Synthesis and Chemistry of Agrochemicals III - American Chemical

Chapter 33

Nematicidal Activity of 5-Substituted-2-S-(3,4,4trifluoro-3-butenyl)-1,3,4-thiadiazoles 1

Thomas G. Cullen, James M. Willut, Carmen P. DiSanzo , and Anthony J. Martinez Downloaded by PENNSYLVANIA STATE UNIV on June 22, 2012 | http://pubs.acs.org Publication Date: September 22, 1992 | doi: 10.1021/bk-1992-0504.ch033

2

Agricultural Chemical Group, FMC Corporation, P.O. Box 8, Princeton, NJ 08543

The 5-substituted-2-S-(3,4,4-trifluoro-3-butenyl)-1,3,4-thiadiazoles are effective in the control of root-knot nematode. In addition to excellent initial control, these compounds provide good residual control of the root-knot nematode. The strategy to optimize the control is discussed and a quantitative structure activity relationships (QSAR) model is presented. Finally, control of other nematode species is discussed. The goal of our research program was to discover a nematicide which had good initial activity against the root-knot nematode, as well as residual control. Additionally, control of other economically important plant-parasitic nematodes, such as cyst, lesion and stunt nematodes was desired. Control of plant-parasitic nematodes, which are tiny but abundant soil-borne pests, is difficult and expensive. Nematodes are protected from many environmental stresses by their cuticle which withstands the penetration of many pesticides. The soil itself is a formidable barrier preventing many chemicals from penetrating to target sites efficiently, or degrading or inactivating them before they can reach sites of activity in concentrations sufficient to exert control. As a consequence, nematicides must be applied at relatively high rates and frequently hazardous concentrations to be minimally effective. Chemical control of nematodes can be accomplished with two types of control agents. The first type are the fumigants which include the halogenated aliphatic hydrocarbons such as methyl bromide, 1,3-dichloropropene, 1,2-dibromoethane and chloropicrin. Methyl isothiocyanate derivatives, such as dazomet and metham sodium, are also considered fumigants. The other chemical class is the non-volatile contact materials. These materials are either organophosphates, such as fenamiphos, or carbamates, such as carbofuran. A major disadvantage of all nematicides is their inherent toxicity coupled with the potential to be environmentally hazardous. As such, the development of new 1

2

Current address: Environmental Protection Agency, Pesticide Section, 841 Chestnut BuUding, Philadelphia, P A 19107 Current address: Mercer County Community College, P.O. Box B, Trenton, NJ 08690

0097-6156/92/0504-0361$06.00/0 © 1992 American Chemical Society

In Synthesis and Chemistry of Agrochemicals III; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1992.

Downloaded by PENNSYLVANIA STATE UNIV on June 22, 2012 | http://pubs.acs.org Publication Date: September 22, 1992 | doi: 10.1021/bk-1992-0504.ch033

362

SYNTHESIS A N D CHEMISTRY O F A G R O C H E M I C A L S III

nematicides was the goal of this research, but it was also realized that the costs to prepare and test new compounds wererisingdramatically. Therefore, we concluded that if we used a rational design strategy to select synthesis targets at the beginning of a project, then we could identify the most active materials more rapidly, and be confident that active materials were not overlooked. By that, we meant that QSAR was to be used not as a retrospective analysis technique to understand properties contributing to biological activity, but it was to be used to direct our synthesis. Compounds containing the -S-(3,4,4-trifluoro-3-butenyl) fragment were known to impart significant nematicidal activity (7-5). The 5-substituted-2-S-(3,4,4-trifluoro-3butenyl)-l,3,4-thiadiazoles, 1, were one example of such compounds where a rational design strategy was used at the beginning of a project. The first step was the selection of targets, followed by synthesis and then determination of nematicidal activity. This biological data was analyzed to develop a QSAR model. The use of a rational design strategy before initializing synthesis has been shown to be an efficient method for die discovery and optimization of nematicidal activity.

Set Selection A set of 2-S-(3,4,4-trifluoro-3-butenyl)-l,3,4-thiadiazoles substituted at the 5-postion was designed to explore the physiochemical parameter space represented by π , σ, L and B l . In order to adequately cover the chosen parameter space, a 2 factorial design was utilized (4). Austell suggests that a 2 factorial design can be an objective method for selecting substituent sets (5,6). Our choice of parameters represented the basic linear free energy parameters of lipophilicity, electronics and shape/size. The selected compounds are shown in Table I. This group of compounds was examined to determine whether or not the physiochemical properties were crosscorrelated. This set was found not to be cross-correlated (Table Π), and it was confirmed that the selected compounds represented the design parameter space using factor analysis (7). With this method, an orthogonally arranged set afforded as many factors (Eigenvectors) as there were properties represented. In this case, all factors were separated which was desirable (Table ΙΠ). n

