Download - Quantitative structure-activity relationships of the inhibition of photosynthetic electron flow by substituted diphenyl ethers

Pestic. Sci. 1982, 13, 29-38

Quantitative Structure-Activity Relatioiiships of the Inhibition of Photosynthetic Electron Flow by Substituted Diphenyl Ethers

Gerard van den Berg and Jacobus Tipker

Duphar B. V. Biochemistry Department, Crop Protection Division, PO Box 4, 1243 ZG 's-Graveland, The Netherlands

(Manuscript received 30 September 1980)

The effect of 41 substituted diphenyl ethers (derivatives of nitrofen and chloroxuron) on photosynthesis in isolated spinach chloroplasts has been studied. All the chemicals were found to be inhibitors of non-cyclic electron transport; the pI50 values varied from 3.17 to 7.16 (150 is the molar concentration causing 50% inhibition; PISO= -log 150). Based on their structures, the compounds were divided into four groups; for most groups, a correlation between the inhibition of photosynthesis and physicochemical parameters was found. Lipophilicity proved to be the most important parameter; electronic effects did not play a role. Introduction of substituents into the nitrophenyl ring of nitrofen lowered activity considerably. Nitrofen and and chloroxuron analogues seemed to inhibit at different sites in the electron transport chain. A relationship between inhibition of photosynthesis and herbicidal activity was not clear.

1. Introduction

In 1963, nitrofen (2,4-dichlorophenyl 4-nitrophenyl ether) was introduced as a selective pre- and post-emergence herbicide. Especially in Japan, this compound was widely used for pre-emergence weed control in transplanted rice. Many derivatives have been synthesised since, and a few have proved useful herbicides under field conditions.1

It has been known for a long time that nitrofen requires light for ac t iva t i~n .~ - -~ White rice mutants were found to be tolerant whereas normal green and yellow mutants were susceptible.3 The same phenomenon has also been reported for other crop specie^.^ Probably light and pigments like chlorophylls and/or carotenoids are indispensable for herbicidal activity. The hypothesis that nitrofen itself is inactive but is converted into a toxic substance by light could never be proven.2 On the other hand, the light requirement was obvious only for para- and/or ortho-substituted diphenyl ethers; metu-substituted derivatives were also active in the dark and showed a different selectivity for Echinochloa cru~galli.~, Recent studies by Vanstone and Stobbe showed light of wavelengths between 565 and 615 nm to be the most active in activating oxyfluorfen.6 The relation between light and herbicidal effect became more obvious after the experiments by Moreland et ul.7 They showed nitrofen and two analogues to inhibit electron transport and non-cyclic phosphorylation in isolated spinach chloroplasts, whereas cyclic phosphorylation was unaffected. The site of action appeared to be close to the DCMU-sensitive site. These results were recently confirmed by Bugg et al. although these authors concluded that the site of the action was between plastoquinone and cytochrome f, rather than at the DCMU site.s Contrariwise, Lambert et al. showed that, at least in the alga Bumilleriopsisfiliformis, inhibition of photophosphorylation is the most important feature of nitrofen a ~ t i o n . ~ Because of the successful use of substituted diphenyl ethers as herbicides, the diphenyl ether structure was used more than once to replace a phenyl ring in known herbicides. The herbicide chloroxuron is derived from monuron and the herbicide diclofop-methyl is based on 2,4-D.

0031-613X/82/02o(Mo29 $02.00 8 1982 Society of Chemical Industry 29

30 G. van den Berg and J. Tipker

Chloroxuron appeared more active than monuron in inhibiting photosynthetic electron transport.1° Recently Trebst et al. showed that dinitrophenyl ethers of bromo- or iodothymol are also strong inhibitors of photosynthesis.ll9 l2 The objectives of this study were to investigate the relationship between chemical structure, inhibition of photosynthesis and the herbicidal effects of a series of diphenyl ethers. Chloroxuron analogues were also included.

