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Invited Trends Article

Peroxidizing Herbicides (II):Structure-Activity Relationship and Molecular DesignKo Wakabayashi11 and Peter Bögerba Chair of Physiology and Biochemistry, D ept. A gricultural Chemistry, Tamagawa University,

Machida-shi. Tokyo 194, Japan b Lehrstuhl für Physiologie und Biochem ie der Pflanzen, U niversität Konstanz,

D-78434 Konstanz, B undesrepublik D eutschlandZ. Naturforsch. 50c, 591-601 (1995); received May 31, 1995Diphenyl Ethers, Cyclic Imides. S tructure and Activity, M olecular Design,Conversion of Isoimides

IntroductionThe p-nitrodiphenyl ethers (DPEs) and cyclic

imides (Cyls), here called peroxidizing herbicides of the first generation (1965-1980), induce inhibi­tion of chlorophyll biosynthesis and photooxi- dative destruction of plant membranes affecting photosynthetic pigment contents. The detailed mechanism of action of the peroxidizing herbi­cides has been outlined in the first part of this re­view (Böger and Wakabayashi, 1995). The imme­diate physiological response of the plant against these herbicides is a halt of chlorophyll biosynthe­sis in chloroplasts by specific inhibition of proto- porphyrinogen-IX oxidase (protox). This inhibi­tion is accompanied by an abnormal accumulation of protoporphyrin-IX (proto-IX or a derivative thereof), which acts as a photosensitizer in the light and induces radical formation with subse­quent destruction of cellular constituents. The old light-dependent herbicidal-action theory of DPEs and Cyl compounds (Matsunaka, 1969; Matsu- naka, 1976; Suzuki et al., 1975; Wakabayashi et a l , 1979; Fedtke, 1982) can be now discussed on the basis of this principle.

The substantial steps made forward in recent years to elucidate the mechanism of action gave a strong impetus to molecular design of the second generation (since 1980) of peroxidizing herbicides. At least 20 different herbicide candidates includ­ing Cyls, pyrazoles, triazoles, triazolidines, thia- diazolidines and oxazolidines with an N-(2-fluoro-

R eprint requests to Prof. Dr. P. Böger. Telefax: (+49) 7531-883042.

4-chloro-5-substituted)phenyl moiety, 2-chloro-4-trifluoromethylphenyl 3'- substituted-4'-nitro- phenyl ethers, and certain pyridine derivatives are currently in development and more may be inves­tigated (Fig. 1; Wakabayashi and Böger, 1993,1994). The basic structures of peroxidizing herbi­cides including those of 1st and 2nd generation can now classified into five larger groups: (1) diphenyl ethers, (2) cyclic imides, (3) N-aryldiazoles, (4) N- heterocyclic five-membered compounds without N-aryl linkage, and group (5) including com­pounds with a pyridine-carboxamide or a carba­mate moiety (Fig. 2). Oxyfluorfen and SUAM- 16476 of group 1 are representatives of the most active DPE peroxidizers. Within the five groups, the Cyl class (group 2) is most flourishing in designing new peroxidizing herbicides, starting from modification of the old parent compound, chlorophthalim, as outlined by Fig. 3. To design Cyl-type peroxidizers, the N-(2-fluoro-4-halogen (Cl or Br)-5-substituted) aryl moiety is essential to produce highly active compounds (Wakabaya­shi et a l, 1979; Wakabayashi, 1988). Herbicides of group 3 and 4 of Fig. 2 are the immediate family of Cyl peroxidizers. It should be noted that in the pyrazole series of group 3 a 2,4,6-substituted aryl moiety proved to be effective. More recent N-het- erocyclic five-membered peroxidizers (group 4) without an N-aryl linkage to the heterocycle should be emphasized (Miura et a l , 1993; Miura et a l , 1994; Hamper et a l, 1995), indicating that an N-aryl linkage, although dominant in peroxidiz­ers, is not mandatory. The active compounds of this series include the C-(2-fluoro-4-halogen-5- substituted) aryl moiety, which markedly contrib-

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592 Trends Article • K. W akabayashi and P. Böger • Peroxidizing Herbicides (II)

V-/I

O N—i— Oxadiazon

0 ‘

Chlorophthalim

c f 3— o N02

Oxyfluorfen

1st Generation of peroxidizing herbicides [1965-1980]

MK-106 [ R, = H , R2 =OCH2C=CH U MK-170 [ Rt = F . R2 = H ’

'r 2 S-23142 [ R, = F , R2 = OCH2C=CH]Flumipropyn l Ri = F . R2 = OCH(CH3)C=CH]

CI 3O*___q F _ ^ C I n h 2 j f TX X X X ----------- m V

u

-Ci'SCH2COOCH3

Fluthiacet-methyl MB-39279

7 3 /=\C sHsC O ^ ^ C O N H C H h Q

KPP-300A A ,

CpHcCI. . . 0 ^ H3

CF3- r f - 0 - Ö - N v 0 F CH3

SU AM-16476

CH

BrY yCONH—y jN C3H7 C2H5

DLH-1777

2 nd Generation of

peroxidizing herbicides [1981-1993]

Fig. 1. D evelopm ent of peroxidizing herbicides: Two generations since 1965.

