Contribution of Quantitative Agrochemical Design Strategies to

Chapter 11

Contribution of Quantitative Agrochemical Design Strategies to Mechanism-of-Action Studies

Downloaded by UNIV OF MICHIGAN ANN ARBOR on February 18, 2015 | http://pubs.acs.org Publication Date: November 14, 1989 | doi: 10.1021/bk-1989-0413.ch011

E. L. Plummer, J. A. Dixson, and R. M. Kral Agricultural Chemical Group, FMC Corporation, P.O. Box 8, Princeton, NJ 08543

The context provided by quantitative design strategies offers many benefits towards improving the efficiency of agrochemical discovery programs. Amongst these are an understanding of mechanism of action and the factors, other than active-site interactions, that govern the efficacy of agrochemicals. Two areas of insecticide chemistry, where the mechanism of action is poorly understood, are pyrethroids and benzoylurea insect development disrupters (IDDs). The QSAR approach has been used to provide an insight into the active-site requirements for these compounds. From a knowledge of the active-site structure a greater understanding of the exact mechanism of action can be obtained. In addition, once the mechanism is better understood, mechanism based intrinsic assays can be designed to separate active-site interactions from factors of transport and metabolism. The value of such mechanism based intrinsic assays will also be discussed particularly with regard to the IDDs. The application of the strategies that have evolved from the QSAR paradigm offer many benefits to their practitioners which in total lead to higher efficiency in the design process. To many, the primary goal of QSAR strategies is to develop rules that will efficiently lead to the most active compound in a series. Clearly this is not the only benefit. In providing a context within which one can understand chemical structure-activity relationships these strategies also allow one to recognize compounds that fail to fit the rules, i.e. outliers, and thus form the basis for new leads. Molecular modeling programs are strengthened by the selection of compounds to effectively represent the factors important to activity, by previous development of quantitative rules and by the use of standard QSAR strategies for validation of their often subjective results. Together these tools might be used to generate new lead molecules having significantly different connectivity but 0097-6156/89/0413-O157$06.00/0 © 1989 American Chemical Society

In Probing Bioactive Mechanisms; Magee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.


158

PROBING BIOACTIVE MECHANISMS

m a i n t a i n i n g the b i o l o g i c a l a c t i v i t y o f the compound u s e d t o d e v e l o p the model. Today's most c h a l l e n g i n g g o a l f o r p e s t i c i d e d e s i g n p r o j e c t s i s the development o f s e l e c t i v i t y : compounds t o c o n t r o l h a r m f u l i n s e c t s w h i l e s p a r i n g man and o t h e r n o n - t a r g e t organisms o r h e r b i c i d e s t h a t c o n t r o l weeds w i t h o u t damaging c r o p s . A r t based a p p r o a c h e s t o t h a t g o a l have been o n l y m o d e r a t e l y s u c c e s s f u l . An a l t e r n a t i v e i s to d e v e l o p q u a n t i t a t i v e models f o r t a r g e t and nont a r g e t and t h e n t o seek d i f f e r e n c e s i n t h e s e models w h i c h can be exploited for selectivity. As a p l a n n i n g t o o l QSAR can improve the o v e r a l l management o f design projects. Perhaps the s i n g l e most i m p o r t a n t outcome o f the s t r a t e g y i s the a b i l i t y to know when a p r o j e c t i s complete, t o u n d e r s t a n d when one more compound w i l l n o t l e a d to the e l u s i v e commercial compound. O f t e n the b e s t compound i s among the f i r s t made i n a p r o j e c t . Thousands o f a d d i t i o n a l compounds p r o v i d e no improvement. I f a p r o j e c t i s w e l l d e s i g n e d and c a r r i e d out s i g n i f i c a n t s a v i n g s i n r e s o u r c e s can be r e a l i z e d F i n a l l y the c o n t e x t o f s t r u c t u r e a c t i v i t y r e l a t i o n s h i p s t h a t e x i s t s as the r e s u l t o f a p p l y i n g good e x p e r i m e n t a l d e s i g n s t r a t e g i e s can a l s o p r o v i d e i n f o r m a t i o n v i t a l t o u n d e r s t a n d i n g the mode o f a c t i o n o f a compound. A t the v e r y l e a s t i t can p r o v i d e c l u e s to u n d e r s t a n d i n g f a c t o r s t h a t i n f l u e n c e the compound's b i o l o g i c a l f a t e and can be s e p a r a t e d from s p e c i f i c i n t e r a c t i o n w i t h the a c t i v e site. I t i s t h i s l a t t e r aspect of p e s t i c i d e design that t h i s a d d r e s s e s w i t h two examples, one from an o l d e r p r o j e c t on p y r e t h r o i d i n s e c t i c i d e s and the o t h e r from a more r e c e n t p r o j e c t on I n s e c t Development D i s r u p t e r s (IDDs). A Pyrethroid

