Vd. 17 No. 6 CHINESE JOURNAL OF CHEMBTRY 1999

Design, synthesis and bioactivity of novel herbicides targeted ALS (VII) : Quantitative structure-

activity relationships of herbicidal sulfonylureas

YANG, Guang-Fu * ( $$ % ) YANG, Hua-Zheng'( ~ @) a Institute of Organic Synthsir, central China N o d University, W h , Hubei 430079, China

Institcue of EhentuOrganic Chemistry, Nankai Uniyersity , Tiarjin 300071, China

Absbrad The quantitative mlationship between the structures of 20 sulfonylureas and their herbicidal activi- ties against rape was analyzed using physicochemical parameters and regression analysis. ?he results showed that the electronic properties of the molecules are the dominant factor to the activity and there is apparently an opti- mum electmnic property (2 or pKa) for the molecules to fit the receptor. Combined with the previow QSAR results for herbicidal triiazolopyrimidine2-~ulfonamides, we can conclude that the shuctm~activity relationships of these two sets of compounds are identical, which suggested that these two sets of compounds acted on the same

target site.

Keywords -4LS inhibitors, QSAR, sulfonylureas, herbicides

Introduction

Inhibition of essential amino acid biosynthesis in plants is one of the most prominent and attractive principles of herbicidal action. Acetolactate synthase ( ALS, EC 4 . 1 . 3 .18 ) , the first common enzyme in the biosynthetic route to the branched cham amino acids, valine , leucine and isoleucine, has been i- dentlfied as the target of action of seved structurally distinct classes of compounds with high herbicidal activity, such as sulfonylureas , sulfonamides , imidazolinones and pyrimidylsalicylates . These four classes of herbicides were all obtained by traditional screening methods and have been developed as new weapons in the weed control. The attributes of low application rates, good crop selectivity, environmental safety and compatibility with the trend towards postemergence weed control exhlbited by these compounds are of important characteristics for modem agnxhemicals, which led to the rapid success of ALS inhibitors as herbicidal products and attracted a world-wide research commitment.

Sulfonylureas and fused hetemyclic sulfonamides are the most important two kinds of ALS in- hibitoxs. Sulfonylurea herbicides were first discovered by Levitt at DuPont.' Fused heterocyclic sulfon- amides were discovered by Kleschick at Dow , which was the product of a research effort initially aimed at preparing bioiscsteric analogues of sulfonylureas . In previous papers, 3-5 we investigated the spatial distri-

1

Received January 4 , 1999; accepted May 14, 1999.

Project (No. 29802002) supported by the National Natural Science Foundation of China.

YANG & YANG Herbicidal sulfonylureas 65 1

bution of benzene rings and fused heterocycle moieties relative to the sulfonyl moieties of these two set of compounds using X-ray diffraction analysis and quantum chemistry methods and perfonned a quantitative structure-activity relationship ( QSAR) analysis for triazolopyrimidine-2-sulfonamide herbicides. For the purpose of further understanding the molecular mechanism of action of these two kinds of herbicides, a quantitative analysis was canied out in this paper for 20 sulfonylureas using physicochemical substituent parameters and regression analysis.

Materials and methods

compounds

The compounds studied in this paper are listed in Table 1, which were designed and synthesized ac- cording to the conventional m e t h d so as to cover the potential range as widely as p i b l e . All com-

pounds were purified by repeated recrystallization and their chemical structures were conhned by ‘H NMR spectra and elemental analyses.

X

The herbicidal activities of the compounds against rape was measured as described previously’l in t e r n of I&, the molar concentration required to inhibit root elongation to half that of the control. The I& measurements were repeated at least twice. The PIS value averaged over repeats, the standard devia- tion being symbol * 0.20, was used for the analyses. The PIS values of the compounds am listed in Table 1.

Hammett ’ s electronic parametem (6, , op + or op-) were taken fmm literature6 to represent the elec- tronic pmperties of suhtituents. 0, was used to represent electron-withdmwing effect f h m the substituents on pyrimidinyl moiety and mtu-substituents on the benzene ring3. op + or op- was used for the electmn- withdrawing and electron-donating substituent at para-position of the benzene ring, respectivity. As for ortho substituents, op of the corresponding para substituents is taken as the constant. Fo* is the Swain- Lupton-Hansch7 field-effect mnstant of ortho substituents to delineate the “proximity” electronic effect overlapping the “ordinary” effect repmsented by ap .