The following abbreviations are used in the text: DBIMB 2,5-dibromo-3-isopropyl-6-methyl-p- benzoquinone (also known as dibromothymoquinone); DCMU 3-(3,4-dichlorophenyI)-l,l- dimethylurea ; FeCy hexacyanoferrate(II1) ; MV methylviologen (paraquat dichloride) ; PD p- phenylenediamine; PMS 5-methylphenazinium methyl sulphate; and TMPD N,N,N,N-tetra- methyl-p-phenylenediamine.

2. Experimental methods 2.1. Chemicals All inhibitors used were synthesised in the Organic Synthesis Department according to known methods.

2.2. Photosynthesis measurements Chloroplasts were isolated from spinach leaves by grinding the leaves in a medium containing 0.3~-sorbitoI, SOmM-HEPES/sodium hydroxide (pH 7.6), and 5mM-magnesium chloride. HEPES is 2-[4-(2-hydroxyethyl)piperazin-I -yl]ethanesulphonic acid. After filtering through four layers of cheese cloth the homogenate was centrifuged at 5000g for 90 s; the pellet was resuspended in grinding medium, and the chlorophyll content was determined as described by Bruinsma.l3 Unless stated otherwise, photosynthetic processes were measured in a medium (4 ml) containing: tricine/ sodium hydroxide buffer (pH 8.0; 200 pmol) and magnesium chloride (4 pmol). Tricine is N- [2-hydroxy-l,l-bis(hydroxymethyl)ethyl]glycine. The medium also contained chloroplasts equiva- lent to 50 pg of chlorophyll and appropriate electron donors or acceptors such as FeCy (3 pmol), MV (0.04 pmol) plus sodium azide (0.8 pmol), TMPD (0.8 pmol) plus ascorbic acid (30 pmol) or PMS (0.08 pmol) (under nitrogen). Photosystem I1 activity was blocked by DCMU (40 nmol). Phosphorylating systems contained in addition : adenosine 5’-diphosphate (0.8 pmol), inorganic phosphate (4 pmol), glucose (80 pmol) and hexokinase (Sigma type 111; 6 units). Inhibitors were added as methanolic solutions, the final methanol concentration always being 2 % by volume. Incubation mixtures were illuminated by a projector lamp producing a light intensity of 200 W m-2 and incubations were carried out at 25°C.

Electron transport was measured spectrophotometrically or by using a Clark electrode (Gilson Medical Electronics Inc., Middleton, Wisconsin, USA). Adenosine 5’-triphosphate (ATP) forma- tion was determined by colorimetric measurement of the disappearance of inorganic phosphate, or by determining the production of glucose-6-phosphate en~ymical1y.l~

2.3. Herbicide tests The compounds were tested for post-emergence herbicide activity in the greenhouse. The tests included the grass species Avena fatua, Alopecurus myosuroides and Panicum miliaceum, and the broadleaf species Chenopodium album, Galium aparine, Galinsoga parvipora, Polygonum convolvulus and Senecio vulgaris. Plants were sprayed with acetone solutions of the test chemicals, 10 days after germination, and kept in the greenhouse for 3 weeks. Chemicals were applied at dosages of 0.5, 1,3, 5 and 10 kg a.i. ha-l and dose-response curves were drawn for total activity on mono- or dicotyle- don weeds. In this way, the minimum rate producing severe damage (nearly fatal) could be calculated. When this minimum rate was <0.5, 0.5, 1 , 3, 5, 10 or > 10 kg ha-’, a herbicide score of 6, 5, 4, 3, 2, 1 or 0, respectively, was recorded. Of the two figures given in the tables, the first represents the score on monocotyledones, and the second, the score on dicotyledones.

2.4. Multiple regression analysis Biochemical inhibition data were correlated with physicochemical parameters by a multiple regression analysis. Hydrophobic (T) and electronic (u) parameters were taken from Hansch and Leo.15

Inhibition of photosynthetic electron flow by substituted diphenyl ethers 31

Two types of steric parameters were used: Taft's E, parameter,15 and Sterimol parameters from Verloop et aZ.16 Regression equations are presented in section 3.3; in these equations, n is the number of compounds, r is the correlation coefficient, s is the standard error of the estimate, and F represents the overall statistical significance of the equation. The Student's t-test values of the regression coefficients are placed in parentheses.