Discovery

Example

T h e r e i s no more i m p o r t a n t s t e p i n p e s t i c i d e d e s i g n t h a n the o r i g i n a l s e l e c t i o n of substituents. Many a p p l i c a t i o n s o f QSAR appear to f a i l because the o r i g i n a l d e r i v a t i v e s o f the l e a d c o v e r e d o n l y a s m a l l p o r t i o n o f the a v a i l a b l e p h y s i c a l c h e m i c a l space or c o n t a i n e d s u b s t i t u e n t s whose p h y s i c o c h e m i c a l p a r a m e t e r s where h i g h l y c r o s s correlated. The c l u s t e r a n a l y s i s method o f Hansch, e t a l . [Hansch, e t a l , , 1973] was one o f the f i r s t attempts t o a d d r e s s t h i s i s s u e . When we f i r s t i n v e s t i g a t e d p y r e t h r o i d i n s e c t i c i d e s we r e a l i z e d , as had o t h e r s b e f o r e us, t h a t the most a c t i v e d e r i v a t i v e s o f p y r e t h r o i d e s t e r s b a s e d on b e n z y l a l c o h o l s b o r e a s u b s t i t u e n t i n the meta p o s i t i o n o f the b e n z y l r i n g . New l e a d s were sought by p r e p a r i n g a s e t o f meta s u b s t i t u t e d b e n z y l e s t e r s o f c i s . t r a n s d i c h l o r o v i n y l - 2 , 2 - d i m e t h y l c y c l o p r o p a n e c a r b o x y l i c a c i d (DVA) in w h i c h the s u b s t i t u e n t s were c h o s e n by r e f e r e n c e t o the c l u s t e r s e t s s u g g e s t e d by Hansch. The o r i g i n a l s e t was made up o f 18 s u b s t i t u e n t s . From t h e s e and subsequent s e t s p r e p a r e d t o t e s t the e a r l y s t r u e t u r e - a c t i v i t y r e l a t i o n s h i p s t h a t were found, the equivalent a-cyano e s t e r s o f a t o t a l o f 15 o f the s e l e c t e d s u b s t i t u e n t s were prepared. These compounds ( F i g u r e 1) r e p r e s e n t a wide range o f physicochemical properties. The compounds were t e s t e d i n a t o p i c a l a s s a y . Each s e t o f a s s a y s i n c l u d e the s t a n d a r d p e r m e t h r i n t o h e l p a c c o u n t f o r i n t e r -



11.

PLUMMERETAL.

Quantitative Agrochemical Design Strategies 159

t e s t v a r i a t i o n . T h i s was a c c o m p l i s h e d b y c a l c u l a t i n g t h e i n d i v i d u a l L D 5 0 o f t h e s t a n d a r d and t h e t e s t sample and t h e n c a l c u l a t i n g the p o t e n c y o f t h e t e s t compound r e l a t i v e t o t h e s t a n d a r d . The b i o l o g i c a l r e s p o n s e u s e d f o r r e g r e s s i o n a n a l y s i s was t h e l o g o f t h e r e l a t i v e p o t e n c y (RP). The use o f a t o p i c a l t e s t was a compromise r e q u i r e d b y t h e f a c t t h a t a s p e c i f i c a c t i v e s i t e a s s a y was n o t available. I t has advantages o v e r f o l i a r s p r a y t e s t s , i n t h a t t h e e n v i r o n m e n t a l f a c t o r s o f l i g h t , l e a f p e n e t r a t i o n and p l a n t m e t a b o l ism a r e removed and t h e dose t h a t t h e i n s e c t r e c e i v e s i s b e t t e r controlled. The r e s u l t a n t b i o l o g i c a l r e s p o n s e i s c l e a r l y a compos i t e o f a c t i v e s i t e i n t e r a c t i o n , p e n e t r a t i o n , m e t a b o l i s m and seques t e r i n g b u t does b e t t e r r e f l e c t t h e r e l a t i o n s h i p o f c h e m i c a l s t r u c t u r e t o mode o f a c t i o n t h a n a f o l i a r a s s a y . was