(1)o c 2h 5

NO,

Oxyfluorfenc h 3

CF3 0 " ° “Ö - Nch!F

SUAM-16476

(5) 0 C2H5 V / NH - CH

CH,

CH3 ' N CH3LS 82-556

o oBri Y ' NH 0

c h 3

DLH-1777

" 0 - ^ 3O-Phenylpyrrolidino-O-Phenylpiperidino-

carbamates

(2)

(X> 0 Cl

Chlorophthalim o F

n-C ,yc\

c'xx\Y o ^ o

Oxadiazon

o OCH2COOC5H, Flumiclorac pentyl

Kumiai type

S 275

>aKN—1L f °)

v °Nippon Soda type, Schering, Thidiazimin

(3)h2n

NCX J aMB 39279

cf3

J O Clcf3s^ nRohm and Haas

(4)

chf2o n ch3

Nihon Nohyaku type

Mitsubishi Petrochem. type

Monsanto

Fig. 2. Peroxidizing herbicides: The bas­ic structures can be arranged in five groups.

utes to design peroxidizers with a lower use rate than found with the original Cyl class of per­oxidizers of group 2. Many of the Cyl compounds with N-aryl linkage, however, are unstable in the environment (Sato et al., 1991; Hoshi et al.. 1993; Sato et al., 1994a; Iida et al., 1995). Compounds

belonging to group 5 have also been confirmed as peroxidizers. although their activity is not so strong compared with the other four groups (Wakabayashi and Böger. 1993).

Molecular design of peroxidizing herbicides has been integrated into other scientific disciplines.

Trends Article • K. W akabayashi and P. Böger • Peroxidizing H erbicides (II) 593

Fig. 3. The lead structure, an N-aryl- te trahydrophthalim ide can be m odi­fied as indicated by the form ulas assigned to the arrows.

e.g. biochemistry, plant physiology, weed biology, to understand and optimize the phytotoxic proper­ties. This review has the following three objectives concerning molecular design, giving a bird's-eye view of development of the peroxidizing herbicides:

(1) To find out what structural modification can be made to the parent compound without losing its unique phytotoxic properties. This information should indicate an optimized feature of the mole­cule essential for its activity.

(2) To find out whether the parent peroxidizers are active per se, or whether their activity results from modification within,or in the vicinity of, the plant cells.

(3) To design new peroxidizing herbicides with similar or improved activity by making use of the results analyzed.

Consideration of the First Generation of Peroxidizing Herbicides

The DPEs and Cyls, exhibiting the socalled light-dependent herbicidal action and bleaching activity related to photooxidative destruction of thylakoid and cell membranes, are now verified as peroxidizing herbicides (Wakabayashi and Böger, 1993; Böger and Wakabayashi, 1995). Several key studies sorting new leads have been introduced and are discussed here.

7. SAR studies o f DPE and C yl peroxidizers

Diphenyl ethers: Various analogues have been assayed to find a correlation between chemical structures, their peroxidizing activity and protox inhibition (Lambert et al., 1983; Nandihalli et al.,1992). Many 2-chloro-4-trifluoromethylphenyl 3'- substituted-4'-nitrophenyl ethers exhibit protox inhibition and light-induced peroxidation. 3'-Sub- stituents, such as COOCH3, OCH3, OC2H5, NHC2H5 and CONHCH3, enhance the peroxidiz­ing activity. A free carboxyl group in 3-position will reduce activity, its esterification generally markedly increases activity. Activity will be gen­erally enhanced by substituents with positive Hammett o parameters at 2- or 4-position at the phenyl ring not bearing a nitro group. Neither protox inhibition nor initial phytotoxic activity is changed by substituting 4'-chloro for a 4'-nitro group. The phytotoxic activity is completely lost when the CF3-group is moved from 4- to 5-posi- tion. Compounds with S, SO, S 0 2 or an NH-link- age between the two phenyl rings are herbicidally inactive. The promising structures of peroxidizing herbicides are shown in Fig. 4 (left part).

Cyclic imides: It has already been considered that the peroxidizing activity of Cyls is extremely high amongst compounds whose structures con­form to the following rule (see Fig. 4, right part; Wakabayashi et al., 1979; Wakabayashi, 1988;

594 Trends A rticle ■ K. W akabayashi and P. Böger ■ Peroxidizing H erbicides (II)

Peroxidizing p-nitrodiphenyl ethers 1

A ' AC F 3 -\J~° ■ v J r N° 2

R : -C O O H , - C 00C H 3,

-C O N H C H 3 - n h c 2h 5,

-O C H 3, - 0 C 2H5, etc.

Peroxidizing cyclic imides: Moieties A to D

A B c D

n : 3 - 4 R' : —OC3H7 - i . -OCHjCECH ,

P-Q c=c, N-C, —NHCH(C3H7)COOC4H9 ,

X, VN-N0, S

—SCH2COOCH3 etc.Fig. 4. M odification of active d i­phenyl e ther and cyclic-imide type peroxidizers.

Wakabayashi and Böger, 1993): (1) Q and C2 car­bon atoms in moiety A should form an alkylene ring. A suitable lipophilicity of the alkylene group may play an important role to produce high activ­ity. (2) Moieties B and C should form a planar arrangement. The double bond and bridgehead nitrogen atom(s) in the electron-donating moiety B may play a concerted role for the mechanism of action. (3) The 4-substituent on the benzene ring in moiety D should have a proper size and orienta­tion (see chapter 2 on QSAR studies). A p-substi- tutent, like halogen (especially Cl or Br), lower alkyl, lower alkoxy or a benzyloxy group is essen­tial for activity. Introduction of another halogen atom (especially F) at 2-position of the active4-substituted aryl derivatives substantially en­hances the peroxidizing activity. Introduction of an accessory substituent, such as alkoxy, alkenyloxy, alkinyloxy, amino acid, carboxymethyl-thio group and the like, as well as a 5-substituent at the active4- or 2,4-arylsubstituted compounds increases ac­tivity. Certain 5-substituents (e.g. amino acid resi­dues or a carboxymethylthio group may possibly undergo metabolic modification thereby contrib­uting to selectivity (e.g. in fluthiacet methyl; Shi­mizu et al., 1995 and personal commun.). The com­pounds of this line of molecular design may improve their uptake by plant cells or the affinity for the target enzyme protox (Kohno et al., 1993). The 2-fluorophenyl group fused together with het­erocyclic rings mostly in 4 -5 position also pro­duces quite good peroxidizing activity in recent molecular design (Wakabayashi and Böger, 1993: comp. Fig. 3).

