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New generation of protox-inhibiting herbicides
Crop Protection 19 (2000) 533}535
New generation of protox-inhibiting herbicides George Theodoridis*, James T. Bahr, Frederick W. Hotzman, Saroj Sehgel, Dominic P. Suarez Agricultural Products Group, FMC Corporation, P.O. Box 8, Princeton, NJ 08543, USA
Abstract Benzfendizone belongs to the 2-[(4-heterocyclic-phenoxymethyl)-phenoxy]alkanoate class of herbicides which are potent inhibitors of the plant enzyme protoporphyrinogen oxidase (Protox). Benzfendizone, when applied postemergence, provides control of a number of key grass and broadleaf weeds in orchards and no-till crop situations. Benzfendizone can also be used as a potato desiccant and cotton defoliant. Crops such as soyabean and corn showed no injury when planted 2}3 days following postemergence application of benzfendizone. 2000 Elsevier Science Ltd. All rights reserved. Keywords: Herbicides; Protox inhibitors; Benzfendizone
1. Introduction The area of protoporphyrinogen oxidase (Protox) inhibiting herbicides has been extensively investigated for over 30 years (Duke and Rebeiz, 1994). During the period covering the years 1970}1980, a great deal of work was done on several areas of Protox herbicides, though at that time the exact mode of action was not known. These areas included the diphenyl ether, the oxadiazoles, and the phthalimides. Later on, during the 1980s further work was done at the FMC Corporation in the area of Protox herbicides, which resulted in the discovery of several new classes of Protox inhibitors, including two new aryl triazolinone herbicides, sulfentrazone (Theodoridis et al., 1992; Van Saun et al., 1991) and carfentrazone-ethyl (Theodoridis et al., 1995a; Van Saun et al., 1993) (Fig. 1). These two herbicides were commercialized in the late 1990s. More recently, in the 1990s several signi"cant chemistry developments in our laboratories resulted in the discovery of 2,3-fused benzoheterocyclic uracils, such as compound 3, and the area of 2-[(4-heterocyclicphenoxymethyl)-phenoxy]alkanoates herbicides (Fig. 2). The present paper will discuss a representative compound, benzfendizone, from the latter class of chemistry.
* Corresponding author. Tel.: #1-609-951-3522; fax: #1-609-9513835. E-mail address: george}[email protected] (G. Theodoridis).
2. Discovery of 2-[(4-heterocyclic-phenoxymethyl)phenoxy]alkanoates The 4-chlorobenzyloxyphenyl tetrahydrophthalimide 4 shown here was reported by Ohta and coworkers in 1980 (Fig. 3). The chloro group in the para position of the benzyloxy group was reported to provide optimum biological activity. A number of articles present molecular modeling evidence that Protox diphenyl ethers herbicides act by mimicking two of the pyrrole rings of protoporphyrinogen IX (Protogen IX), the substrate for the Protox enzyme, (Duke and Rebeiz, 1994). In 1995 the "rst Protox molecule designed to mimic three of the pyrrole rings of Protogen IX was reported (Theodoridis et al., 1995b). A number of con#icting structure}activity relationships of a series of Protox herbicides were recently examined (Theodoridis, 1997), and the suggested explanation was that multiple binding modes are possible at the same binding site. Following a close review of the initial SAR conclusions for compounds of structure 4, we concluded that it represented only half of the story, and that an alternative structure was also possible. The Protogen IX molecule can be thought as having two distinctive regions, as de"ned by the pyrrole ring substituents. One half of the molecule has a predominantly lipophilic region, and the other half with the propionic acid chains has a much more hydrophilic domain. Fig. 4 shows structural alternatives depending on spatial orientation of the benzyloxy ring region.