3. Results 3.1. Effects of nitrofen on photosynthesis The effects of 3, 10, 30 and 100pM-nitrofen (compound 12) on different photosynthetic reactions were studied and the molar concentrations causing 50% inhibition (150) were determined. The results are presented in Table 1 in which p h = -log 150. The effect of nitrofen on basal electron transport seemed pH-dependent and therefore this effect was studied over a pH range of 6 to 8.5

Table 1. Effect of some substituted diphenyl ethers on various photosynthetic reactions in chloroplasts

pI50 values for following inhibitorsn ___ ___. - Measurement

Electron transport pathway made 1 2 12 21 26 35 - ~ ~ ~ ~ _ _ -~

HzO+FeCy, pH 7.5, basal Reduction 3 . 5 3 . 5 4.05 4.40 3 .7 6.64 Hz0-t FeCy, 2m~-ammonium chloride Reduction 3.85 4 .34 4.55 4.19 4.01 6.68 HzOjFeCy, pH 8.0, basal Reduction 4.26 4 .75 4.92 4.57 4 . 5 2 6.97 Hz0-r FeCy, phosphorylating Reduction 4.25 4.72 4.92 4.49 4.37 7.13

ATPformation 4.26 4.72 4.98 4 .59 4.42 7.12 HzO-tMV, basal Oxygenuptake 3.94 4.43 4.67 4.32 (38) 6.98

TMPD/ascorbate+ MV PMS (nitrogen)

Oxygen uptake (0) (0) (0) (0) (0) (0) ATPformation (35) (22) (11) (0) (18) 4.38

a See Tables 2-5 for the structures of the inhibitors. 150 is the molar concentration causing 50% inhibition; PISO= -log 150. Data in parentheses are the percentage inhibition at 0 . ImM. Except for the first reaction, all the activities were measured at pH 8.0.

I

4 300 e

8 I 0

I " I I I I I I I 6 6.5 7 7.5 8 8 . 5

0

I I 1 I I 2 3 4 5 6 7

PH Log P

Figure 1. The effect of pH on the inhibition of hexacyanoferrate(ll1) reduction (Hill reaction) (pmol mg-1 of chlorophyll h-I), using HEPES buffers of pH 6 .O, 6.5, 7 . 0 and 7.5, and tricine buffers of pH 7.5, 8 .O and 8 . 5 : 0, control; +, IOpM-nitrofen; and 0 , 0 . 3 p ~ - D C M U .

Figure 2. Relationship between the inhibition of the reduction of hexacyanoferrate(II1) (Hill reaction) and log P (the log of the octan-I-ol/water partition coefficient): 0, compounds from Table 2 by equation 7; and 0 , compounds from Table 5 by equation 8.


as can be seen in Figure I . At higher pH values, greater inhibition was found for nitrofen as well as for DCMU.

3.2. Effects of related compounds The effects of five different series of substituted diphenyl ethers on basal electron transport at pH 8.0, using FeCy as acceptor, were studied at three different concentrations, and the 150 values were determined graphically. The negative logarithms of these values (PISO) are presented in the tables. Because of the limited solubility of the compounds O.lmM was the highest concentration used.

At first, a study was made of the effect of altering the substitution pattern of the halogenated ring of nitrofen. Many para-substituted-phenyl 4-nitrophenyl ethers were studied in addition to some nitrofen isomers having chloro atoms at different positions (see Table 2). The second series of compounds consisted of nitrofen analogues in which the nitro group was replaced (see Table 3). In this series, the herbicide diclofop-methyl (HOE 23 408; compound 21) was included. Nitrofen derivatives having another substituent in the nitro-substituted ring are listed in Table 4. Compound 26 is the herbicide chlormethoxynil (X-52).