When t h e b i o l o g i c a l d a t a f o r t h e e s t e r s and t h e a-cyano a n a l y z e d t h e f o l l o w i n g models were d e v e l o p e d : log R P ( _ X

n - 10

C N

esters

) - - 1.02 n (meta) + 2 . 6 ( t - 5.93)

r - 0.903

s - 0.33

g - 35.2 ( p ' - 0.0003)

l o g R P ( _ ) - - 1.09 * (meta) + 2 . 7 ( t - 4.20) X

n - 11

H

r - 0.814

s - 0.56

F 9 - 17.7 ( p ' - 0.002) x

A l t h o u g h n, F and R, t h e f i e l d and r e s o n a n c e e l e c t r o n i c a f f e c t s , and t h e STERIMOL p a r a m e t e r s were s t u d i e d , one p a r a m e t e r , t h e h y d r o p h o b i c s u b s t i t u e n t c o n s t a n t n, e x p l a i n e d t h e m a j o r i t y o f b i o l o g i c a l v a r i a n c e f o r each s e t . The l o c a l i z e d h y d r o p h o b i c p o c k e t w h i c h has b e e n s u g g e s t e d [Plummer 1984] as p r e s e n t a t t h e a c t i v e s i t e a p p a r e n t l y b i n d s i n a s i m i l a r manner f o r t h e two s e t s o f compounds, t h a t i s , as t h e l i p o p h i l i c i t y o f t h e meta s u b s t i t u e n t i n c r e a s e s , so does t h e a c t i v i t y . However, t h e a-cyano e s t e r s ( T a b l e I ) a r e g e n e r a l l y 1.5 t o 2.0 f o l d more a c t i v e t h a n t h e i r r e s p e c t i v e e s t e r s . The e x c e p t i o n i s t h e b i p h e n y l and h e t e r o a r o m a t i c b e n z y l e s t e r s w h i c h were e s s e n t i a l l y i n a c t i v e and t h e b e n z o y l e s t e r w h i c h was a l s o s i g n i f i c a n t l y l e s s a c t i v e than p r e d i c t e d . I t i s important to n o t e , however, t h a t t h e p h e n y l e t h y l and t h e p h e n y l e t h e n y l s u b s t i t u e n t , w h i c h b e c a u s e o f t h e i r l e n g t h were o u t l i e r s i n t h e e s t e r s e t , have d o u b l e d a c t i v i t y l i k e o t h e r members o f t h e s e t . The f a c t t h a t the b i p h e n y l s , w h i c h f i t so w e l l i n t h e e s t e r s e r i e s , a r e now out l i e r s m i g h t be e x p l a i n e d by a change i n t h e way t h e a-cyano e s t e r s b i n d a t t h e a c t i v e s i t e o r by a change t o a d i f f e r e n t a c t i v e s i t e . T h i s r e s u l t p r o b a b l y r e f l e c t s t h e l a t t e r , a change i n a c t i v e s i t e t h a t h a s s i n c e been d e f i n e d as a Type I I p y r e t h r o i d s i t e as opposed t o t h e Type I s i t e where p y r e t h r o i d e s t e r s , i n c l u d i n g t h e b i p h e n y l e s t e r l e a d s g e n e r a t e d from t h i s s t u d y , a r e a c t i v e [Gammon, 1981] . However, a t t h e time o f t h e o r i g i n a l s t u d y t h e a l t e r n a t i v e cause was i n v e s t i g a t e d . I f one assumes t h a t t h e s e c o n d a r o m a t i c r i n g o f t h e b i p h e n y l a l c o h o l and t h e s e c o n d a r o m a t i c r i n g o f t h e