The determination of hydrophobicity parametem ( logP) of the compounds is inconvenient due to their weak-acidity. So, the hydrophobic parameter ( x ) was taken directly from literature.6 Furthermore,

652 Chinese Journal of Chemistry Vol. 17 No. 6 1999

we also estimated the ClogP value of all compounds by the ClogP program on the SGI workstation and obtained the logK (capacity factors) values of HPLC (pH = 4.49, KH2F'04-Na2HP0,)8 to reflect the whole hydrophobicity of molecules. AU substituent parameters used are listed in Table 1.

Table 1 Structure, herbicidal activity and physicochemical parameters of sulfonylurea compounds

Compound R, x Y z PIX, Electronic parameters Hydrophobic parameters O M . ca F pK, CX ClagP logK

1 2 3

4 5

6 7

8

9

10

11

12 13 14 15

16

17

18

19

2-COOMe CH3 OCH3 2-COOMe C H 3 CH3 2-COOMe OCH3 OCH3 2-COOE! C H 3 C H 3 2-COOEt OCH, OCH3

2-c1 CH3 cH3 2-NC4 C H 3 H

H CH3 a 3

2-COOEt Cl c1

2-NC4 CH3 CH3 3-C1 Cl OCH, 3-c1 CH3 CHH,

4-CH3 O C H 3 C H 3

4CH3 OCH3 O C H 3

4-CH3 CH3 CH3 H OCH3 OCH3

H OCH3 c1 2-COOEt OCH3 Cl 2-COOMe a 3 H

N CH CH CH CH CH CH CH CH CH CH CH N

CH CH CH CH CH CH

8.24 8.11 8.28 8.24 8.53 7.10 8.10 8.30 7.49 8.37 7.20 7.17 6.23 7.84 6.03 8.10 7.15 7.47 8.20

0.50 0.33 0.31 0.33 0.69 0.33 0.31 0.33 0.69 0.33 1.19 0.33 0.09 0.41 0.71 0.67 -0.14 0 0.64 0.67 0.86 0 0.23 0 -0.26 0 -0.07 0 -0.45 0 0.24 0 0.49 0 0.94 0.33 0.38 0.33

5.86 6.94 6.75 7.00 6.97 4.98 7.24 5.59 6.91 6.01 5.65 6.85 7.19 7.21 7.12 6.90 6.27 6.20 6.68

0.53 1.80 1.11 2.31

-0.05 2.69 1.63 2.84 0.47 3.22 1.93 3.19 1.83 2.65 0.28 1.41 1.12 2.32 0.84 1.91 1.40 3.59 1.83 3.05 1.10 2.32 0.52 3.20 1.68 2.82

-0.04 2.71 0.69 2.88 1.20 3.38 0.55 1.82

0.36 0.14 0.66 0.43 0.95 0.26 0.29 - 0.53 0.16 -0.11 0.56 0.91 0.48 0.97 -0.85

0.67 0.38 0.69

-0.16 - 20 2-Cl CH3 OCH3 N 7.88 0.28 0.41 5.97 1.25 2.14 -0.14

Determination of p K ,

The pK, values of all compounds were determined by potentiometric titrations in aqueous dimethyl

sulfoxide (80% wt/wt) according to the literature method.g It was reported that relative acidities in this solvent system are consistent with those obtained in water.' So, the pK, values obtained are suitable for QSAR analyses.