2. QSAR studies on peroxidizing herbicides

For a large number of compounds, it has been established that their herbicidal efficiency in greenhouse tests and growth-inhibition activity against Echinochloa can be quantitatively corre­lated with high significance through the peroxida- tive phytotoxic parameters obtained from auto- trophic Scenedesmus cells (Böger and Wakabaya­shi, 1995; Wakabayashi et al., 1988; Watanabe et al., 1992; Böger and Sandmann, 1994). Those are growth inhibition, decrease of chlorophylls and carotenoids, short-term accumulation of proto-IX and light-induced ethane formation, even the protox inhibition using corn etioplasts can be now combined with this network. A reli­able quantitative correlation has been established with the six parameters mentioned. For example, QSARs of the peroxidizing compounds can be ac­complished either with the Echinochloa root- growth inhibition test, by measuring light-induced ethane formation, or with decrease of chlorophyll content in sensitive green microalgae. The investi­gator may choose any one of the six parameters, whichever he can handle best in the laboratory.

The QSARs between structures and phytotoxic parameters obtained from 40 N-aryl-3.4,5,6-tetra- hydrophthalimides have been analyzed using physico-chemical parameters and regression anal­ysis (Ohta et al., 1980; Wakabayashi, 1988; Sato et al., 1992). The results shown in Table I indicate that the position-specific steric effect of aromatic substituents, as presented by the STERIMOL val­ues of /?flra-substituents, are highly important in determining the phytotoxic potency of cyclic imide

Trends A rticle • K. W akabayashi and P. B öger • Peroxidizing H erbicides (II) 595

Table I. Q uantitative structure-activity relationship of cyclic imide peroxidizers (N -aryl-3,4,5,6-tetrahydrophthal- imides).

p l50 (Echinochloa) = 4.062 - 0.876a + 2.086Lp - 0.370Lp2 — 1.079B5P (1)(± 0.197) (±0.383) (±0 .336) (±0.098) (±0.221)

[n = 40. r = 0.912, 5 = 0.345]p150 (Scenedesmus) = 5.595 - 0.944a + 2.652Lp - 0.471 Lp2 - I . 3 8 OB5P (2)

(± 0.252) (±0.487) (±0 .427) (±0.125) (±0.282)[n = 40, r = 0.912, 5 = 0.439]

p l50 (Chlorophyll) = 5.738 - 1.174a + 2.768Lp — 0.508Lp2 - I . 3 9 OB5P (3)(± 0.264) (±0.513) (±0 .450) (±0.131) (±0.296)

[n = 40. r = 0.909, 5 = 0.462]p i5o (C arotenoid) = 5.688 - 1.155a + 2.773Lp — 0.505Lp2 -1.412B 5P (4)

(± 0.258) (±0.502) (±0.441) (±0.128) (±0.291)\n = 40, r = 0.914, 5 = 0.452]

p l50 (E thane) = 5.200 (± 0.171)

+ 0.772Lp ( ± 0.307)

- 0.041 Lp2 -0.304B 5P (±0.031) (±0.254)[n — 13, r — 0.985, s - 0.145]

(5)

pi so (Protox) = 5.417 (± 0.443)

+ 2.172Lp (± 1.104)

— 0.195Lp2 -0.947B 5P (±0.110) (±0.899)[n = 16, r = 0,900, s = 0.493]

(6)

p l50 values were determ ined by a roo t grow th inhibition assay with Echinochloa utilis in a light/dark regim en (Eqn. (1)), growth inhibition of au to trophic Scenedesmus acutus (Eqn. (2)), decrease of chlorophyll and carotenoids in autotrophic cultures (E qns (3), (4)), light-induced ethane form ation by Scenedesmus acutus (Eqn. (5); the p l50 value really is the “activity value” as explained in B öger and W akabayashi, 1995). Eqn. (6) represents the structure- activity relationship of ST E R IM O L param eters with the inhibition of isolated protoporphyrinogen oxidase from corn (Zea mays), o = 2 (H am m ett o constants of substituents). Lp is the ST ER IM O L param eter for the length along the bond axis connecting C {para) and the atom of the para-substituents. B5p is the largest one am ong the ST ER IM O L width param eters of para-substituents. n is the num ber of experim ental data, s the standard deviation, and r the correlation coefficient. Figures in parentheses are the 95% confidence intervals.