n

Target Synthesis The synthesis of targets was accomplished as shown in the following schemes. Compounds were prepared from the commercally available 2,5-dimercap to-1,3,4thiadiazole by treatment of this compound with either sodium hydride or sodium ethoxide to give the mercapto ion. The material was treated with l-bromo-3,4,4trifluoro-3-butene to give compound 9. Compound 9 was used to prepare compounds 7,8,11 and 12 by the method of Martinez and Cullen (2) (Scheme 1). The appropriate thioacylhydrazides, 17, were treated with carbon disulfide to give the 2-mercapto-5-substituted-l,3,4-thiadiazoles, 18. These materials were converted to desired materials using the synthesis route described in reference (2) (Scheme 2).


33.

CULLEN ET AL.

363

Nematicidal Activity of Substituted Thiadiazoles

Table I. Factorially Designed Analog Set Ν—Ν


F 1 Phvsicochemical Data No. R 1 NH2 2

NH(C=0)C6H5

3 4

C(CH )3 H 3

OC5H11

5

6 CL

SCH3 SCH2CCH

7 8

9 SH 10 C H 6

11 12 13

5

SC2H5 SCH(CH3)2 NH(C=0)CH3

14 C H C H 2

15 16

6

NHC6H5 NHC2H5

5

π

σ

L

Bl

-1.23 0.49 1.98 0.00 2.04 0.71 0.61 0.21 0.39 1.96 1.07 1.40 -0.97 2.01 1.37 0.08

-0.66 -0.19 -0.20 0.00 -0.34 0.23 0.00 0.11 0.15 -0.01 0.03 0.07 0.00 -0.09 -0.40 -0.61

2.93 8.40 4.11 2.06 8.11 3.52 4.30 6.89 3.47 6.28 5.24 4.95 5.15 4.62 4.53 4.96

1.50 1.94 2.59 1.00 1.35 1.80 1.70 1.70 1.70 1.70 1.70 1.70 1.50 1.52 1.50 1.50

Variable 1 π 2σ

3L 4B1

L Bl

Largest Value

-1.2300 -0.6600 2.0600 1.0000

2.0400 0.2300 8.4000 2.5900

Table Π. Correlation Matrix for Analog Set L σ π

Parameters

π σ

Smallest Value

1 2 3 4

1

2

3

1.000 0.163 0.324 0.325

1.000 -0.050 0.134

1.000 0.160


Bl 4

1.000

364

SYNTHESIS AND CHEMISTRY O F A G R O C H E M I C A L S III


Table ΠΙ. Factor Analysis for Analog Set

Parameters

Factor 1

Factor 2

Factor 3

Factor 4

L Bl σ π

0.984 0.000 0.000 0.000

0.000 0.983 0.000 0.000

0.000 0.000 0.995 0.000

0.000 0.000 0.000 0.970

VP

1.002

1.002

1.001

0.995

F

Scheme 1. Preparation of Dithio-1,3,4-thiadiazoles

F

Scheme 2. Preparation of Remaining Synthesis Targets Biological Testing Compounds were formulated as dust formulations (5% active ingredient) for determination of initial and residual activity. The activity against root-knot nematode (Meloidogyne incognita) was determined by incorporating the formulated test compound in nematode-infested soil at rates in the range of 10 ppm to 0.078 ppm. A cucumber seedling was planted in the treated nematode infested soil. Two weeks after planting, the test pots were evaluated to ascertain the degree of galling (swelling) on



33.