The compounds 32 and 35 of Table 5 can be regarded as being derived from nitrofen and, consequently, they should have been reported in Tables 2 and 3, respectively. However, because of the rather high activity of these compounds, they do not fit well in these series. As will be discussed later, these compounds are members of a totally different group of photosynthesis inhibitors,

Table 2. Inhibition of the reduction of hexacyanoferrate(II1) (Hill reaction) and the herbicidal effects of a series of substituted 4-nitrophengl phenyl ethers

Compound

Number

1 2 3 4 5 6 7 8 9

10 11 12 13 14 15 16 17 18

R x

.~ .~

H 0.00 4-CI 0.74 4-0-CO-NH-CH3 - I .21 4-CH.1 0.51 4-0-cH3 0.05 4-SOz-CH3 - 1-67 4-CO-CHs -0.48 4-NHz -1.10 4-S-CH3 0.61 4-0-CzHj 0.56 4-C(CH3)3 2.05 2,4-CIs 1.48 2,3-Cla 1.48 2,6-C1z 1.48 2,5-Clz I .48 3,4-Ch 1.48

2,3,4,6-C14 2.96 2,6-(CHa)z 1.02

Observed -

4.26 4.15 3.61 4.63 4.48 3.17 4.11 3.65 4 .95 4.19 5 05 4.92 4.71 4.89 4.72 4.89 4.63 5.42

pled' ~

Calculated

Equation I Equation 2 Herbicide

score0

4.44 4.34 4.79 4.68 3.59 3.62 4.69 4.58 4.47 4.31 3.17 3.29 4. I4 4.08 3.68 3.69 4.74 4.63 4.12 4.60 5.08 5.09

4.94 4.94 4.94 4.94 4.94 4.79 5.23

a Is0 is the molar concentration causing 50% inhibition; pIso= -log 150.

0 Defined in section 2.3.


Table 3. Inhibition of the reduction of hexacyanoferrate(lI1) (Hill reaction) and the herbicidal effects of a series of 2,4-dichlorophenyl 4-substituted-phenyl ethers

('I /

Compound ____ .~ ~ ~ -_- Herbicide Number R PIsoa scorch

12 -NO2 4.92 616 19 -OH 4.39 20 -0-CO-N H-CHs 4.54 010 21 -O--CH(CHs)--COO--CH3 4.57 413

a 150 is the molar concentration causing 50% inhibition; p150= -log 150.

b Defined in section 2.3.

Table 4. Inhibition of the reduction of hexacyanoferrate(lI1) (Hill reaction) and the herbicidal effects of a series of nitrofen analogues

Compound Plsob Herbicide ___ _____ _.

Number X B4" Observed Calculatedc scored

12 H I .o 4.92 4.87 616 22 -NHe 1.8 4.61 4.68 216 23 c 1 1.8 4.69 4.68 415

25 -NH-(CH&-CH3 4.4 4.12 4.06 415 26 -0-CHs 2.9 4.52 4.42 616 27 -CH(CH& 3.2 4.26 4.34 010

____ ~ ~ .______ -___- __

24 -S -CHs 3.3 4.24 4.32 215

a Sterimol parameter. h 150 is the molar concentration causing 50% inhibition; PISO= -log 150.

c Calculated from equation 3. d Defined in section 2.3.

namely analogues of chloroxuron (compound 29). Many derivatives of chloroxuron were studied and the results are presented in Table 5. A few analogues of nitrofen, in which the oxygen bridge between the two phenyl rings has been changed, are included in Table 6.

Some representatives of each series were studied in more detail in order to ascertain if all the chemicals act in the same way. Table 1 shows the effects on FeCy reduction under basal, uncoupled, and phosphorylating conditions. Moreover, the effects on typical photosystem I activity, such as PMS phosphorylation and electron transport using MV as acceptor, are reported. Further experiments to characterise the site of action showed that the inhibition of the MV reduction by the compounds listed in Table 1 could not be abolished by TMPD alone. However, the inhibition of the FeCy reduction by compounds 1, 2, 12, 21 and 26 could be partially reversed by O.lmM-PD, whereas the inhibition by compound 35 and by DCMU was not.