peroxidizers. In Eqns (1) to (6), the phyto-toxic activities are satisfactorily delineated by taking into account the combined electronic effect ex­pressed as 2o as well as the steric influence of /wa-substituents, although the o term is not signif­icant in Eqns (5) and (6) due to insufficient number (n) of data available on ethane formation and protox inhibition. There exists an optimum length of para-substitutents for protox inhibition in a series of Cyls as shown in Eqn. (5), where the length effect is represented by a parabolic function of the Lp parameter. The smaller the width of the /wa-substituent, the more feasible will be the interaction with the target enzyme. The QSAR study of other series of Cyl class of peroxidizers, namely N-aryl-l,5-tetramethylene-hydantoins, 4- aryl-l,2-tetramethylene-l,2,4-triazolidine- 3,5-diones and their thiocarbonyl analogues, also have been demonstrated using STERIMOL pa­rameters and Hammett o constants (Wakabayashi, 1988; Sato et al., 1992). The herbicidal activity of N-(2-fluoro-4-substituted-5-methoxy)phenyl-3,4,5,6-tetrahydrophthalimides has recently been discussed in relation to hydrophobicity constants,

inductive and resonance parameters, and molar re- fractivity (Lyga et al., 1991). It is concluded that the 4-position of the N-phenyl moiety should be occupied by a small, hydrophobic and electron- negative group for optimum activity.

The QSARs between molecular properties of 24 DPEs and their effects on protox and herbicidal activity have been reported (Nandihalli et al.,1992). The QSARs indicate that the electronic (partial charge, superdelocalizability, dipole mo­ment) and hydrophobic properties account for the variation in protox inhibition, and molecular bulk and overall electronic potentials are responsible for the herbicidal effect.

3. Peroxidizing activity and X-ray structures o f peroxidizers

Nandihalli et al. (1992) have reported the molec­ular similarity between protoporphyrinogen-IX (protogen) and acifluorfen by comparing their mo­lecular size as derived from semiempirical molecu­lar orbital (MO) calculation. Such a comparison is feasible since protox inhibitors compete with the

596 Trends Article • K. W akabayashi and P. Böger • Peroxidizing H erbicides (II)

substrate at the target enzyme (cf. our review, part I). They reported that the maximum length (12.29 A) and width (5.53 A) of acifluorfen matched closely with the full length and one-half width of protogen molecule. In addition, the tor­sion angle of acifluorfen at the ether oxygen matched with the angle at the methylene bridge between two neighboring pyrrole rings (Fig. 5: left upper part). In our crystallographic studies, the longest length of KPP-314 (see also Fig. 2), chloro- phthalim and of oxyfluorfen were 12.56 A, 11.37 A and 12.31 A, respectively (Kohno et al., 1993). These values indicate that the molecular size of three peroxidizing herbicides is about the same. The values 11-13 A may indicate the length of the receptor size of protox. The torsion angles of KPP314 and oxyfluorfen, which show good phytotoxic activity, were found approx. 65-85° also in X-ray analysis. It appears that both length and angle of the molecules have some bearing on peroxidizing activity and may contribute a steric factor to match with protox. Recent calculations based on molecular orbitals of our group have shown that

cyclic imides (chlorophthalim. Fig. 5. left part, bot­tom) and triazolidine-type inhibitors do not match with the (b) and (c) pyrrole rings of protoporphy­rinogen (as does acifluorfen). but favorably match with the (c) ring and the propanoic acid part (e). (Fujii et al., 1995). The different fitting of inhibi­tors with protogen obviously points to different amino acid residues of protox functioning as the binding partners of these inhibitors. Lack of sub­stantial cross-resistance between oxyfluorfen and chlorophthalim corroborates this assumption (Watanabe, 1992). Recently, Hagiwara and Naka- yama (1994) have also reported the molecular sim­ilarity of three peroxidizing herbicides, namelyl,2,4-triazolin-3-one-3,4,5,6-tetrahydrophthal- imide (S-23142 in Fig. 1) and 1,2.4-thiadiazoline derivatives with a 2-fluoro-4-chloro-5-propargyl- oxyphenyl group (NS-1556 in Fig. 9) through con­formational analysis for the rotation of the phenyl ring of these compounds. We strongly suggest that molecular properties of a peroxidizing inhibitor have to be compared with those of protogen, the substrate of the enzyme. Comparison of different

Van der Waals volume of protoporphyrinogen-IX as well as of acifluorfen and chlorophthalim is represented as a dot face of CPK radius. Dihedral angle and molecular size of KPP-314

Protoporphyrinogen-IX Acifluorfen

CF3

0

^COOHn o 2 —

|-« -5 .5 3 A —

Chlorophthalim

Fig. 5. M atching of peroxidizing m olecules with protoporphyrinogen-IX (protogen), the substrate of p ro toporphy­rinogen-IX oxidase: C onsideration of m olecular size and torsion angles in both substrate and inhibitors. Acifluorfen and chlorophthalim match best with different parts of the protogen molecule. An N -aryloxazolidinedione inhibitor (KPP-314) with its torsion angle is shown in the right part of the figure.

Trends A rticle • K. W akabayashi and P. Böger • Peroxidizing H erbicides (II) 597

inhibitors alone (e.g. DPEs and cyclic imides) is not sufficient to give a clue for possible molecular design (comp. Akagi and Sakashita, 1993).

