5
45
5
5
5
10
100
20
17
18
19
20
—
10
—
40
30
60
30
40
10
60
100
65
1. Regnault-Roger, C.; Philogène, B. J.; Vincent, C. Biopesticides of
plant origin. Ed. 2. Editions Tec & Doc, 2008.
2. Jacobson, M. ACS Symposium series - American Chemical Society.
1989. 387, 1.
3. Isman, M, B. Pest Manag. Sci., 2008, 64, 8.
Fungicidal Activities. These derivatives exhibited good
fungicidal activities against 14 kinds of plant fungi, especially
against Cercospora arachidicola Hori (Table 3). The fungicidal
activities of compound 8 exhibited more than 70% inhibition rate
against Cercospora arachidicola Hori, Alternaria solani,
Bipolaris maydis, and Rhizoctonia solani at 50 mg/kg. Just like
the anti-TMV activities, it was detrimental to the fugicidal
activity when the esters on 3-position were changed to amides.
For example, the activity of the compound containing butyl ester
(8) on 3-position was much higher than that of compound
containing N-butylamide (16) on 3-position. To our surprise, the
compound containing hydrazide structure (15) which showed the
best anti-TMV activity didn’t show ideal fungicidal activity. The
chirality of C-3 (lead compound, 12 and 14) had no effect on the
activity.
4. Wang, K. L.; Hu, Y. N.; Liu, Y. X.; Mi, N.; Fan, Z. J.; Liu, Y.,
Wang, Q. M. J. Agric. Food Chem. 2010, 58, 12337.
5. Wang, Z. W.; Wang, L.; Ma, S.; Liu, Y. X.; Wang, L. Z.; Wang, Q.
M. J. Agric. Food Chem. 2012, 60, 5825.
6. Massaro, E. J. Handbook of neurotoxicology; Humana Press:
Totowa, NJ, USA, 2002; p 237.
7. Callaway, J. C.; McKenna, D. J.; Grob, C. S.; Brito, G. S.;
Raymon, L. P.; Poland, R. E.; Andrade, E. N.; Andrade, E. O.;
Mash, D. C. J. Ethnopharmacol. 1999, 65, 243.
8. Reniers, J.; Robert, S.; Frederick, R.; Masereel, B.; Vincent, S.;
Wouters, J. Bioorg. Med. Chem. 2011, 19, 134.
9. Srivastava, S. K.; Agarwal, A.; Chauhan, P. M. S.; Agarwal, S. K.;
Bhaduri, A. P.; Singh, S. N.; Fatima, N.; Chatterjee, R. K. J. Med.
Chem. 1999, 42, 1667.
Insecticidal Activities. The insecticidal activity of these
derivatives against lepidopteran pests and mosquito larvae were
not much high (Table 4). However, some of the compounds such
as 16 and 20 exhibited more than 60% insecticidal activities
against oriental armyworm (Mythimna separate) and pyrausta
nubilalis (Ostrinia nubilalis), and the lead compound and 16
exhibited more than 60% insecticidal activity against mosquito
larvae at 5 mg/kg.
10. Tang, J. G.; Wang, Y. H.; Wang, R. R.; Dong, Z. J.; Yang, L. M.;
Zheng, Y. T.; Liu, J. K. Chem. Biodiver. 2008, 5, 447.
11. Miller, J. F.; Turner, E. M.; Sherrill, R. G.; Gudmundsson, K.;
Spaltenstein, A.; Sethna, P.; Brown, K. W.; Harvey, R.; Romines,
K. R.; Golden, P. Bioorg. Med. Chem. Lett. 2010, 20, 256.
12. Song, H. J.; Liu, Y. X.; Liu, Y. X.; Wang, L. Z.; Wang, Q. M. J.
Agric. Food Chem. 2014, 62, 1010.
13. General 1H NMR spectra were obtained at 400 MHz using a
Bruker AV400 spectrometer in CDCl3 or DMSO-d6 solution with
tetramethylsilane as the internal standard. Chemical shift values
(δ) are given in parts per million. HRMS data were obtained on an
FTICR-MS instrument (Ionspec 7.0 T). The melting points were
determined on an X-4 binocular microscope melting point
apparatus and are uncorrected. Yields were not optimized. All
anhydrous solvents were dried and purified by standard techniques
just before use.
In summary, a series of 1,2,3,4-tetrahydro-β-carboline-3-
carboxylic acid derivatives with improved stability and solubility
were designed, synthesized and first evaluated for their antiviral
activities against TMV. The bioassay results showed that most of
these derivatives exhibited good antiviral activity against TMV in
vitro and in vivo. Generally, the compound containing a
hydrazide structure (15) exhibited higher activity than that of
compounds containing ester (7–12, 14) and amide (16–20),
which showed higher activity than carboxylic acid containing
compounds (1–2, 5–6). The activities of butyl ester 8 (48.2 % in
vitro and 51.3, 42.2, and 43.2 % at 500 µg/mL in vivo) were
much higher than that of ribavirin (40.0 % in vitro and 37.4, 36.2,
and 38.5 % at 500 µg/mL in vivo), hydrazide 15 exhibited higher
curative and protection activities in vivo (48.2 and 49.6 % at 500
µg/mL) than the lead compound (ethyl (1S,3S)-1-methyl-2,3,4,9-
tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate) (43.9 and 47.9
% at 500 µg/mL), therefore, this compound (15) can be used as a
lead structure for the development of anti-TMV drugs. We also
found the fungicidal activities of compound 8 exhibited more
than 70% inhibition rate against Cercospora arachidicola Hori,
Alternaria solani, Bipolaris maydis, and Rhizoctonia solani at 50
mg/kg, compounds 16 and 20 exhibited more than 60%
insecticidal activities against oriental armyworm (Mythimna
separate) and pyrausta nubilalis (Ostrinia nubilalis), and the lead
compound and 16 exhibited more than 60% insecticidal activity
against mosquito larvae at 5 mg/kg. Further studies on structural
optimization are in progress in our laboratory.
14. Wang, K. L.; Su, B.; Wang, Z. W.; Wu, M.; Li, Z.; Hu, Y. N.; Fan,
Z. J.; Mi, N.; Wang, Q, M. J. Agric. Food Chem. 2010, 58, 2703.
15. Zhao, H. P.; Liu, Y. X.; Cui, Z. P.; Beattie, D.; Gu, Y. C.; Wang,
Q. M. J. Agric. Food Chem. 2011, 59, 11711.
16. Song, H. J.; Liu, Y. X.; Xiong, L. X.; Li, Y. Q.; Yang, N.; Wang,
Q, M. J. Agric. Food Chem. 2012, 60, 1470.
Acknowledgments
This work was supported by the National Natural Science
Foundation of China (21132003, 21121002, 21372131,
21102077), and the Specialized Research Fund for the Doctoral
Program of Higher Education (20130031110017).
References and notes