160

PROBING BIOACTIVE MECHANISMS R OC H C H C=OC H thien-2-yl furan-2-yl I OCH C H 6

6

5

5


2

o

5

6

5

*CH2CH2CgH5 *CH=CH2CeH5 CF

R

cf "ci

6

x

3

Br CI OCH F NHC=OCH 3

3

'Outliers in the Ester Study F i g u r e 1.

a-Cyanobenzyl E s t e r s o f DVA

Table I. a-Cyanobenzyl Esters of D V A

R OC H 6

5

C=OC H Thien-2-yr Furan-2-yr 1 OCH2C6H5 CH CH C H "CH CHCgHg CF Br CI CH OCH3 F NHC=OCH 6

2

5

2

6

=

3

3

3

5

Relative Potency 7T X =H Z08 1.00 1.96 0.60 1.05 0.40 1.61 0.33 1.36 0.05 1.12 0.03 1.66 0.02 2.66 0.01 2.68 0.01 0.88 0.01 0.86 0.007 0.71 0.006 0.56 0.005 -0.02 0.005 0.14 0.004 -0.98 Inactive

X = CN 1.20 0.001 0.06 Inactive Inactive 0.03 0.05 0.03 0.02 0.01 0.01 0.01 0.01 0.005 0.005 Inactive

CN/H 1.20 0.002 0.15 _

1.00 2.50 2.50 2.50 1.00 1.43 2.00 2.00 1.00 1.25

-

*cis isomer - all other 60/40 cis/trans.


11.

P L U M M E R E T AL.

Quantitative Agrochemical Design Strategies 161


phenoxy b e n z y l a l c o h o l i n t e r a c t w i t h the a c t i v e s i t e i n e x a c t l y the same o r i e n t a t i o n and t h a t the gem-dimethyl groups and v i n y l groups a r e themselves t o t a l l y c o i n c i d e n t , t h e n an e x a m i n a t i o n o f D r e i d i n g models shows t h a t f o r the two a-cyano e s t e r s the cyano groups p o i n t in rather different directions. However, i f one r e p l a c e s the b i p h e n y l b e n z y l e s t e r w i t h a 2 - ( b i p h e n y l - 3 - y l ) - 1 - c y a n o e t h y l e s t e r the groups a r e c o i n c i d e n t . T h i s compound was p r e p a r e d by the method i n F i g u r e 2. Both the e s t e r and a - c y a n o e s t e r were t o t a l l y d e v o i d o f a c t i v i t y , r e i n f o r c i n g the c o n c l u s i o n t h a t t h e s i t e o f a c t i o n o r mechanism o f a c t i o n was n o t the same. An Example from

I n s e c t Development D i s r u p t e r ( I D D )

Discovery

The e x p e r i m e n t a l d e s i g n s t r a t e g y p r o p o s e d by Hansch has been p r o v e n to have f a u l t s w i t h i t s many v i r t u e s . A l t h o u g h I t goes a l o n g way, the method a s s u r e s n e i t h e r good s p r e a d o f s u b s t i t u e n t s i n parameter space n o r a l a c k o f c o l l i n e a r i t y . T h i s has t o be done on a t r i a l and e r r o r b a s i s u s i n g f a c t o r a n a l y s i s . Perhaps the major o b j e c t i o n t h a t one might have t o t h i s o r a more p r e c i s e f a c t o r i a l d e s i g n i s t h a t t o r e p r e s e n t even t h r e e o r f o u r p a r a m e t e r s r e q u i r e s a r e l a t i v e l y l a r g e s u b s t i t u e n t s e t (e.g. 2 compounds). I f more t h a n one p o s i t i o n i s i n v e s t i g a t e d the d e s i g n becomes d i f f i c u l t t o h a n d l e or a t l e a s t v e r y consumptive o f r e s o u r c e s . An a l t e r n a t i v e a p p r o a c h i s s e q u e n t i a l s i m p l e x o p t i m i z a t i o n (SSO), f i r s t i n t r o d u c e d t o d r u g d e s i g n i n 1974 by Darvas [Darvas, 1974]. T h i s method has been a p p l i e d t o many p r o j e c t s i n our l a b o r a t o r y and has b e e n found t o be b o t h e c o n o m i c a l and e f f e c t i v e . A l t h o u g h i t i s p r i m a r i l y an o p t i m i z a t i o n scheme, i t c a n a l s o p r o v i d e the n e c e s s a r y c o n t e x t w i t h i n w h i c h o t h e r elements o f p e s t i c i d e d e s i g n , such as mechanism o f a c t i o n s t u d i e s , c a n be p u r s u e d . Our a p p r o a c h has been t o chose the o r i g i n a l s i m p l e x s e t t o maximize coverage o f p a r a m e t e r space r a t h e r t h a n s e l e c t i n g an o r i g i n a l s i m p l e x t h a t i s c e n t e r e d i n the p a r a m e t e r space. The l a t t e r a p p r o a c h g e n e r a l l y a s s u r e s t h a t the o p t i m a l compound w i l l be o u t s i d e the s i m p l e x . A l t h o u g h t h i s i s l i k e l y t o be more e f f i c i e n t , our l a r g e s i m p l e x approach, a l t h o u g h s u f f e r i n g from some i n i t i a l wandering, w i l l p r o v i d e b o t h parameter space coverage and r a p i d o p t i m i z a t i o n . The SSO e x p e r i m e n t a l d e s i g n has been u s e d e x t e n s i v e l y i n the s t u d y o f b e n z o y l u r e a i n s e c t development d i s r u p t e r s (IDDs). n