4. Structural conversion o f peroxidizing herbicides in plants

The DPEs are relatively stable in the bioassay medium as compared to cyclic imides. N-Aryl-3.4.5.6-tetrahydrophthalimides (imides) and N-3.4.5.6-tetrahydrophthalamic acids (amide-acids) are interconverted to each other during incubation with seedlings of Echinochloa utilis (Sato et al., 1991). N-Aryl-3,4,5,6-tetrahydroisophthalimides (isoimides), which show strong peroxidizing activ­ity like imides, are transferred to amide-acids, and then the amide-acids are cyclized to imides and/ or hydrolyzed to the corresponding anilines and3.4.5.6-tetrahydrophthalic acid during a bioassay in the presence of Echinochloa (Fig. 6; Hoshi et al., 1993). The most effective phytotoxic struc­tures of imides, isoimides and amide-acids are now considered to be imides formed through the (inter)conversion mentioned above. Analogous experiments have been carried out using several sets of isomeric peroxidizing herbicides, namely5-arylimino-3,4-tetramethylene-l,3,4-thiadiazo-

lidine-2-ones and 4-aryl-l,2-tetra-methylene-l,2,4-triazolidin-3-one-5-thiones, exposing them to Echinochloa seedlings, Scenedesmus, or to a spin­ach homogenate (Hoshi et al., 1992; Sato et al., 1994a). The former compounds were readily con­verted into triazolidines, during incubation in the presence of the plants or the homogenate, how­ever, the opposite conversion of triazolidines into thiadiazolidines was not observed. Accordingly, the most powerful phytotoxic principle of the thia- diazolidine peroxidizers appears to be due to for­mation of the triazolidines in the presence of plants; the triazolidines are more potent herbi­cides than the thiadiazolidines. Recently, it has been reported that the conversion of thiadiazoli­dines into triazolidines rapidly proceeds with glu­tathione S-transferase and SH-compounds present such as glutathione, dithiothreitol and others (Iida et al., 1994a, b; Sato et al., 1994b; Shimizu et al., 1994, 1995). This reaction apparently reflects a new functional property of a certain glutathione S- transferase isoenzyme (Nicolaus et al., 1995). The compounds, like isoimides and thiadiazolidines, can be referred to as pro-herbicides with the inten­tion that a more active phytotoxic molecule is formed within, or in the vicinity of, plant cells, preferably at the targeted chloroplast.

Fig. 6. S tructural conversion of cyclic imide com pounds (left part) and thiadiazolidines (right part) in the presence of Echinochloa utilis seedlings. Seedlings were cultured with the chemicals for 7 days in darkness according to Sato et al. (1994a). C onversion of the com pounds to other structures was analyzed by HPLC.

598 Trends Article • K. W akabayashi and P. Böger ■ Peroxidizing H erbicides (II)

The Second Generation of Peroxidizing Herbicides

The first generation of peroxidizing herbicides, such as oxadiazon, chlorophthalim and oxyfluor- fen, have handed down their unique phytotoxic properties to more than 20 different peroxidizing herbicides or candidates of a second generation including DPEs, Cyls. pyrazoles, triazoles, triazo- lidines, thiadiazolidines, oxazolidines and so on, which have been developed mostly in the second half of the 1980's (Figs. 7, 8 and 9). By studies in our laboratories many of these compounds have experimentally been confirmed to be peroxidizing herbicides by inhibiting protox, causing photooxi- dative ethane formation and a strong bleaching effect in the light, although their structures are quite different. Some candidates, e.g. KPP-300, KPP-314, S-23142, flumipropyn, flumioxazin, flu- thiacet-methyl (KIH-9201), NS-1556, thidiazimin, ET-751, PPG-1013 and SUAM-16476, are cur­rently developed as practical herbicides. In Figures7 to 9 these and further structures of candidates

for peroxidizing herbicides are illustrated for the reader’s information. Also a compilation of com­pounds with possible peroxidative properties writ­ten by Anderson et al. (1994) should be consulted. Experiments are under way to determine in detail the peroxidizing characteristics of these com­pounds in our laboratories.

Design for Future Peroxidizing HerbicidesThe general characteristics of these herbicides

are attractive features to develop a number of new target products by herbicide design. These charac­teristics are nowadays obtained mostly by mecha­nism of action studies. The inhibition of chloro­phyll biosynthesis is an important mechanism of the peroxidizing action which results in decrease of plant pigments via radical reactions started by sensitized tetrapyrroles in the light. Obviously, protox is a favorable target, although it is inhibited competitively and reversibly. The low inhibitor constants for plant protox in combination with an apparent rapid turnover of proto IX to generate

[ A ] Peroxidizing diphenyl ether herbicidesß\ _ ci

CI- ~ -0- -N02 F3C-^y-0-^Nitrofen Nitrofluorfen

Cl COOCH3

Bifenox

CH3Cl OCHCOOCH2CH2OCH3

f 3c - Q - o - Q - n o 2

CGA-84446

Cl o -C j

f 3c - Q - o h Q - n o 2

MT-124

Cl

SUAM-16476

/-<“ /-c y o'CHpCSCH

CH3Cl COOCHCOOC2H5

f 3c - Q - o - Q - n o 2

Lactofen

Cl C 0C H 20 C H 2C 0 0 C H 3

f 3C O n o 2(1987)Cl C 0 N H S 0 2CH3

f3C-^ -0-^ -N02

h 2c =h c c h =c h 2

f3c~C^°“C ^ o(1988)

N°2f 3c h Q - o - Q - n o 2

Fluorodifen

„ Cl n h 2

n°2Aclonifen

f 3c - ( } o - Ö - n .c

SUAM-19233 CH

Cl o c h c o o c 2h s

F3C' 0 ' 0'O ‘N02

] Peroxidizing herbicides with new structures

?H3y=\H5C2OC CON H C H -^ _ ^

h 3c " ^ n c h 3LS 82-556

C2H5

Bryy com\ )H3C N C3H7C2H5

CH3

c h 3H5Ü2O O C ^ -ci 0-N'CH3

c h 3

(1987)

Fomesafen q

j - P /=<co- nDOt3C\J-0\J-N02 0(1984) CH3 o c h 3

-Cl C =N O CH 2C O OCH3(H) CH3 Cl c = n o c h 2c o o c h 3

f3c > o > no2 C|_ ^ -o- ^ - no2PPG-1013 (PPG-1055) (1993)

CHF20 Nc h 3

ClOCH2CO O C 2H5

ET-751 (1 9 9 1 )

(1993)

Fig. 7. Peroxidizing diphenyl ethers (A ) and peroxidizing herbicides with new structures (B).