YANG & YANG Herbicidal sulfonylureas 653

Results and discussion

Variations in the herbicidal activity of 20 sulfonylm compounds were analyzed using the physico- chemical parameters listed in Table 1 giving

pIm = 7.6049 + 1.498720 - 1.7562(20)~ - 0.25042~ + 1.3336F (1) (0.0778) (0.4134) (0.4379) (0.1448) (0.4254)

n=U), r=0.8987, s=O.3481, F=15.74

with the best comlation. The development of this equation and the intemmlation of variables are shown in Tables 2 and 3, respectively. In this and the following equations, n is the number of compounds, r is the correlation coefficient, and s is the standad derivation. The figures in parentheses under each coefli- cient axe the 95% confidence intervals of the regression coefficient. Eq. ( 1) indicates that electronic factors are the most important physical property in determining herbicidal activity. The negative cueflicient of (%)2 tern indicates that variations in the activity are parabolicdy rehed with the electronic parame- ters. The optimum Sa value in Eq . ( 1 ) is about 0.50. Besides, from Table 2 we can find that introduc- tion of F tern led to a small but sifiicant improvement in the comlation, suggesting that the ortho sub- stituent binding site is electronic in natwe. The positive coefficient of F term indicates the desirability of proximity inductive effect of electron-withdrawing ortho substituents. Replacement of ZK by another hy- drophobic parameter for the whole molecule, ClogP , yielded a similar comlation equation, Eq . ( 2) , although it is significant only at a level of 93% as examined by the F test.

PI% = 6.8218 + 1.6985% - 2.1756( 2 0 ) ~ + 0.1926CZogP + 1.6901F (2) (0.0831) (0.4160) (0.4390) (0.2167) (0.6281 )

n = 2 0 , r=0.8836, s=O.3716, F=13.357

Eq. ( 2 ) indicates that it is practicable to use ClogP to reflect the hydrophobicity for the whole molecule of sulfonylurea compounds. In Table 4 , the pIm calculated from Eqs . ( 1) and (2) is compared with the observed value. Using the whole molecular parameters p K , and logK as variables, variations in the herbicidal activity were analyzed giving

pIm = - 9.6624 + 5.1056pKa - 0 . 3 9 0 4 ( ~ K , ) ~ - 0.6257ZogK + 2.6671F (3) (0.1011) (3.2771) (0.2618) (0.2315) (0.5371)

n =20, r=0.8219, s =0.4521, F=7.8080

Table 2 Development of QSAR of E+. (1)

Intercept zs (W 23r F S r F-test 7.4533 0.6505 0.6686 0.3852 3.16 7.5508 2.3479 -2.3941 0.4420 0.8053 15.68 7.7849 2.1032 -2.1057 -0.2321 0.4336 0.8255 11.41 7.6049 1.4987 -1.7562 - 0 . m 1.3336 0.3481 0.8987 15.74

- 654 chmese Joumal of Chemistry Vol. 17 No. 6 1999

Table 3 Correlation matrix for variables used to derive Eq. ( 1 )

% (%a)2 cx F

i&l2 0.6688 LT 0.0139 F 0.2443

1 .Ooo 0. 0214 0.0746

1 .ooo 0.0153 1 .ooo

Table 4 QSAR results of sulfonylurea herbicide

Compound pIs0 pIdCalcd. 1 O M . Ea. (1) 6' Ea. (2) 6 Ea. (3) 6

1 8.24 8.22 0.02 8.03 0.21 7.95 0.29 2 8.11 8 .M 0.05 8.14 - 0.03 7.93 0.18 3 8.28 8.26 0.02 8.03 0.25 8.30 -0.02 4 5

6 7 8

9

10 11

12 l3 14

8.24 8.53 7.10 8.10 8.30 7.49 8.37 7.20 7.17 6.23 7.84

7.93 8.13 6.86 7.81 8.61 7.08 8.53 7.24 7.40 6.82 7.36

0.31 0.40 0.24 0.29

- 0.31 0.41

- 0.16 - 0.04 - 0.23 -0.59 0.48

8.24 8.14 6.93 8.16 8.33 6.99 8.52 7.36 7.68 6.68 7.31

0 0.39 0.16

- 0.06 - 0.03 0.50

- 0.15 - 0.16 - 0.51 - 0.45

0.53

8.09 8.43 7.12 8.11 8.13 7.07 8.64 7.07 7.56 7.16 7.46

0.15 0.10

- 0.02 - 0.01

0.17 0.42

-0.27 0.13 0.36

-0.93 0.38

15 6.03 6.15 - 0.12 6.16 -0.13 6.36 -0.33 16 8.10 7.87 0.23 7.63 0.47 7.39 0.71 17 7.15 7.74 -0.59 7.69 - 0.54 7.24 -0.09 18 7.47 7.60 - 0.13 7.70 - 0.23 8.30 -0.83 19 8.20 8.22 -0.02 8.06 0.14 7.80 0.40 20 7.88 8.12 -0.24 8.23 - 0.35 7.91 -0.03

* 6=(pI,)dd -(pIY))crld.