S i n c e the i n t r o d u c t i o n o f d i f l u b e n z u r o n by P h i l l i p s - D u p h a r i n the mid 1970's t h e r e has been c o n s i d e r a b l e i n t e r e s t i n the b e n z o y l ureas. Current i n f o r m a t i o n suggests t h a t they e x e r t t h e i r e f f e c t on i n s e c t s by i n t e r f e r i n g w i t h the f o r m a t i o n o f c h i t i n , the p r i m a r y s t r u c t u r a l component o f the a r t h r o p o d e x o s k e l e t o n . The b i o c h e m i c a l p r o c e s s t h a t i s r e s p o n s i b l e f o r c h i t i n f o r m a t i o n i s shown i n F i g u r e 3. The most l i k e l y s t e p s where b e n z o y l u r e a s may be a c t i v e a r e the l a s t two s t e p s : the assembly o f U r i d i n e d i p h o s p h a t e N - a c e t y l glucosamine from UTP and N - a c e t y l g l u c o s a m i n e - 1 - p h o s p h a t e and the p o l y m e r i z a t i o n o f N - a c e t y l g l u c o s a m i n e from U D P - N - a c e t y l g l u c o s a m i n e under the m e d i a t i o n o f c h i t i n s y n t h e t a s e . Since studies [ G i j s w i j t , e t a l . , 1979] have i n d i c a t e d t h a t b e n z o y l u r e a i n t o x i c a t i o n i s accompanied by the b u i l d u p o f U D P - N - a c e t y l g l u c o s a m i n e , the l a t t e r




F i g u r e 2.

Synthesis o f 2-Biphenylethanol Analogs

Trehalose Glucose

I Glucose-6-phosphate Fructose-6-phosphate L

Glutamine

Ss

| ^ - G l u t a m i c acid Glucosamine-6-phosphate L—Acetyl-Co-A 1^-Co-A N-Acetylglucosamine-6-phosphate N-Acetylglucosamine-1-phosphate

C

UTP PPi

UDP-N-acetylglucosamine |

[Chitin synthetase]

Chitin (N-acetylglucosamine) F i g u r e 3.

n+1

The B i o c h e m i c a l Pathway A f f e c t e d by Benzoylphenylureas


11.

P L U M M E R E T AL.

