Chapter 37
Novel Class of Pyridyl Fungicides 1
2
3
Don R. Baker , Keith H. Brownell , Ian R. Matthews , and Paul Worthington 3
1
Zeneca Ag Products, 1200 South 47th Street, Richmond, CA 94804 Zeneca Ag Products, Route 1, Box 117, Whitakers, NC 27891 Zeneca Agrochemicals, Jealott's Hill Research Station, Bracknell, Berkshire RG12 6EY, United Kingdom 2
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These novel cyclopropane carboxamides came about as the result of a new in vivo fungicide test for Botrytis cinerea. The test compounds were applied to rose petals which were later innoculated with the fungal spors and then incubated at room temperature. Among the first compounds tested were these compounds as exemplified by Compound 1. The various structural types related to these compounds were prepared and tested for their antifungal activity. There seems to be a fairly narrow structure activity relationship for this new class of fungicides.
O Compound 1 During the last 40 years there have been major changes in the science associated with agrochemicals (1). There has been a revolution in the analytical tools such as nmr, gas chromatography, and mass spectral analysis. There are many new specialized reactions and reagents. There are a variety of chromatography tools. The first generation of organic agrochemicals came about as a result of the random screening approach. Here all manner of organic compounds were tested for action on plants, insects or fungi. By the 1950s it became apparent that certain groups such as the phosphates, carbamates, or amides conferred certain toxic responses when a part of certain compounds. It then became a race to attach such groups to just about any kind of backbone molecule imaginable and to then test the result. Active natural products such as the pyrethrins became models for synthesis. Here we see that over a period of many years many groups have added to our knowledge of what constitutes the synthetic pyrethroids. 0097-6156/95/0584-0434$12.00/0 © 1995 American Chemical Society
Baker et al.; Synthesis and Chemistry of Agrochemicals IV ACS Symposium Series; American Chemical Society: Washington, DC, 1995.
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Novel Class ofPyridyl Fungicides
The mimicking of auxin in the plant by 2,4-D and its herbicidal effect led to many modifications. This mimicking process whether applied to natural products or to other active materials has often been referred to as "me too chemistry" and has yielded a variety of commercial materials. Another interesting approach is the design of new compounds which interact with a critical enzyme of interest. This strategy has been labeled biochemical design. It has shown commercial success in the pharmaceutical field, however, as yet there have been no commercial agrochemicals which have come through this route. Molecular modeling is another similar approach which is currently widely used in the design of new agrochemicals.
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Lead Discovery How do you find that new active compound with that unexpected superior biological activity. Most often this comes about by what some have called "serendipity." However, this is usually much more than luck. It usually comes about with individuals prepared to recognize the unexpected. The lead compounds in this series came about as a result of an intermediate in a herbicide synthesis program being tested in a new series of fungicide tests (25). Here two white rose petals are placed in a petri dish lined with wet filter paper. The compound to be tested is diluted with a 50/50 acetone /water solution to produce decreasing concentrations. One half ml of test solution is atomized onto the petals, and allowed to dry. Inoculum of Botrytis cineria of 20 microliters is placed on each petal . The petri dishes with inoculated petals are stored in sealed plastic boxes to maintain saturated humidity. Results are read four days following inoculation as a percent reduction in necrotic area compared to the acetone/water controls. Compound concentrations which provide 90% disease control are determined from dosage/dilution curves. The results are presented in parts per million. Among the first compounds tested in this new test were Compounds 1 and 2:
O
Compound 2
Compound 1 Synthesis and Testing
The data below shows the IC from this new test for these two compounds. These compounds were also active on a variety of other organisms, such as leaf rust, powdery mildew, apple scab, and rice blast. However, here we will only report the results coming from this new in vivo type test. 90
Baker et al.; Synthesis and Chemistry of Agrochemicals IV ACS Symposium Series; American Chemical Society: Washington, DC, 1995.
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SYNTHESIS A N D C H E M I S T R Y O F A G R O C H E M I C A L S IV
The keys to developing new agrochemical materials which meet the criteria of the 21st century are tests which provide the synthesis chemist with data as to how new test compounds meet the requirements of the marketplace. In addition to efficacy, safety and environmental factors are of prime concern. Also properly designed screening tests are very important. In a standard in vitro screening test the lead compounds would not have been found. In this particular example an in vivo test with Botrytis c/neria provided an indication of the high activity of the compounds. Botrytis Bud Blight Test IC (ppm) 90
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A
NHHT^C)CH3
Y
20
O Compound 1
25
O Compound 2 Potential Sites for Structure Modification Once that new active compound is identified modifications can be made in the basic structure of the molecule to determine the range and scope of the biological action. Structure Activity Relationships can be determined. Molecular modeling is employed to gain insight into possible modifications which may be effective in design of new compounds. The following structure indicates potential modifications which can be made in order to determine the scope of the biological activity.
X
R
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Baker et al.; Synthesis and Chemistry of Agrochemicals IV ACS Symposium Series; American Chemical Society: Washington, DC, 1995.
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Novel Class of Pyridyl Fungicides
R Types of Modifications 1
There are a wide variety of substituents which can be tried for R,. As can be seen below, substituents in this position greatly modify the fungicidal effect. Botrytis Bud Blight Test IC (ppm) 90
CH ^A o
N H
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l f
0°
C H
=
750
Compound 3
nhh
^y O~°
CH3
200
o Compound 4
O CH / 3
NhKv
y
//-OCH,
25
^ - N
O Compound 5
O
NH-(v