The development of h s equation and the intercomlation of variables are shown in Tables 5 and 6, respectively. Eq. (3) indicates that the herbicidal activity is parabolically dependent on pK, values of the compounds with the ,optimum p K , value being about 6.54.

Table 5 Development of QSAR of Fiq. (3)

Intercept PK. (pK.)* l%K F S r F-test

8.0847 -0.0588 0.7234 0.0543 0.05 - 14.0687 7.0932 -0.5704 0.7041 0.3283 1.03 - 14.0722 7.1184 -0.5762 0.2809 0.7114 0.3795 0.89 -9.6624 5.1056 -0.3904 0.62S7 2.6671 0.4521 0.8219 7.81

YANG & YANG Herbicidal sulfonylureas 655

Table 6 Cordation &for variable used to derive Eq. (3) P K (pKJZ logK F

(pK,)* 0.9976 1 .Ooo logK 0.0508 0.0510 1 .Ooo

F 0.1652 0.17oO 0.1290 1 .Ooo

In the previous paper,5 we p e r f o d a QSAR analysis for 16 herbicidal triazolopyrimidine-2-sulfon- amides and found that the substituents also made to modulating the pK, value and the hydrophobicity of the compounds. The activity is also parabolically dependent on the pK, value of compounds, the optimum being about 6.93. So, combined the QSAR analyses herein with the previous results,5 we can conclude that the structure-activity relationships between sulfonylureas and sulfonamides are very similar. Thus, we extented the analysis to include 20 sulfonylureas and 16 triazolopyrimidine-2-sulfonamides and obtained the following equation

PIS = 6.0102 + 0.8392% - 0.8191(%)2 + 2.7357F - 0.4579% + 1.41791 (0.1026) (0.5203) (0.5387) (0.4833) (0.1792) (0.2129)

(4)

n=36, r=0.8!948, s=0.6159, F=24.1066

with the best correlation. ?he development of this equation is given in Table 7 and the correlation of vari- ables in Table 8. 1 is an indicator variable assigned to be 1 for sulfonylurea compounds, but which is ze- ro for sulfommide compounds. The coefficient of the 1 tern means that the sulfonylurea compounds have an much stronger activity than sulfonamide compounds with the same electronic and hydrophobic sub- stituents. Q. 4 indicates that the optimum % is 0.51, which is almost equivalent to those of sulfony- lureas and sulfonamides.

Table 7 Development of QSAR of Eq. (4) Intempt 2 (2aY F 2rc I S r F-test 6.6082 1.1802 1.1951 0.3871 5.99 6.6670 2.6069 -1.9061 1.1460 0.4910 5.24 6.2700 1.1877 -0.9598 2.8787 0.9641 0.6922 9.82 6.5819 1.2490 -0.9930 2.9526 -0.3599 0.9538 0.7115 7.94 6.0102 0.8392 -0.8191 2.7357 -0.4579 1.4179 0.6159 0.8948 24.11

TaMe 8 correlation mahix for variable used to derive Eq. (4) % (%a)* F % I

(%)2 0.7057 1 .Ooo

F 0.1725 0.0416 1 .ooo ZiT 0.0116 3.71 x lU3 0.0156 1 .ooo

I 0.0416 0.0172 0.0279 0.0122 1 .Ooo

656 Chinese J o d of Chemistry Vol. 17 No. 6 1999

Table 9 DeveloDment of OSAR of Eq. (5)

Intercept pK, ( p K J 2 Cl@ F I S r F-test 11.2926 -0.6201 1.1987 0.5304 13.31 -0.0653 2.6529 -0.2303 1.0605 0.5918 8.89 -1.4852 3.7853 -0.3033 -1.0540 0.9148 0.7287 12.08 -2.0057 3.3509 -0.2609 -0.6691 1.9633 0.8336 0.7892 12.80 2.4648 1.3219 -0.0976 -0.3807 2.4678 1.2101 0.6723 0.8732 19.27