163 Quantitative Agrochemical Design Strategies


s t e p has been s u g g e s t e d as the f a t a l l e s i o n . The most l i k e l y mechanism would be the i n h i b i t i o n o f c h i t i n s y n t h e t a s e , b u t t h i s does n o t seem t o be the case [Reynolds, 1987], O t h e r workers [ M i t s u i , e t a l . , 1985] have i n d i c a t e d t h a t b e n z o y l u r e a s i n h i b i t the t r a n s p o r t o f UDP-N-acetylglucosamine from the i n t e r n a l t o the e x t e r n a l s u r f a c e o f the c e l l membrane, where the c h i t i n polymer i s assembled by c h i t i n s y n t h e t a s e . M o d e l i n g s t u d i e s i n our l a b o r a t o r y u s i n g the f a c i l i t i e s o f MDL's CHEMLAB s u g g e s t t h a t the b e n z o y l u r e a s c o u l d mimic the u r i d i n e phosphates o r UDP-N-acetylglucosamine at a binding s i t e . The c r y s t a l s t r u c t u r e o f d i f l u b e n z u r o n was p u b l i s h e d i n 1978 by Cruse [Cruse, 1978]. F i g u r e 4 i s an ORTEP r e p r e s e n t a t i o n o f t h a t c r y s t a l structure. The u r e a forms a s i x membered r i n g by v i r t u e o f a s t r o n g h y d r o g e n bond between the a n i l i n e h y d r o g e n and the b e n z o y l group carbonyl. There a r e many p o i n t s o f s i m i l a r i t y between the b e n z o y l u r e a s t r u c t u r e and the s t r u c t u r e o f u r i d i n e . CND02 c a l c u l a t i o n o f e l e c t r o n d e n s i t y f o r the u r e a s i x membered r i n g and u r i d i n e a r e shown i n F i g u r e 5. The t h r e e p o i n t s o f s i m i l a r i t y shown, as w e l l as s e v e r a l o t h e r s , were u s e d t o form the w o r k i n g h y p o t h e s i s t h a t the b e n z o y l u r e a s mimic the u r i d i n e m o i e t y a t the a c t i v e s i t e . A model o f UDPN - a c e t y l g l u c o s a m i n e was assembled from p u b l i s h e d c r y s t a l s t r u c t u r e s o f U r i d i n e and N - a c e t y l g l u c o s a m i n e . An ORTEP r e p r e s e n t a t i o n o f t h a t m o l e c u l e i n a l i n e a r form i s shown i n F i g u r e 6. I f i n d e e d the b e n z o y l u r e a s mimic t h i s m o l e c u l e a t a c a t a l y t i c o r b i n d i n g s i t e , i t i s a p p a r e n t t h a t t h e r e i s c o n s i d e r a b l e room a t the s i t e f o r the i n h i b i t o r m o l e c u l e . T h i s i s a c o n t r a d i c t i o n to the o r i g i n a l QSAR s t u d y done by the Duphar group i n w h i c h t h e y c o n c l u d e d t h a t a s h o r t , t h i c k s u b s t i t u e n t i n the p a r a p o s i t i o n enhances a c t i v i t y [ V e r l o o p , e t a l . , 1976], However, b e n z o y l u r e a s i n t r o d u c e d s i n c e t h a t time have tended t o have l o n g e r , b u l k i e r groups i n the p a r a p o s i t i o n , s u p p o r t i n g t h i s q u a l i t a t i v e p i c t u r e . Some o f the p r o d u c t s o f our own work i n t h i s a r e a appear i n F i g u r e 7. The QSAR models d e v e l o p e d i n the s t u d i e s a r e i n c l u d e d a l o n g w i t h the g e n e r a l s t r u c t u r e s . One o v e r a l l c o n c l u s i o n drawn from t h e s e compounds was t h a t the l e n g t h c o u l d i n f a c t be extended i n the d i r e c t i o n o f t h e p a r a position of aniline ring. The s e r i e s t h a t b e s t e x e m p l i f i e d t h i s was the 2 - p h e n y l - 1 , 1 , 2 , 2 - t e t r a f l u o r o e t h o x y a n a l o g s . The approach t o t h i s s e r i e s i n v o l v e d n o t o n l y b a s i c QSAR d e s i g n b u t a l s o the use of i n t r i n s i c assays. These were s e l e c t e d t o c o n t r a s t w i t h i n v i v o t e s t i n g t o t a k e f u l l advantage o f the c o n t e x t p r o v i d e d by a QSAR d e s i g n t o u n d e r s t a n d e n v i r o n m e n t a l f a c t o r s as w e l l as p r o b i n g the mechanism o f a c t i o n . The i n i t i a l s i m p l e x s e t was p r e p a r e d t o c o v e r F, R, and the STERIMOL parameters L and B^ r e p r e s e n t i n g the e s s e n t i a l f a c t o r s l i p o p h i l i c i t y , e l e c t r o n i c s and s i z e / s h a p e . The STERIMOL parameter B4 was n o t i n c l u d e d b e c a u s e o f i t s h i g h c o l l i n e a r i t y t o n. S i n c e f i v e parameters (n) were t o be e v a l u a t e d , the s i x s u b s t i t u e n t s (n + 1) i n F i g u r e 8, chosen by c l u s t e r a n a l y s i s , were p r e p a r e d . S e v e r a l t e s t methods, T a b l e I I , were u s e d t o e v a l u a t e the compounds. The c h i t i n s y n t h e s i s a s s a y was d e s i g n e d t o m i n i m i z e



