Chapter 15
Structure—Activity Relationships for Insecticidal Pyrroles
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David G. Kuhn Cyanamid Agricultural Research Center, P.O. Box 400, Princeton, NJ 08543-0400
A new class of insecticides, the 2-arylpyrroles, based on a naturally occuring compound, dioxapyrrolomycin, has been prepared. Through a program of synthesis and biological evaluation, the parameters necessary for optimal insecticidal activity have been investigated. These structure-activity comparisons along with mode of action studies for this series will be discussed.
A program to identify novel sources of compounds possessing insecticidal activity has been in place in our laboratories for a number of years. As part of this program, we found that fermentation of a Streptomyces fumanus (Sveshnikova) culture, derived from a soil sample collected in Oklahoma, led to an extract having activity against a spectrum of agronomic pests. Using standard isolation techniques, guided by screening for insecticidal activity, the active component was identified by Carter and co-workers in 1987 (1). The compound was named dioxapyrrolomycin. The structure, along with the insecticidal activity associated with the pure material, is shown in Figure 1. At about the same time, this pyrrole was reported by scientists at Meiji Seika and SS Pharmaceutical Company in Japan as having antibacterial and antifungal activity (2,3). Neither group reported insecticidal activity. This natural product became the focal point for an extensive synthesis program aimed at discovering less complex analogs having improved insecticidal activity (4). This work culminated in the identification of the 2-arylpyrroles as a new class of insecticides. The general structure is shown in Figure 2. Our synthesis efforts have allowed us to define the substitutions at the various positions of the pyrrole nucleus necessary for optimal insecticidal activity (5, 6). This paper will focus on these relationships between structural features and biological activity. Structure - Activity Relationships During the course of this work, it became apparent that, for optimal insecticidal activity, all of the positions on the pyrrole ring had to be substituted (5a). We
© 1997 American Chemical Society In Phytochemicals for Pest Control; Hedin, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1997.
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PHYTOCHEMICALS F O R PEST C O N T R O L
Dioxapyrrolomycin CI CI
N0
2
1
V^ci H
O
v
Insecticidal Activity (LC50 - ppm) Southern Armyworm Tobacco Budworm Two-Spotted Mite Western Potato Spodoptera eridania Heliothis virescens Tetranychus urticae Leafhopper 3rdinstur 3rd instar OP-Resistant Empoassa abrypta Mixed
40
32
10
F i g u r e 1. S t r u c t u r e and of D i o x a p y r r o l o m y c i n
X
F i g u r e 2.
Insecticidal
1000 nM) whereas the parent was highly active (U50 = 2.4 nM). In the insect, it was found that CL 303,630 (25) was converted to the parent pyrrole. Further support for the concept of CL 303,630 functioning as a proinsecticide was gainedfromwork on Colorado potato beetles as shown in Figure 4. In this study, CL 303,630 (25) gave complete control at a dose rate of 10 ppm. Addition of piperonyl butoxide, an inhibitor of mixed function oxidases, which partially blocks the metabolic conversation of CL 303,630 (25) to the active N-H pyrrole (7), reduced the level of control to less than 10%. This mode of action work suggests that the 2-aryl pyrroles should have activity on insects resistant to other agents. Recent workfromour laboratories
In Phytochemicals for Pest Control; Hedin, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1997.
15. KUHN
Structure-Activity RelationsMps for Insectiddal Pyrroles
confirms this. Table VI shows the results of a study utilizing pyrethroid-resistant Plutella xylostella. At a dose rate of 3.1 ppm, the pyrethroid fenvalerate gave 100% control of the susceptible strain of insects, as did C L 303,630 (25). However, at the same dosage, while CL 303,630 (25) continued to give 100% mortality of the resistant species, the pyrethroid failed to give any control. Table VI. TOXICITY OF CL 303,630 TO PYRETHROID-RESISTANT Plutella xylostella, THIRD-INSTARS % CONTROL @ 3.1 PPM Downloaded by UNIV OF OKLAHOMA on October 27, 2014 | http://pubs.acs.org Publication Date: March 19, 1997 | doi: 10.1021/bk-1997-0658.ch015
COMPOUND
Br.
SUSCEPTIBLE STRAIN
RESISTANT STRAIN
100
100
CN
F3C
Fenvalerate*
100
* Fenvalerate @ 50 ppm did not cause mortality in R-strain
The activity of CL 303,630 (25) against susceptible and OP and carbamate resistant strains of mites is shown in Table Vu. TABLE VD. TOXICITY OF C L 303,630 TO SUSCEPTIBLE AND RESISTANTSTRAINS OF Tetranychus urticae (LC95PPM)
S-STRAIN
OP-RESISTANT
CARBAMATE RESISTANT
CL 303,630 (25)
11.3
13.0
7.0
Phosalone
56.6
>40,000
Formetanate
13.2
COMPOUND
>5,000
In Phytochemicals for Pest Control; Hedin, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1997.
203
204
PHYTOCHEMICALS FOR PEST CONTROL
The standards in this study were phosalone, an organophosphate and formetantate, a carbamate. All three compounds were toxic to the susceptible strain of mites. CL 303,630 (25) retained activity against both strains of resistant mites while phosalone and formetanate showed no activity. Table Vffl.