Table 10 Correlation matrix for variables used to derive Eq. (5)

PK, (pK,)* Cl%P F I (pK,)* 0.9913 1 .Ooo C l O g P 0.0340 0. M76 1 .ooo

F 0.2067 0.2089 0.2175 1 .Ooo

I 0.2245 0.2528 0.0321 0.0279 1 .Ooo

Table 11 OSAR results of sulfonylurea and sulfonamide compounds

1 8.24 2 8.11 3 8.28 4 8.24 5 8.53 6 7.10 7 8.10 8 8.30 9 7.49 10 8.37 11 7.20 U 7.17 13 6.23 14 7.84 15 6.03 16 8.10 17 7.15 18 7.47

8.30 8.00 8.54 7.77 8.30 7.29 7.78 9.32 6.78 9.08 6.90 6.74 6.69 7.13 6.20 7.60 7.33 7.85

-0.06 8.20 0.11 8.08 -0.26 7.94 0.47 7.88 0.23 7.73 -0.19 7.44 0.32 8.13 -1.02 9.13 0.71 7.26 -0.71 9.02 0.30 6.66 0.43 6.99 -0.46 7.25 0.71 6.91 -0.17 7.06 0.50 7.12 -0.18 7.03 -0.38 7.65

0.04 0.03 0.34 0.36 0.80 - 0.34 - 0.03 - 0.83 0.23 - 0.65 0.54 0.18 - 1.02 0.93 1.03 0.98 0.12

19 8.20 20 7.88 21' 6.16 22 6.28 23 7.27 24 6.45 25 5.98 26 5.18 n 4.48 28 8.06 29 6.09 30 4.69 31 6.29 32 7.44 33 5.31 34 8.23 35 3.98

8.28 8.15 5.58 6.01 6.85 5.79 5.74 5.29 5.70 7.62 6.41 5.47 5.57 6.73 5.59 7.60 5.41

- 0.08 -0.27 0.58 0.27 0.42 0.66 0.24 - 0.11 - 1.22 0.44 - 0.32 - 0.78 0.72 0.71 - 0.28 0.64 - 1.43

8.27 8.25 5.57 5.71 6.% 5.71 5.43 5.33 5.56 7.60 6.21 5.33 5.76 6.99 5.66 7.92 5.51

0.07 - 0.40 0.59 0.57 0.30 0.74 0.55 - 0.15 - 1.08 0.46 - 0.12 - 0.64 0.53 0.45 -0.35 0.31 - 1.53

-0.18 36 4.98 5.49 -0.51 5.61 -0.64

a Compounds 21-36 are triiazol0pyrimidine-2-sulf0namide derivertives taken from previous paper.'

Furthemre, variations in the herbicidal activity were analyzed using pK, and ClogP as variables

giving

YANG & YANG Herbicidal sulfonylureas 657

PI% = 2.4648 + 1.3219pKa - 0.0976(~K,)~ - 0.3807ClogP + 2.4678F + 1.21011 ( 5 ) (0.1120) (1.2442) (0.0894) (0.2571) (0.5889) (0.2880)

n = 36, r = 0.8732, s = 0.6723 , F = 19.27

The development of &. ( 5 ) and the intemmlation of variables are shown in Tables 9 and 10, re- spectively. Eq. ( 5 ) indicates that variations in the herbicidal activity of the two sets of compounds are parabolically related with the pK, value. The optimum pK, value in Eq. ( 5 ) is about 6.77, which is i- dentical to that of sulfonylureas and sulfonamides. The herbicidal activities calculated by E q . (4 ) and Eq. (5) are listed in Table 11.

conclusion

In summary, QSAR analyses revealed that the structure-activity relationships of sulfonylureas and sulfonamides are identical, suggesting that this two set of compounds act on the same site on the receptor. The electronic pmperties were dominant factors on determining herbicidal activity of the two set of com- pounds. Hydrophobicity is also important. There is a p p n t l y an optimum electronic pmpeq, 2.0 or pK, , for these molecules to fit the receptor. 'Ihe effect of the ortho-substituent on the benzene rings of

the two set of compounds is significant in the binding with the site of action.

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(SONG, J . P . ; LING, J . )