0261-2194/00/$ - see front matter 2000 Elsevier Science Ltd. All rights reserved. PII: S 0 2 6 1 - 2 1 9 4 ( 0 0 ) 0 0 0 6 9 - 7
534
G. Theodoridis et al. / Crop Protection 19 (2000) 533}535
If compounds such as 4 were acting by mimicking Protogen IX, then the lipophilic 4-chlorobenzyloxy group (ring C) of 4-(4-chlorobenzyloxy)phenyl heteroaryl molecule, would be expected to bind in the lipophilic region of the enzyme. It follows that if this hypothesis is true, then a 4-chloro-2-propionic acid benzyloxy group, made more hydrophilic by the presence of a propionic chain at the 2-position, should also be highly active. That is exactly what was found. Not only both molecules were biologically active, but the presence of the ester chain in the
benzyloxy group, compound 6 in Table 1, dramatically increased the biological activity of the resulting molecule. A detailed structure-activity analysis of these compounds is beyond the scope of this work. Replacement of the chlorine in the four position of the benzyl ring with alkyl substituents resulted in increased biological activity. It is interesting to note that in the new molecules such as 7, the 4-ethyl and not the 4-chloro, is the most active
Fig. 1. Protox inhibiting herbicides developed by the FMC Corporation.
Fig. 4. Structural alternatives depending on spatial orientation of benzyloxy ring. Table 2 Postemergence biological activity of benzfendizone under greenhouse conditions Fig. 2. New generation of Protox herbicides. Biological activity based on four experiments (Mean % control$standard deviation)
Fig. 3. Chemical structure of MK-129.
Application rate g ai/ha
100
Ipomoea hederacea var. hederacea Convolvulus arvensis Abutilon theophrasti Echinochloa crus-galli Setaria viridis Sorghum halepense
100 100 100 100 100 100
30 100 100 100 100 96$4 100
10 98$2 100 100 71$10 65$13 75$5
Table 1 Postemergence biological activity under greenhouse conditions
Biological activity ED
g ai/ha (mean$standard deviation)
Compound
R
Sorghum halepense
Abutilon theophrasti
No. of tests
5 6 7
4-Cl 4-Cl; 2-OCH(CH )CO CH 4-C H ; 2-OCH(CH )CO CH
214$16 124$34 18$10
25$7 17$10 6$3
3 3 4
G. Theodoridis et al. / Crop Protection 19 (2000) 533}535 Table 3 Percent weed control at 30 days following postemergence application of benzfendizone in European Tree Fruits and Vines (1996, 12 experiments) Species
% Control at application rate of 70 g ai/ha
Erigeron canadensis Chenopodium album Amaranthus retroyexus Portulaca oleracea Poa annua Setaria species
80 100 100 100 73 85
535
Benzfendizone has also shown good activity as cotton defoliant and as potato desiccant, Tables 4 and 5. All treatments include 1% crop oil concentrate. 4. Conclusions Benzfendizone is a new postemergence Protox herbicide with clear weed management applications that should prove useful to the agricultural community. Its discovery emphasizes the pitfalls of relying on QSAR analysis alone when dealing with complex binding sites such as that of the Protox herbicides.
Table 4 Cotton defoliation 14 days after postemergence "eld application of benzfendizone (USA, 1996, 7 experiments) Application rate (g ai/ha)
% Defoliation
70 140
74 77
Table 5 Potato desiccation 22 days after postemergence application of benzfendizone. (Europe 1996, 15 experiments) Application rate (g ai/ha)
% Leaf desiccation
% Stem desiccation
40 70
92 95
91 94
group. Table 2 shows that under greenhouse conditions, postemergence rates of application as low as 10 g/ha can provide excellent broadleaf weed control. At 30 g/ha both grass and broadleaf weeds are controlled.
3. Benzfendizone 3.1. Weed control Benzfendizone has been extensively tested in no-till, post harvest, and orchard situations in the United States, Europe, Asia and Latin America. Table 3 shows weed control following the postemergence application of benzfendizone on tree fruit and vines in European trials.