STRUCTURE - ACTIVITY TRENDS
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X
L
EWG
X=Y=Br or CI are approximately equal in activity. Best activity seen for X=BrorCl and Y=CF . Approximately the same activity seen for EWG=CN, N0 , or CF S0 . R! requires some electron-withdrawal. The best groups are CI, Br, or CF . Best activity seen when Ri is in the 4-position. N-Derivatized pyrroles (R^H) act as pro-insecticides with the highest activity seen for R =alkoxyalkyl. The parent pyrroles (R =H) are uncouplers of oxidative phosphorylation. They show correlations between pKa, log P, and insecticidal activity. 3
IL ΙΠ. IV. V.
2
3
2
3
2
VI.
2
Conclusions The 2-aryl pyrroles, a new class of insecticides that exert their activities through uncoupling of oxidative phosphorylation, have been investigated in our laboratories. Through an extensive synthesis program coupled with biological screening, we have developed the structure-activity correlations described in Table Vm. These trends, and more extensive physicochemical studies correlating pKa and log Ρ with insecticidal activities, are currently being used to design more potent, insect specific molecules (13). Currently, one compound CL 303,630 is undergoing full scale development. Acknowledgements The author would like to gratefully acknowledge the past and present members of the Insect Control Synthesis and Insecticide Discovery groups whose contributions made this work possible. Literature Cited 1. Carter, G.T.; Nietsche, J.N.; Goodman, J.J.; Torray, M.J.; Dunne, T.S.; Borders, D.B.; Testa, R.T. J. Antibiotics 1987, 40, 233. 2. Nakamura, H.; Shiomi, K.; Iinuma, H.; Naganawa, H.; Obata, T.; Takeuchi, T.; Umezawa, H. J. Antibiotics 1987, 40, 899. 3. Yano, K.; Oono, J.; Mogi, K.; Asaoka, T.; Nakashima, T. J. Antibiotics 1987, 40, 961.
In Phytochemicals for Pest Control; Hedin, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1997.
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KUHN
Structure—Activity Relationships for Insecticidal Pyrroles 205
4. For a review of early work in this project, see: Addor, R.W.; Babcock, T.J.; Black, B.C.; Brown, D.G.; Diehl, R.E.; Furch, J.A.; Kameswaran, V.; Kamhi, V.M.; Kremer, K.A.; Kuhn, D.G.; Lovell, J.B.; Lowen, G.T.; Miller, T.P.; Peevey, R.M.; Siddens, J.K.; Treacy, M.F.; Trotto, S.H.; Wright, D.P. In Synthesis and Chemistry of Agrochemicals III; Edited by Baker, D.R.; Fenyes, J. G.; Steffens, J.J.; American Chemical Society: Washington, D.C., 1992; pp 283-297. 5. For discussions describing the mode of action of the 2-aryl pyrroles as uncouplers of oxidative phosphorylation, see: a) Kuhn, D.G.; Addor, R.W.; Diehl, R.E.; Furch, J.A.; Kamhi, V.M.; Henegar, K.E.; Kremer, K.A.; Lowen, G.T.; Black, B.C.; Miller, T.P.; Treacy, M.F. In Pest Control with Enhanced Environmental Safety; Edited by Duke, S.O.; Menn, J.J.; Plimmer, J.R.; American Chemical Society: Washington, D.C., 1993; pp 219-232; b) Hunt, D.A. In Advances in the Chemistry of Insect Control III; Edited by Briggs, G.; Royal Society of Chemistry: Cambridge, U.K.; 1994; pp 127-140. 6. Brown, D.G.; Siddens, J.K.; Diehl, R.E.; Wright, D.P., U.S. Patent 5,010,098, 1991. 7. Addor, R.W.; Furch, J.A.; Kuhn, D.G., U.S. Patent 5,030,735, 1991. 8. Kuhn, D.G.; Kamhi, V.M.; Furch, J.A.; Diehl, R.E.; Trotto, S.H.; Lowen, G.T.; Babcock, T.J.; In Synthesis and Chemistry of Agrochemicals III; Edited by Baker, D.R.; Fenyes, J.G.; Steffens, J.J.; American Chemical Society: Washington, D.C. 1992; pp 298-305. 9. Barnes, K.D.; Furch, J.A.; Rivera, M.A.; Trotto, S.H.; Ward, R.K.; Wright, D.P.; In Synthesis and Chemistry of Agrochemicals IV; Edited by Baker, D.R.; Fenyes, J.G.; Basarab, G.S.; American Chemical Society: Washington, D.C., 1995; pp 300-311. 10. Barnes, K.D.; Ward, R.K. J. Heterocyclic Chem. 1995, 32, 871. 11. Kuhn, D.G.; Kamhi, V.M.; Furch, J.A.; Diehl, R.E.; Lowen, G.T.; Kameswaran, V. Pesticide Science, 1994, 41, 279. 12. a) Kirby, A.H.M. and Hunter, L.D. Nature London, 1965, 208, 189; b) Saggers, D.J.; Clark, M.L. Nature (London), 1967, 215, 275. 13. Gange, D.M.; Donovan, S.; Lopata, R.J.; Henegar, K. In Classical and Three-Dimensional QSAR in Agrochemistry; Edited by Hansen, C. and Fujita, T.; American Chemical Society: Washington, D.C., 1995; pp 199212.
In Phytochemicals for Pest Control; Hedin, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1997.