3

34 G . van den Berg and J. Tipker

Table 5. Inhibition of the reduction of hexacyanoferrdte(lI1) (Hill reaction) and the herbicidal effects of a series of substituted I , 1 -dimethyl-3-(4-phenoxyphenyl) ureas

Number

28 29 30 31 32 33 34 35 36 31 38 39 40

Compound

R 7r

H 4-CI 4-0-CHs 4-CH3 4-NOa 4-CF3 4-SOz-CH3 2,4-Clz 3,4-CIa

2-CN; 3-C1 2,4,5-C13

2,6-(CH&

2,6-(NO&; 4-CF3

0.00 0.74 0.05 0.51

I .08

1.48 I .48 I .02 0.37 2.22 0.52

-0.28

- I .67

PISO“ ~~

Calculated

Equation Equation - ~

Observed 5 6 ~.~ ~~~ ~

6.18 6.24 6.34 6.76 6.86 6.74 6.52 6.28 6.38

6.67 6.64 6.71 6.00 6.01 6.14 7.09 7.14 6.86 4.80 4.85 4.75 6.97 6.95 7.16 6.95 6.36 6.84 6.44 6.57 6.87 6.97 6.92 6.64

< 4

< 4

6.81

oio

fl Iso is the molar concentration causing 5 0 % inhibition; pIso= -log Isa, b Defined in section 2.3.

3.3. Quantitative structure-activity relationships The inhibition data were analysed using the Hansch a p ~ r 0 a c h . l ~ The parameters used in the final equations are listed in the corresponding tables. In all cases, the lipophilicity appeared the most important parameter and sometimes the relationship was quadratic. Electronic effects were never very important.

For the para-substituted derivatives of Table 2, equation 1 was derived: pI50 = 4.440+ 0 . 5 5 9 ~ - 0.120~‘

(16.844) (-4.533) n = l l rz0.985 F=145.33 s=0.117

whereas equation 2 was obtained for all compounds of Table 2: PISO= 4.340 + 0 . 5 1 2 ~ - 0 . 0 7 1 ~ ~

(1 3.623) (- 3.279) ~ = 1 8 r=0.965 F=107.64 s=0.159


Table 6. Inhibition of the reduction of hexacyanoferrate(Il1) (Hill reaction) and the herbicidal effects of some analogues of nitrofen

"1

Compound

Number X p150a Herbicide score6 ~ .-

4.92 616 12 -0.- 43 -NH-- < 4 . 0 010 44 -0-CHz- < 4 . 0 010 45 -O-CH(CHa)- 4.94 010

~~ ~

150 is the molar concentration causing 50% inhibition; pI50= -log 150.

* Defined in section 2.3.

The number of compounds in Table 3 was too small to be analysed in this way. From Table 4 it can be concluded that substitution into the nitrophenyl ring always lowered activity. This points to a steric effect. However, using the steric E, parameter of Taft, a good correlation could not be found (r=0.831), whereas the use of the Sterimol B~parameter was more successful, see equation 3:

PISO 7 5.107 - 0.239B4 (- 7.999)

n=7 ~=0.928 F=63.98 s=0.084

Combining the data of Tables 2 and 4 yielded equation 4:

PISO = 4.594 + 0.507~~ - 0.070~~' - 0.259B4 (X) (1 5 .099) ( - 3 .57 1) ( - 8.486)

n=24 r=0.961 F=92.01 s=0.140

(3)

(4)

The activities of the 3-[4-(para-substituted-phenoxy)phenyl]-l,l-dimethylureas (Table 5) were dependent only on T (equation 5), whereas for the whole series, a r2 term must be added to obtain a good equation (equation 6):

p150= 6.243 + 0.831~ ( 5 ) (14.746)

n=7 r=0.989 F=217.44 s=O.124

p150= 6.34+0.664~- 0.173~' (9.068) (- 3.578)

n=13 r=0.939 F=41.11 ~=0.236

3.4. Herbicide effects All compounds were tested as post-emergence herbicides as described in section 2.3 ; the results are given in Tables 2-5. The effect of light on herbicidal activity was studied for compounds 1, 2, 12 and 26 only. The chemicals were sprayed on 10-day-old bean plants (Phaseolus vulgaris) at various rates. Two plants of each treatment were kept in darkness, and two others in the light, for 48 h; herbicidal effects were then recorded, and again after the following 5 days of light exposure.