References Duke, S.O., Rebeiz, C.A., 1994. Porphyric Pesticides, Chemistry, Toxicology, and Pharmaceutical Applications, American Chemical Society Symposium Series, vol. 559. Ohta, H., Jikihara, T., Wakabayashi, K., Fujita, T., 1980. Quantitative structure-activity study of herbicidal N-aryl-3,4,5,6-tetrahydrophthalimides and related cyclic imides. Pestic. Biochem. Physiol. 14, 153}160. Theodoridis, G., 1997. Structure-activity relationships of herbicidal aryltriazolinones. Pestic. Sci. 50, 283}290. Theodoridis, G., Bahr, J.T., Davidson, B.L., Hart, S.E., Hotzman, F.W., Poss, K.M., Tutt, S.F., 1995a. Alkyl 3-[2,4-disubstituted-4,5dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]propenoate derivatives. In: Baker, D.R., Fenyes, J.G., Basarak, G.S. (Eds.), Synthesis and Structure-activity Relationships, Synthesis and Chemistry of Agrochemicals IV, ACS Symposium Series, vol. 584, pp. 90}99. American Chemical Society, Washington. Theodoridis, G., Hotzman, F.W., Poss, K.M., 1995b. Herbicidal 1(2,4-dihalo-5-phenoxyphenyl)-4-di#uoromethyl-4,5-dihydro-3methyl-1,2,4-triazolin-5(1H)-one derivatives. In: Baker, D.R., Fenyes, J.G., Basarak, G.S. (Eds.), Synthesis and Structure-activity Relationships. Synthesis and Chemistry of Agrochemicals IV, ACS Symposium Series, Vol. 584, pp. 78}89. American Chemical Society, Washington. Theodoridis, G., Baum, J.S., Hotzman, F.W., Manfredi, M.C., Maravetz, L.L., Lyga, J.W., Tymonko, J.M., Wilson, K.R., Poss, K.M., Wyle, M.J., 1992. Synthesis and herbicidal properties of aryltriazolinones. In: Baker, D.R., Fenyes, J.G., Basarak, G.S. (Eds.), Synthesis and Chemistry of Agrochemicals III. ACS Symposium Series, vol. 504, pp. 134}146. Van Saun, W.A., Bahr, J.T., Crosby, G.A., Fore, Z.A., Guscar, H.L., Harnish, W.N., Hooten, R.S., Marquez, M.S., Parrish, D.S., Theodoridis, G., Tymonko, J.M., Wilson, K.R., Wyle, M.J., 1991. Proceedings of the Brighton Crop Protection Conference on Weeds, pp. 77}82. Van Saun, W.A., Bahr, J.T., Bourdouxhe, L.J., Gargantiel, F.J., Hotzman, F.W., Shires, S.W., Sladen, N.A., Tutt, S.F., Wilson, K.R., 1993. Proceedings of the Brighton Crop Protection Conference on Weeds, pp. 19}22.
New generation of protox-inhibiting herbicides George Theodoridis*, James T. Bahr, Frederick W. Hotzman, Saroj Sehgel, Dominic P. Suarez Agricultural Products Group, FMC Corporation, P.O. Box 8, Princeton, NJ 08543, USA
Abstract Benzfendizone belongs to the 2-[(4-heterocyclic-phenoxymethyl)-phenoxy]alkanoate class of herbicides which are potent inhibitors of the plant enzyme protoporphyrinogen oxidase (Protox). Benzfendizone, when applied postemergence, provides control of a number of key grass and broadleaf weeds in orchards and no-till crop situations. Benzfendizone can also be used as a potato desiccant and cotton defoliant. Crops such as soyabean and corn showed no injury when planted 2}3 days following postemergence application of benzfendizone. 2000 Elsevier Science Ltd. All rights reserved. Keywords: Herbicides; Protox inhibitors; Benzfendizone
1. Introduction The area of protoporphyrinogen oxidase (Protox) inhibiting herbicides has been extensively investigated for over 30 years (Duke and Rebeiz, 1994). During the period covering the years 1970}1980, a great deal of work was done on several areas of Protox herbicides, though at that time the exact mode of action was not known. These areas included the diphenyl ether, the oxadiazoles, and the phthalimides. Later on, during the 1980s further work was done at the FMC Corporation in the area of Protox herbicides, which resulted in the discovery of several new classes of Protox inhibitors, including two new aryl triazolinone herbicides, sulfentrazone (Theodoridis et al., 1992; Van Saun et al., 1991) and carfentrazone-ethyl (Theodoridis et al., 1995a; Van Saun et al., 1993) (Fig. 1). These two herbicides were commercialized in the late 1990s. More recently, in the 1990s several signi"cant chemistry developments in our laboratories resulted in the discovery of 2,3-fused benzoheterocyclic uracils, such as compound 3, and the area of 2-[(4-heterocyclicphenoxymethyl)-phenoxy]alkanoates herbicides (Fig. 2). The present paper will discuss a representative compound, benzfendizone, from the latter class of chemistry.