Trends A rticle • K. W akabayashi and P. Böger • Peroxidizing H erbicides (II) 599

CIY 5T C I|

OjNO xadiazon (1969)

R i v ^ s - C l C hlorophthalim | R , = R2 = H : 1970 ] n I J L M K-106 [ R , = H , R2 =OCH2C5CH; 19761

r 2 M K-170 [ R 1 = F , R 2 = H; 1976 I ( " J 0 S-23142 [ R , = F . R2 =O CH2C sCH : 1983 1

Flum ipropyn ( R , = F , R2 =OCH(CH3)C=CH ; 1983 ]

-N,N. Kq t y

[ X , Y = O or S ] (1974)

f(FJy^CI

cY°V nM o% )

’ (1976)

JlA j> q (1989)

NH2

NC

ClJ yCF3

C-VN|V

M & B-39779(1986)

C l v ^ , C F 3

IfN tX n ci

(1989)

O (1991)

(1991)

(1991)

j r ? (1989)

Ri r N

Cf[ R = C I , c h 3 , c h 3o , CH3S ,C=N ]

(1976, 1984,1986)

:iY"N' CF3y -n Xj N(1989) C jN

_ l(F )L - ,c i

°1~1N ^ (0 ^ ) f N? Nk J (1978)

NH2. NX J (*c h f 2)

X ' c i (1989) N 0 2^ n

CI y ,CF3n h 2 V (<CHF2)

C H a S ^ N Cl (1989) (CF3S O - ; CF3S 0 2»)

X ? ( * o c f 3)

c f 3s ^ 'n ' j Cl

NC

C|x — N

s O ^ N(1990) CF3 CH3 <1987)(S)

Cl

CH30 *N,inn1v N02 fN

ACF3 N O (1990 ) CH3

'n—n' CH3V ~ n'

(1991)

(1991)

Oc h 3 nux k

r-o*+z,u ^(1985) CF3' ^ ^ 0 ( 1987) 0 (1987)

N N

CF3> N ' t O (1991)

o . n .

(1991)

(1991)

(1989)

EXP9301(1990)

(1993)

(1993)

Fig. 8. Recent structural modifications of peroxidizing compounds belonging to the cyclic imide class: pyrrolidinones, pyrazoles, triazolones. pyrimidinones, pyridazinones and their analogues. For some compounds the dates are indi­cated when they were first patented (see also Fig. 9).

CV- N '^ 'cA0 | N

Oxadiazon (1969)f r o

KPP-300 | KPP-314

1 (1986)

vV| ' ° ^ 0 (1987)

0 t " N'T ^ ° ( 1 9 8 8 )

CH3

Ci C h lo roph thalim [ R , = R2 = H ; 1970 ] M K -106 | R , = H , R2 =OCH2C=CH ; 1976]

R2 M K -170 i R , = F , R2 = H ; 1 9 7 6 ]S -23142 | R , = F , R2 =OCH2C ;C H ; 1983 ] F lum ipropyn ( R, = F , R2 = OCH(CH3)CsCH

____l__________y________

.N . MyU 1 Y

1 9 83] [X , Y = O o r S ] (1974)

(F)

— COOH (OR)I (1971) (1970)

r 'n n-cooc2H5^ (1975)

f N ' 1k - N . (

N'N ^ NCJCl

(1989)

(1990)

N— S

SCH2COOCH3

Fluthiacet-methyl KIH-9201

,o> (1987) O ^ N ^ N O - ----- ' NS-1552

N~~.il - ” <1986>(f N N N— S

NCI-876648 (1989)

COOC2H5(1974)

C CONH-

n y o c 2h 5

O (S ) (1993)

,C O N H -

°>— N'(1991)

Cl' N'o^Ofws)>cö-

j—°r ' N ' ^ N '

(1989)

V - srN-N^N'1-----1 (1993)

S " N " * N ‘R -|-----1 NS-1556

R (1986)

N - S

jAl'Sl'P Thidiazimin

[ R = H or CH3 ] <1989)

u^ ny oc2h5O (1993)

O.CH3COO.

(1974)

, c 3h 7(1981)

(1978)

\ j ~ a — o c h 2c = c h

1 (1983)

S'* (1981)

(1987)

(1993)

f CIR

(1983)

(1983)(1983)

(1984)

R : O C 3H7 - i•OCH(CH3)C=CH•o c h 2c = n

•OCH2COOC5H,i(Flumiclorac pentyl)

•OCsHg-cycIo (1987)•OCHF2 (1987)•OCH2CH2OCH2CF3 (1990)•S 0 2CH3 (1990)•SCH2C=CH (1985)•SCH2COOCH3 (1985)

•S 0 2NHCH3 (1993) •NHCH(C2H5)CONHC4H9 - i (1981)

(MK-147)

•NHCH(C3H7)COOC4H9 (1983) (MK-162)

*NHS02C2H5 (1993)

•COOC3H7 - i (1981)•COOCH2COOC2H5 (1984)•CH2=NOCH3 (1987)

_ < = N <1990>

Fig. 9. Recent structural modifications of peroxidizing compounds belonging to the cyclic imide class: oxazolidines, triazolidines, thiadiazolidines and cyclic imides with new aryl moieties.