36 G . van den Berg and J. Tipker

Table 7. Light activation of some substituted diphenyl ether herbicides

Herbicidal effect after 48 h"

- ~~~~~~ Dose Compound (kg ha-') Light Dark

1 5 + (++ ) f (+) 2 5 * (f) -

12 0 . 5 + + (++) - (++) 26 0.05 + + (++) - (+)

" Scoring: (-) no damage; (+) slight damage; (+) severe

The scoring in parentheses are the effects after the following damage: (+ +) dead.

5 days of exposure to light.

Results are presented in Table 7. Compounds 21 and 35 were also included in these tests, but because they are slow-acting herbicides, no damage was observed after a week.

4. Discussion

Table 1 shows that nitrofen is an inhibitor of non-cyclic electron transport whereas photosystem I (TMPD-t MV) and cyclic phosphorylation (PMS-catalysed) are not affected. This is in good agree- ment with previous studies.7.8 The activities of nitrofen and five derivatives are also compared in Table 1. The compounds exhibited almost similar PI50 values for inhibition of basal (pH 8.0) and coupled electron transport and corresponding phosphorylation, indicating a primary effect on non-cyclic electron transport only. Uncoupled electron transport was inhibited somewhat less, which was also reported by Bohn and Rieck for related diphenyl ethers.17 None of the chemicals was able to produce inhibition of photosystem 1 activity or cyclic phosphorylation at comparable concentrations. These latter features have also been reported for other diphenyl ether^.^-^, 11, l7 As shown in Figure 1, the effects of nitrofen on electron transport could be modified dramatically by changing the pH value. Lack of inhibition at lower pH values seemed typical of nitrofen analogues, although DCMU and compound 35 showed less inhibition at lower pH values as well (Table 1). The exact site of action of these substituted diphenyl ethers was not clear. However, because the inhibition of the FeCy reduction by compounds 1, 2, 12, 21 and 26 could be partially reversed by catalytic amounts of PD, it may be concluded that these chemicals inhibit at the plastoquinone region rather than at the DCMU site, as has been suggested b e f ~ r e . ~ Similar results have been presented by Trebst et al. for dinitrophenyl ethers of bromo- and iodothymol.11 Moreover, Bugg et al. and Trebst et al. demonstrated the same inhibition site, for chemicals closely related to nitrofen and diclofop-methyl, by using different artificial electron donors and acceptors8 or by studying the replacement of [Wlmetribuzin from its binding site on the thylakoid membrane.18 This means that different groups of substituted diphenyl ethers, probably including the chemicals listed in Tables 2 4 , N-alkylated-nitroanilines and the well-known inhibitor DBIMB, all inhibit at a site close to plastoquinone and clearly distinct from the DCMU site. On the other hand, the inhibition of MV reduction by the chemicals of Table 1 could not be reversed by TMPD alone, as has been reported for DBIMB,IS which suggests that the substituted diphenyl ether site and the DBIMB site of inhibition were not completely identical.

Because the inhibition of the FeCy reduction by compound 35 could not be reversed by PD, the site of action of the chemicals of Table 5 was probably identical to the DCMU site, rather than the nitrofen site. Further evidence for this distinction will be presented later. Inhibitory activities were successfully correlated with physicochemical parameters. In most cases, n appeared the most important parameter (equations 1 , 2 and 46) . This is not surprising because a relationship between