CULLEN ET A L

Nematicidal Activity ofSubstituted Thiadiazoles

365

the roots of the plants, indicating the control provided by the test chemical (8). From the percent control at each rate the LC50 was determined. The residual root-knot nematicidal activity was evaluated by incorporating dust formulations (5% active ingredient) of the compound into uninfested soil at test rates of 5 and 10 ppm. The soil treated with test compound was placed in 7.6 cm diameter fiber pots and held in a greenhouse. At one, two and four weeks post-treatment, the appropriate number of pots were infested with root-knot nematode eggs and larvae. A cucumber or tomato seedling was planted in each pot and evaluated at two weeks as described above. The test results are reported as percent control at each rate tested. Activity against three additional nematode species was determined. The stunt nematode (Tylenchorhynchus claytoni) test procedure was essentially the same as in the initial root-knot nematode tests described above, except that the rates of application of formulated compound (5% dust active ingredient) were 2.5 and 5 ppm in soil containing a corn seedling, and the subsequent inoculation of the soil combined larvae and adult stunt nematodes. The pots were evaluated approximately four weeks after infestation. The percent control was determined by extracting the nematodes from the soil and counting the number in treated versus untreated pots. The lesion nematode (Pratylenchus penetrans) test procedure was essentially the same as in the stunt nematode test described above except that pea seedlings were used and nematodes present in soil and in roots were determined. The cyst nematode (Heterodera glycines) test was the same as described in the stunt nematode test, except soybean seedlings were used. Structure Activity Relationships The sixteen compounds of our analog set were prepared and the initial root-knot activity was determined (Table IV). This data was reported as an LC50 in parts per million and converted to the negative Log(LC50). Our first analysis, shown in equation 1, was a disappointment. From this, only one variable was statistically significant, that is, σ with a r2 of 0.33 (r=0.575). It was realized that a factorial design was not a complete design, such as a central composite design, and it was possible to translate the center point of our design to one of the more active compounds in our original analog set. Compound 11 was chosen as the center point of a new half fractional design. The physiochemical data is shown in Table V; the correlation matrix in Table VI and the factor loadings in Table VII. It was evident from Table VI and Table VII that our new design represented the chosen physiochemical properties. Equation 2 was the result of this new analysis. As this shows, the two significant parameters were sigma and π, with an r of 0.82 (r=0.906). 2

- L o g O X ^ = -0.05 + 1.15 (± 0.437) σ η = 16 r = 0.575 s = 0.445 σ

t = 2.63

(ρ =

0.02)

F = 6.914 (ρ = 0.020) (-0.66 - 0.23)

-Log(LC50) =- 0.14 + 1.78 (± 0.39) σ + η=8 σ π

t = 4.56 t = 1.66

r = 0.906 s = 0.264 (ρ = 0.01) (ρ = 0.16)

(1)

0.19 (±0.12) π F =11.530 (ρ = 0.013) (-0.61-0.15) (0.08-2.04)


(2)

366

SYNTHESIS AND CHEMISTRY O F AGROCHEMICALS III

Table IV. Initial Root-knot Biological Data


Ν—Ν

L C 5 0 (ppm)*

No. R 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

NH2 NH(C=0)C6H

C(CH ) 3

5

3

Η

OC Hn CL SCH 5

3

SCH2CCH

SH C H SC H 6

5

2

5

SCH(CH ) 3

2

NH(C=0)CH3 CH C H NHC6H5 NHC2H5 2

6

5

1

logCLCso- ) -0.24 -0.17 -0.32 -0.40 -0.27 -0.49 0.42 -0.15 0.16 -0.02 0.63 0.65 -0.23 -0.10 -1.17 -1.24

1.8 1.5 2.1 2.5 1.9 3.1 0.4 1.4 0.7 1.1 0.2 0.2 1.7 1.3 15 17

The next question that we asked ourselves was could we separate the sigma term into its field (F) and resonance (R) contributions? As before, we had to determine whether F, R and π were well represented and whether the factors were separated. Table VIII and Table IX show the correlation matrix and the factor loadings, respectively. The examination of this output revealed that the parameters were independent of each other. Equation 3 was significant with an r of 0.78 (r=0.884), wherein the contribution of field and resonance effects to nematicidal activity has been shown. However, we felt that equation 2 was the better model for understanding nematicidal activity in a soil environment, as it contained both an electronic component and a lipophilic component. 2

-Log(LC50) = -0.09 + 2.25 (±0.66) F + 1.38 (±0.53) R n =8 F R

t = 3.40 t = 2.62

r = 0.884 (ρ = 0.02) (p = 0.05)

s = 0.293

F = 8.949 (ρ =0.022) (-0.11 -0.28) (-0.57 - -0.01)


(3)

33.