600 Trends A rticle • K. W akabayashi and P. Böger • Peroxidizing Herbicides (II)

radicals lead to amazingly low use rates. These are down to some grams per hectare (e.g. 10-20 g/ha for flumipropyn or 5-10 g/ha for fluthiacet- methyl: formulas in Figs. 8 and 9, respectively), which makes such herbicidal compounds interest­ing candidates for future ecology-oriented chemi­cal weed control. Leaching problems are minor ones; many of the peroxidizing herbicides in devel­opment (see Fig. 1 in Böger and Wakabayashi,1995) exhibit a reduced persistence in soil. A vari­ety of compounds with different core structures are good protox inhibitors giving the synthetic chemist a fair chance to find more. Prospects are good that this chance will be improved by more

Akagi T. and Sakashita S. (1993), A quantum chemical study of “ light-dependent herbicides”. Z. N aturforsch. 48c. 345-349.

A nderson R. J., Norris A. E. and Hess F. D. (1994), Syn­thetic organic chemicals that act through the porphy­rin pathway. In: Porphyrie Pesticides (S. O. D uke and C. A. Rebeiz, eds.). ACS Symp. Ser. no. 559. A m er. Chemical Soc., W ashington. D. C., pp. 18-33.

Böger P. and Sandm ann G. (1993), Pigment b iosynthe­sis and herbicide interaction. Photosynthetica 28. 481-493.

Böger P. and W akabayashi K. (1995), Peroxidizing herb i­cides (I): Mechanism of action. Z. N aturforsch. 50c, 159-166.

Fedtke C. (1982), Diphenyl ether herbicides. In: B io­chem istry and Physiology of H erbicide A ction. Springer Publ., Berlin.

Fujii H.. Koura S., Takusuka S., Uraguchi R.. Iida T., Sato Y., Nicolaus B., Böger P. and W akabayashi K.(1995), Protoporphyrinogen oxidase inhibition and m olecular structures of cyclic imide herbicides. A b ­stract, 20th M eeting Pestic. Soc. Japan. Tokyo, p. 133.

Hagiwara K. and Nakayam a A. (1994), M olecular sim ­ilarity of peroxidizing herbicides: Bioisosterism in A2-1,2,4-thiadiazolines and related heterocyclic com ­pounds. J. Pestic. Sei. 19, 111-117.

H am per B. C., Leschinsky K. L., Massey S. M., BellC. L., Brannigan L. H. and Prosch S. D. (1995),3-Aryl-4-substituted-5-(halo)alkylisoxazoles. Design, synthesis, and herbicidal activity of a unique class of pre- and postem ergent herbicides. In: Synthesis and Chem istry of Agrochemicals IV (D. R. Baker. J. G. Fenyes, G. S. Basarab, eds.). ACS Sympos. Ser. 584. Am er. Chem. Soc., W ashington D. C.. pp. 114-121.

Hoshi T.. Sato Y., Kohno H., W akabayashi K. and Böger P. (1992), Hydrolysis and phytotoxic activity of cyclic imides. Proceedings, 6th China-Japan Symposium Pes­ticide Science, Fukuoka, pp. 125-128.

Hoshi T., Koizumi K., Sato Y. and W akabayashi K.(1993), Hydrolysis and phvtotoxic activity of N-arvl- 3.4.5.6-tetrahydroisophthalimides. Biosci. Biotechn. Biochem. (Japan) 57, 1913-1915.

knowledge of the biochemistry of the peroxidation reaction system and of the enzymology involved. “Me-Too” design as well as the development of compounds with new core structures and substi­tuents, should be based on rational approaches using advanced biochemical investigations.

Acknowledgement

The authors wish to thank to the Japanese Society for the Promotion of Science, Tokyo, for support which led to cooperative research and fruitful information exchange between German and Japanese colleagues.

Iida T., Takasuka S., Ihara T.. Sato Y.. W akabayashi K. and B öger P. (1994a), M echanism of action of thiadi- azolidine herbicides: Com parison of phytotoxicities betw een herbicidal l,3.4-thiadiazolidin-2-ones andl,3,4-triazolidine-2-thiones. A bstract, 19th Annu. M eeting Pesticide Society Japan, Sapporo, p. 89.

Iida T.. Senoo S., Sato Y., Nicolaus B.. W akabayashi K. and B öger P. (1994b), Isom erization of thiadiazoli- dine-herbicides and their phytotoxic principle. A b­stract, 29th A nnu. M eeting Society Chemical R egula­tion Plants, Wako-shi. pp. 123-124.

Iida, T., Senoo S., Sato Y., Nicolaus B., W akabayashi K. and Böger P. (1995). Isom erization and peroxidizing phytotoxicity of thiadiazolidine-thione compounds. Z. N aturforsch. 50c, 186-192.

Kohno H., H irai K., H ori M., Sato Y., Böger P. and W akabayashi K. (1993), New peroxidizing herbicides: Activity com pared with X-ray structure. Z. N atur- forsch. 48c, 334-338.

Lam bert R.. Sandmann G. and Böger P. (1983). C orrela­tion betw een structure and phytotoxic activities of ni- trophenyl ethers. Pestic. Biochem. Physiol. 19,309-320.

Lyga J. W., Patera R. M., Theodoridis G.. Halling B. P.. H otzm an F. W. and Plum m er M. J. (1991), Synthesis and quantitative structure-activity relationship of her­bicidal N-(2-fluoro-5-methoxyphenyl)-3,4,5,6-tetrahy- drophthalim ides. J. Agric. Food Chem. 39, 1667-1673.