the inhibition of photosynthesis and lipophilicity has also been reported for other series, such as carbamates, ureas, acylanilides, triazines, aminotriazinones, pyrimidinones and benzimidazoles (see review in reference 12). In equations I , 2 ,4 and 6, a n2 term appeared significant. This has been reported in only a few other cases, but because the chemicals used in the present study were much more lipophilic than those described in the literature, the maximum inhibitory activity will already be reached after a moderate increase in lipophilicity. Electronic parameters proved not to be important in this present series of substituted diphenyl ethers. However, they did play a part in some other series mentioned earlier. In those cases, the substituents were always introduced into the ring that also carried the ureido, carbamate or other important -NH- structure; therefore, electron-withdrawing groups may produce a direct effect on, for example, -NH- acidity. In the chloroxuron series, on the other hand, the substituents were too far away from the --NH- group to exert any electronic effect. In the substituted 4-nitrophenyl phenyl ether series, however, the increase of lipophilicity was only favourable when the substituents were not introduced into the nitro-carrying ring (Table 4). Each substituent in this ring, regardless of its lipophilic or electronic character, had a negative effect on activity. This phenomenon can be described excellently in terms of the Sterimol B4 parameter, indicating that the width of the substituent rather than its length is of consequence (equation 3). Although the activities of Table 3 cannot be analysed quantitatively, they are not governed by lipophilicity only. The poor activity of compound 21 is in good agree- ment with results reported for diclofop-methyl and the closely related compound trifop-methyl (HOE 29 152).s,1s As already mentioned in section 3.2, compounds 32 and 35 of Table 5 could equally have been presented in Tables 2 and 3, respectively. The activity of compound 32 can also be calculated by means of equation 1 to give a value of 4.59 instead of 6.00, which is 25 times too low. Likewise, compound 35 is an outsider in Table 3. Probably the introduction of a 3,3-dimethylureido substituent into a diphenyl ether structure produces a greater increase in activity than is predicted by the equations. This discrepancy points to a difference in the mode of action between the compounds of Tables 2-4, on the one hand, and the compounds of Table 5 on the other.

In order to compare the series of Tables 2 and 5 more precisely, the T values were changed into calculated log P values (P is the octan-1-ol/water partition coefficient). By means of data published by Hansch and Leo,15 log P values were calculated for compounds 1 and 28 as follows:

log P (compound 1) =log P (diphenyl ether) + T (NO4

=4.20-0.28=3.92

log P (compound 28)= log P (diphenyl ether) + T [NH--CO-N(CH&]

=4.20-0.61=3.59

or =log P (DCMU) - 24C1) + n (phenoxy)

For compound 1, the calculated value was used, and for compound 28, the mean value of 3.48. All other log P values were derived from these two by using T values. Equations 2 and 6 were trans- formed into equations 7 and 8, respectively:

pI~jo=l.24+1.07logP-O.O7(logP)~ (7)

pI50=1.91+1.87 log P-O.I7(logP)2 (8)

and these were plotted in Figure 2. From Figure 2 it can be concluded that a 3-(4-aryloxyphenyl)-l,l-dimethylurea is about 100

times more active than a nitrophenyl phenyl ether having the same lipophilicity. In addition, DCMU is more active than expected (the calculated value for DCMU is 5.75 instead of 6.81). The clear distinction found between the series of Tables 2 and 5 (equations 7 and 8 in Figure 2) may point to different sites of action, as has been described earlier.

Table 6 shows some strange phenomena. Replacing the ethereal oxygen bridge with a nitiogen