CULLEN ET A L

367



Table V. Translated Set of Analogs

Phvsiochemical Data F σ

No R

π

2 3

NH(C=0)C6H5 C(CH3)3

4

OC5H11

8

SCH2CCH

0.49 1.98 2.04 0.21 0.39 1.40 2.01 0.08

9 SH 12 SCH(CH3)2 14

CH2C6H5

16

NHC2H5

-0.19 -0.20 -0.34 0.11 0.15 0.07 -0.09 -0.61

0.09 -0.07 0.25 0.16 0.28 0.28 -0.08 -0.11

R -0.27 -0.13 -0.57 -0.03 -0.11 -0.19 -0.01 -0.51

L

Bl

8.40 4.11 8.11 6.89 3.47 4.95 4.62 4.96

1.94 2.59 1.35 1.70 1.70 1.70 1.52 1.50

Variable

Smallest Value

Largest Value

1π 2σ 3L 4B1

0.0800 -0.6100 3.4700 1.3500

2.0400 0.1500 8.4000 2.5900

Table VI. Correlation Matrix for Translated Analog Set Parameters

Ρ s L Bl

1 2 3 4

π 1

σ 2

L 3

Bl 4

1.000 -0.033 -0.063 0.154

1.000 -0.220 0.129

1.000 -0.253

1.000


368

SYNTHESIS AND CHEMISTRY O F A G R O C H E M I C A L S III

Table VH. Factor Loadings for Translated Analog Set Parameters σ


π Bl L

Factor 1

Factor 2

Factor 3

Factor 4

2 1 4 3

0.992 0.000 0.000 0.000

0.000 0.997 0.000 0.000

0.000 0.000 0.987 0.000

0.000 0.000 0.000 0.986

VP

1.001

1.000

1.000

0.999

Table V m . Correlation Matrix of Electronic and Lipophilic Parameters Physiochemical Data Parameters 1 2 3

π F R

π 1 1.000 -0.078 0.022

F

R

2

3

1.000 -0.031

1.000

Smallest Value

Variable

0.0800 -0.1100 -0.5700

lit

2F 3R

Largest Value 2.0400 0.2800 -0.0100

Table IX. Factor analysis for F, R and MR Parameters R π

F

3 1 2

Factor 1 1.000 0.000 0.000

Factor 2 0.000 0.999 0.000

Factor 3 0.000 0.000 0.999

VP

1.000

1.000

1.000


33.


CULLEN ET AL.

369


Nematicidal Evaluations The control of root-knot nematodes was our primary goal. It was known that while good initial activity was necessary, it was not sufficient. Residual control of root-knot nematode was needed. Accordingly, compounds 7 and 11 were selected for residual testing and the percent control was determined at seven days, 14 days and 28 days (Table X). From this test it was found that compound 11 gave nearly complete control at 28 days, while compound 7 was ineffective after seven days. In addition, compounds 7 and 11 were tested against the cyst, lesion and stunt nematodes (Table XI). While these materials provided initial control of these nematode species, it was marginal. For example, compound 11 provided only fifty percent control of cyst and stunt nematodes in these tests. Table X. Residual Activity Against Root-knot (Percent Control at 5 ppm) F \

N—N // \\

F

Compound

R Group

7

SCH

11

SQHs

7 days

14 days

28 days

97

38

43

98

97

95

3

Table XL Percent Control of Nematode Species (Rate = parts per million (ppm)) Species R Group

Cyst (5 ppm)

SCH

70

3

SC H 2

5

52

Lesion (2.5 ppm)

Stunt (5 ppm) 65

72

53

Conclusions The use of a design strategy to choose the original set for synthesis has been shown to be an effective method to optimize lead activity. In our case, 5-substituted-2-S-(3,4,4trifluoro-3-butenyl)-l,3,4-thiadiazoles were found to be effective, broad spectrum nematicides. The use of a rational design set allowed us to identify the more active


370

S Y N T H E S I S 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 III

analog quickly and efficiently. Furthermore, fewer compounds required evaluation in spectrum and residual tests, as we were confident that the more active materials were included based on the results of our QSAR analyses. However, the 5-substituted-2-S(3,4,4-trifluoro-3-butenyl)-l,3,4-thiadiazoles were not sufficiently active in residual and spectrum tests to warrant further development as nematicides.


Acknowledgments The authors would like to acknowledge the contributions of our many co-workers in this program, Edward J. Barron, Patricia L. Morris and Patricia J. Aikens prepared many of the compounds discussed; Michael J.Bonner and Russel J. Savage performed the nematode evaluations. Susan A. Meissner aided in manuscript preparation. Finally, the authors acknowledge the support of FMC Corporation. Literature Cited 1. 2. 3. 4. 5. 6. 7. 8.

Brokke, M . E.; (Stauffer Chemical Co.) U . S. Patent 3,513,172, 1970. Martinez, A . J.; Cullen, T. G.; (FMC Corporation) U . S. Patent 4,952,580, 1990. Cullen, T. G . ; Martinez, A . J.; Vukich, J. J.; (FMC Corporation) U . S. Patent 4,748,186, 1988. Austel, V . ; Eur. J. Med. Chem., 17, (1982), 9. Austel, V.; Eur. J. Med. Chem., 17, (1982), 339. Austel, V.; In Quantitative Approaches to Drug Design, Edited by Dearden, J. C.; Elsevier Science Publishers: Amsterdam, 1983. Martin, Y . C.; Panas, Η. Ν.; J. Med. Chem., 22, (1979), 784. Barker, K. R.; Townshend, J. L . ; Bird, G . W.; Thomson, I. J.; Dickson, D. W.; In Methods for Evaluating Pesticides for Control of Plant Pathogens; American Phytopathological Society Press, Minneapolis, 1986.

RECEIVED July 6, 1992


Synthesis and Chemistry of Agrochemicals III - American Chemical

Recommend Documents