* Corresponding author. Tel.: #1-609-951-3522; fax: #1-609-9513835. E-mail address: george}[email protected] (G. Theodoridis).
2. Discovery of 2-[(4-heterocyclic-phenoxymethyl)phenoxy]alkanoates The 4-chlorobenzyloxyphenyl tetrahydrophthalimide 4 shown here was reported by Ohta and coworkers in 1980 (Fig. 3). The chloro group in the para position of the benzyloxy group was reported to provide optimum biological activity. A number of articles present molecular modeling evidence that Protox diphenyl ethers herbicides act by mimicking two of the pyrrole rings of protoporphyrinogen IX (Protogen IX), the substrate for the Protox enzyme, (Duke and Rebeiz, 1994). In 1995 the "rst Protox molecule designed to mimic three of the pyrrole rings of Protogen IX was reported (Theodoridis et al., 1995b). A number of con#icting structure}activity relationships of a series of Protox herbicides were recently examined (Theodoridis, 1997), and the suggested explanation was that multiple binding modes are possible at the same binding site. Following a close review of the initial SAR conclusions for compounds of structure 4, we concluded that it represented only half of the story, and that an alternative structure was also possible. The Protogen IX molecule can be thought as having two distinctive regions, as de"ned by the pyrrole ring substituents. One half of the molecule has a predominantly lipophilic region, and the other half with the propionic acid chains has a much more hydrophilic domain. Fig. 4 shows structural alternatives depending on spatial orientation of the benzyloxy ring region.
0261-2194/00/$ - see front matter 2000 Elsevier Science Ltd. All rights reserved. PII: S 0 2 6 1 - 2 1 9 4 ( 0 0 ) 0 0 0 6 9 - 7
534
G. Theodoridis et al. / Crop Protection 19 (2000) 533}535
If compounds such as 4 were acting by mimicking Protogen IX, then the lipophilic 4-chlorobenzyloxy group (ring C) of 4-(4-chlorobenzyloxy)phenyl heteroaryl molecule, would be expected to bind in the lipophilic region of the enzyme. It follows that if this hypothesis is true, then a 4-chloro-2-propionic acid benzyloxy group, made more hydrophilic by the presence of a propionic chain at the 2-position, should also be highly active. That is exactly what was found. Not only both molecules were biologically active, but the presence of the ester chain in the
benzyloxy group, compound 6 in Table 1, dramatically increased the biological activity of the resulting molecule. A detailed structure-activity analysis of these compounds is beyond the scope of this work. Replacement of the chlorine in the four position of the benzyl ring with alkyl substituents resulted in increased biological activity. It is interesting to note that in the new molecules such as 7, the 4-ethyl and not the 4-chloro, is the most active
Fig. 1. Protox inhibiting herbicides developed by the FMC Corporation.
Fig. 4. Structural alternatives depending on spatial orientation of benzyloxy ring. Table 2 Postemergence biological activity of benzfendizone under greenhouse conditions Fig. 2. New generation of Protox herbicides. Biological activity based on four experiments (Mean % control$standard deviation)
Fig. 3. Chemical structure of MK-129.
Application rate g ai/ha
100
Ipomoea hederacea var. hederacea Convolvulus arvensis Abutilon theophrasti Echinochloa crus-galli Setaria viridis Sorghum halepense
100 100 100 100 100 100
30 100 100 100 100 96$4 100
10 98$2 100 100 71$10 65$13 75$5
Table 1 Postemergence biological activity under greenhouse conditions
Biological activity ED
g ai/ha (mean$standard deviation)
Compound
R
Sorghum halepense
Abutilon theophrasti
No. of tests
5 6 7
4-Cl 4-Cl; 2-OCH(CH )CO CH 4-C H ; 2-OCH(CH )CO CH
214$16 124$34 18$10
25$7 17$10 6$3
3 3 4
G. Theodoridis et al. / Crop Protection 19 (2000) 533}535 Table 3 Percent weed control at 30 days following postemergence application of benzfendizone in European Tree Fruits and Vines (1996, 12 experiments) Species
% Control at application rate of 70 g ai/ha
Erigeron canadensis Chenopodium album Amaranthus retroyexus Portulaca oleracea Poa annua Setaria species
80 100 100 100 73 85
535
Benzfendizone has also shown good activity as cotton defoliant and as potato desiccant, Tables 4 and 5. All treatments include 1% crop oil concentrate. 4. Conclusions Benzfendizone is a new postemergence Protox herbicide with clear weed management applications that should prove useful to the agricultural community. Its discovery emphasizes the pitfalls of relying on QSAR analysis alone when dealing with complex binding sites such as that of the Protox herbicides.