bridge abolished activity, whereas the steric configuration is similar in both cases. The introduction of a methylene group between the ring and the oxygen causes a considerable change in configuration; both rings become parallel. The only difference between compounds 44 and 45 is that in the latter, the rings are firmly fixed, whereas in 44, they are free to rotate. However, the difference in activity is difficult to understand. At first the structure was suspected but mass spectrometric measurements showed the proposed structures to be correct.

Any correlation between post-emergence herbicidal activity and inhibition of photosynthesis is far from clear (see Tables 2-5). Roughly, it can be concluded that weak inhibitors of the Hill reaction are weak herbicides, but that strong photosynthesis inhibitors are not necessarily always good herbicides. The same discrepancy has been reported many times for other series (see for example reference 20). It is probable that bioavailability governed by uptake, translocation, solubility and metabolism are responsible for these differences.

One phenomenon that is the most difficult to explain is the variation in activity between the nitrofen isomers (compounds 12-16) and between the 3-(dichlorophenoxyphenyl)-l , 1-dimethylureas (compounds 35 and 36). Regarding inhibition of photosynthesis the isomers are comparable but only a few have good herbicidal activities. The compounds listed in Table 4 are usually strong herbicides but only moderate Hill inhibitors. Although the herbicidal effect of some compounds is light-dependent (Table 7), many authors doubt if inhibition of photosynthesis is the underlying mechanism for nitrophenyl phenyl ethers.2, 5 , Disruption of membranes by some light-dependent process seems more likely. Further experiments are necessary to elucidate the role of light in the herbicidal effects of these compounds.

Acknowledgements The authors are indebted to Dr G . B. Paerels and his staff, who prepared the test chemicals, and to Miss Letteke van Dorsser for skilful technical assistance.

References I .

2. 3. 4.

5. 6. 7. 8. 9.

10.

11. 12.

13. 14.

15.

16.

17. 18. 19. 20.

Cheniie der PJanzenschutz and Schadlingsbekampfungsrnittel Vol. 5, Herbizide (Wegler, R., Ed.), Springer Verlag, Berlin, 1977, pp. 73-76. Matsunaka, S . Residue Rev. 1969, 25, 4548. Matsunaka, S. J. Food Agric. Chem. 1969, 17, 171-175. Matsunaka, S . Herbicides, Chemistry, Degradation and Mode of Action Vol. 2 (Kearney, P. C.; Kaufman, D. D., Eds), Marcel Dekker Inc., New York, 1976, pp. 709-739. Fadayomi, 0.; Warren, G. F. Weed Sci. 1976, 24, 598-600. Vanstone, D. E.; Stobbe, E. H. Weed Sci. 1979, 27, 88-91. Moreland, D. E.; Blackmon, W. J.; Todd, H. G.; Farmer, F. S. Weed Sci. 1970, 18, 636-642. Bugg, M. W.; Whitmarsh, J.; Rieck, C. E.; Cohen, W. S. Plant Physiol. 1980, 65, 47-50. Lambert, R.; Kunert, K. J.; Boger, P. Pestic. Biochem. Physiol. 1979, 11, 267-274. Moreland, D. E. Progress in Photosynthesis Research Vol. 111 (Metzner, H., Ed.), H. Laupp, Tiibingen, 1969, pp. 1693-1711. Trebst, A,; Wietoska, H.; Draber, W.; Knops, H. J. Z. Naturforsch. C . Biosci. 1978, 33, 919-927. Trebst, A,; Draber, W. Advances in Pesticide Science (Geissbiihler, H.; Brooks, G. T.; Kearney, P. C., Eds), Pergamon Press, Oxford, 1979, pp. 223-234. Bruinsma, J. Photochem. Photobiol. 1963, 2, 241-249. Lamprecht, W.; Trautschold, I. Methods of Enzymatic Analysis Vol. 4 (Bergmeyer, H. U., Ed.), Academic Press, 1974, pp. 2101-2110. Hansch, C.; Leo, A. 5. Substituent Constants for Correlation Analysis in Chemistry and Biology J. Wiley, New York, 1979. Verloop, A.; Hoogenstraaten, W.; Tipker, J. Drug Design Vol. 7 (Ariens, E. I., Ed.), Academic Press, 1976,

Bohn, J. A.; Rieck, C. E. Proc. South. Weed Sci. Soc. 1979, 32, 323. Trebst, A. Z. Naturforsch. C . Biosci. 1979, 34, 986-991. Trebst, A,; Reimer, S . Z. Naturforsch. C . Biosci. 1973, 28, 710-716. Brugnoni, G. P.; Moser, P.; Trebst, A. Z. Naturforsch. C. Biosci. 1979, 34, 1028-1031.

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