K. Fukushima, T. Kaya and
S. Imanishi, Acta Physiol. Plant., 22, 324 (2000).
ACKNOWLEDGEMENTS
9. R.L. Guimaraes, R.T. Chetelat and H.U. Stotz, Eur. J. Plant Pathol.,
110, 13 (2004).
This project was supported by the Scientific Research
Fund of Sichuan Provincial Education Department (No.
13ZA0206), the Key Scientific Research Fund of Xihua
University (No. Z1013314), the Chengdu City Science and
Technology Bureau (No. 12DXYB001JH), the Innovation Fund
of Postgraduate of Xihua University (No. ycjj2014130) and the
Research Center forAdvanced Computation, Xihua University.
10. R. Finkers, P. Berg, R. Berloo, A. Have, A.W. Heusden, J.A.L. Kan
and P. Lindhout, Theor. Appl. Genet., 114, 585 (2007).
11. R. Finkers, A.W. Heusden, F. Meijer-Dekens, J.A.L. Kan, P. Maris and
P. Lindhout, Theor. Appl. Genet., 114, 1071 (2007).
12. R. Finkers, Y. Bai, P. Berg, R. Berloo, F. Meijer-Dekens, A. Have, J.
Kan, P. Lindhout and A.W. Heusden, Euphytica, 159, 83 (2007).
13. D.W. Gilroy, Prostag. Leukotr. Ess., 73, 203 (2005).
14. D.M. McCarthy, Best Pract. Res. Clin. Gastroenterol., 26, 101 (2012).
15. R. Eccles, Int. Pharm. J., 6, 7 (1995).
REFERENCES
16. C. Lampl, M. Voelker and H.C. Diener, J. Neurol., 254, 705 (2007).
17. W. Huang and G.F. Yang, Bioorg. Med. Chem., 14, 8280 (2006).
1. X.J. Chen, M.J. Cao, Y. Wang, Y.H. Tong and J.Y. Xu, Chin. J. Oil Crop
Sci., 31, 503 (2009).