Table 4 Cotton defoliation 14 days after postemergence "eld application of benzfendizone (USA, 1996, 7 experiments) Application rate (g ai/ha)
% Defoliation
70 140
74 77
Table 5 Potato desiccation 22 days after postemergence application of benzfendizone. (Europe 1996, 15 experiments) Application rate (g ai/ha)
% Leaf desiccation
% Stem desiccation
40 70
92 95
91 94
group. Table 2 shows that under greenhouse conditions, postemergence rates of application as low as 10 g/ha can provide excellent broadleaf weed control. At 30 g/ha both grass and broadleaf weeds are controlled.
3. Benzfendizone 3.1. Weed control Benzfendizone has been extensively tested in no-till, post harvest, and orchard situations in the United States, Europe, Asia and Latin America. Table 3 shows weed control following the postemergence application of benzfendizone on tree fruit and vines in European trials.
References Duke, S.O., Rebeiz, C.A., 1994. Porphyric Pesticides, Chemistry, Toxicology, and Pharmaceutical Applications, American Chemical Society Symposium Series, vol. 559. Ohta, H., Jikihara, T., Wakabayashi, K., Fujita, T., 1980. Quantitative structure-activity study of herbicidal N-aryl-3,4,5,6-tetrahydrophthalimides and related cyclic imides. Pestic. Biochem. Physiol. 14, 153}160. Theodoridis, G., 1997. Structure-activity relationships of herbicidal aryltriazolinones. Pestic. Sci. 50, 283}290. Theodoridis, G., Bahr, J.T., Davidson, B.L., Hart, S.E., Hotzman, F.W., Poss, K.M., Tutt, S.F., 1995a. Alkyl 3-[2,4-disubstituted-4,5dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]propenoate derivatives. In: Baker, D.R., Fenyes, J.G., Basarak, G.S. (Eds.), Synthesis and Structure-activity Relationships, Synthesis and Chemistry of Agrochemicals IV, ACS Symposium Series, vol. 584, pp. 90}99. American Chemical Society, Washington. Theodoridis, G., Hotzman, F.W., Poss, K.M., 1995b. Herbicidal 1(2,4-dihalo-5-phenoxyphenyl)-4-di#uoromethyl-4,5-dihydro-3methyl-1,2,4-triazolin-5(1H)-one derivatives. In: Baker, D.R., Fenyes, J.G., Basarak, G.S. (Eds.), Synthesis and Structure-activity Relationships. Synthesis and Chemistry of Agrochemicals IV, ACS Symposium Series, Vol. 584, pp. 78}89. American Chemical Society, Washington. Theodoridis, G., Baum, J.S., Hotzman, F.W., Manfredi, M.C., Maravetz, L.L., Lyga, J.W., Tymonko, J.M., Wilson, K.R., Poss, K.M., Wyle, M.J., 1992. Synthesis and herbicidal properties of aryltriazolinones. In: Baker, D.R., Fenyes, J.G., Basarak, G.S. (Eds.), Synthesis and Chemistry of Agrochemicals III. ACS Symposium Series, vol. 504, pp. 134}146. Van Saun, W.A., Bahr, J.T., Crosby, G.A., Fore, Z.A., Guscar, H.L., Harnish, W.N., Hooten, R.S., Marquez, M.S., Parrish, D.S., Theodoridis, G., Tymonko, J.M., Wilson, K.R., Wyle, M.J., 1991. Proceedings of the Brighton Crop Protection Conference on Weeds, pp. 77}82. Van Saun, W.A., Bahr, J.T., Bourdouxhe, L.J., Gargantiel, F.J., Hotzman, F.W., Shires, S.W., Sladen, N.A., Tutt, S.F., Wilson, K.R., 1993. Proceedings of the Brighton Crop Protection Conference on Weeds, pp. 19}22.