M atsunaka S. (1969), A cceptor of light energy in pho to ­activation of diphenyl herbicides. J. Agric. Food Chem. 17, 171-175.

M atsunaka S. (1976), D iphenyl ethers. In: Herbicides: Chemistry. D egradation and M ode of Action (P. C. K earney and D. D. Kaufman, eds.). Marcel D ekker Inc., New York. Vol. 2, pp. 709-739.

M iura Y., Ohnishi M.. M abuchi T. and Yanai I. (1993). ET-751: A new herbicide for use in cereals. Brighton Crop Protection Conference, Weeds, BCPC Publ., Farnham , UK. Vol. 1, pp. 35 -40 .

M iura Y.. T suhata K., Ohnishi M. and M abuchi T. (1994), Study on new herbicide, ET-751. for cereals. A bstract. 19th Annu. M eeting Pesticide Science Soci­ety Japan. Sapporo, p. 52.

Trends Article • K. W akabayashi and P. Böger • Peroxidizing Herbicides (II) 601

Nandihalli N. B., D uke M. V. and Duke S. O. (1992), Q uantitative structure-activity relationships of p ro to ­porphyrinogen oxidase-inhibiting diphenyl e ther her­bicides. Pestic. Biochem. Physiol. 43, 193-211.

Nicolaus B., Sato Y.. W akabayashi K. and Böger P.(1996), Isom erization of peroxidizing thiadiazolidine herbicides is catalyzed by glutathione-S transferase. Weed Sei., subm itted.

O hta H., Jikihara T., W akabayashi K. and Fujita T. (1980), Q uantitative structure-activity study of her- bicidal N-aryl-3,4,5,6-tetrahydrophthalim ides and related cyclic imides. Pestic. Biochem. Physiol. 14, 153-160.

Sato Y., Kojima T., G oto T., O om ikaw a R., W atanabe H. and W akabayashi K. (1991), Hydrolysis and phyto­toxic activity of cyclic imides. Agric. Biol. Chem. 55, 2677-2681.

Sato Y., Noguchi N , Koizumi K. and W akabayashi K.(1992), A pplication of structure-activity relationship and activity-activity relationship for peroxidizing her­bicides research (II). Bull. Fac. A griculture, Tama- gawa University 32, 73-82.

Sato Y., Hoshi T., Iida T., Ogino C., Nicolaus B., W aka­bayashi K. and Böger P. (1994a), Isom erization and peroxidizing phytotoxicity of thiadiazolidine herb i­cides. Z. N aturforsch. 49c, 49 -56 .

Sato Y„ Hoshi T„ Nicolaus B., W akabayashi K. and Böger P. (1994b), Intrinsic phytotoxic structures of cyclic imide class of peroxidizing herbicides. A bstract, 8th IUPAC Intern. Congress Pesticide Chemistry, Washington D. C., Vol. 2, 749.

Shimizu T., N akayam a I., N akao T., M izutani H., U nai T., Yamaguchi M. and A be H. (1994), M echanism of action of new herbicide, KIH-9201. A bstract, 19th Annu. M eeting Pesticide Science Society Japan, Sap­poro, p. 82.

Shimizu T., H ashim oto N., N akayam a J, N akao T., M izu­tani H., Unoi T., Yamaguchi M., A be H. (1995), A

novel isourazole herbicide, fluthiacet-m ethyl is a potent inhibitor of protoporphyrinogen oxidase after isom erization by glutathione S-transferase. Plant Cell Physiol. 36, in press.

Suzuki S., W atanabe H., Jikihara T., O hta H., M atsuya K. and W akabayashi K. (1975), S tructure-activity re la ­tionship of cyclic imide herbicides. Proceedings 5th Asian-Pacific Weed Science Society Conference, Tokyo, pp. 176-182.

W akabayashi K., Matsuya K., O hta H. and Jik ihara T. (1979), Structure-activity relationship of cyclic imide herbicides. In: Advances in Pesticide Science, (H. Geissbühler, ed.), Pergam on Press, Oxford, Part 2, pp. 256-260.

W akabayashi K. (1988), M olecular design of cyclic imide herbicides using biorational approaches. J. Pestic. Sei. 13, 337-361.

W akabayashi K., Sandmann G., O hta H. and B öger P.(1988), Peroxidizing herbicides: C om parison of dark and light effects. J. Pestic. Sei. 13, 461-471.

W akabayashi K. and Böger P. (1993), Peroxidizing herb i­cides: M echanism of action and m olecular design. In: Pesticides/Environm ent: M olecular Biological A p ­proaches (T. Mitsui. F. M atsum ura and I. Yamaguchi, eds.), Pesticide Science Society of Japan, Tokyo, pp. 239-253.

W akabayashi K. and Böger P. (1994), Peroxidizing herb i­cides: M echanism of action and m olecular design. A b ­stract, 8th IUPAC Intern. Congress Pesticide C hem is­try, W ashington D. C., Vol. 2, 751.

W atanabe H., O hori Y., Sandm ann G., W akabayashi K. and Böger P. (1992), Q uantitative correlation betw een short-term accum ulation of protoporphyrin-IX and peroxidative activity of cyclic imides. Pestic. Biochem. Physiol. 42, 99-109.

W atanabe H. (1992), Study of m ode of action of photo- bleaching herbicide chlorophthalim , PhD Thesis, Tamagawa University, Tokyo (in Japanese).