164


F i g u r e 4. permission

Diflubenzuron C r y s t a l Structure (Reprinted from r e f . 1. C o p y r i g h t 1978 E l s e v i e r . ) ^

with

-0.36

CI Uridine Figure

5.

Diflubenzuron

P a r t i a l CND02 E l e c t r o n D e n s i t y C a l c u l a t i o n s

F i g u r e 6.

UDP-N-Acetylglucosamine



11. PLUMMERETAL.

Quantitative Agrochemical Design Strategies

CF log

3

( 1 / L C ) = 0.3 (+0.1) T -0.4 L (+0.1) + 1.7

n = 20

5 0

r = 0.60 2

s = 0.50

F

2 i 1 7

F i g u r e 7.

= 12.5

B e n z o y l u r e a I n s e c t i c i d e s - QSAR

H CI N(CH )2 3

C=OC6H

5

OC5H11

OCH(CH )2 3

F i g u r e 8.

I n i t i a l SSO D e s i g n S e t


165


166


e n v i r o n m e n t a l i n f l u e n c e s on the s t r u c t u r e - a c t i v i t y a n a l y s i s w h i l e the t o p i c a l , d i e t and f o l i a r a s s a y s were meant t o b r i n g the com pounds i n t o the r e a l w o r l d by s t e p w i s e a d d i t i o n o f e n v i r o n m e n t a l factors. The t e s t p r i m a r i l y u s e d f o r the o p t i m i z a t i o n was t h e t o p i c a l assay. T h i s was p a r t i c u l a r l y d e s i r a b l e f o r t h i s purpose s i n c e a s i n g l e dose was a p p l i e d r a t h e r t h a n a dose dependent on how much o r how l o n g the i n s e c t a t e the medium on w h i c h i t i s exposed. The o p t i m i z a t i o n and o r i g i n a l probe s t r a t e g y i n v o l v e d the p r e p a r a t i o n o f t h r e e a d d i t i o n a l compounds and was abandoned when no improvement i n a c t i v i t y was n o t e d beyond f l u o r i n e and c h l o r i n e . The r e s u l t s a r e shown i n T a b l e I I I . M u l t i p l e l i n e a r r e g r e s s i o n a n a l y s i s of t o p i c a l data f o r t h i s s h o r t s e r i e s was c o n d u c t e d . A l t h o u g h no s i n g l e parameter i n the o r i g i n a l s e t , n, F, R, L, B^, showed s i g n i f i c a n t c o r r e l a t i o n , i t was f o u n d t h a t the s u b s t i t u t i o n o f sigma p f o r F and R gave a model t h a t a c c o u n t e d f o r a l m o s t s e v e n t y p e r c e n t o f the b i o l o g i c a l variation: log

(1/ L D

n - 8

5 0

)

r - 0.836

-

3.0 Sigma P + ( t - 3.74)

s - 0.70

F 80.0 73.0 2.0

Chitin Synthesis Inhibition

SAW Diet

(pl90)

(ppm)

6.6 6.9 5.9 5.8

2.5 0.4 19.0 >250 700 75

-

-

LC50

SAW Foliar LC50 (ppm) 67.0 1.8

-

-

117

35.0 1.13 0.08

-

-

2.4

0.99 0.03

7.3 7.1

1.4

48.2

-


-

-

167


16S


C e r t a i n l y t h e e a r l y work o f t h e Duphar group and l a t e r developments i n b e n z o y l u r e a c h e m i s t r y s u p p o r t t h e o b s e r v a t i o n t h a t the p a r a s u b s t i t u e n t on t h e a n i l i n e r i n g c a n be q u i t e l a r g e . A l t h o u g h e l e c t r o n w i t h d r a w a l a t t h a t p o s i t i o n s t i l l seems t o f a v o r a c t i v i t y , groups as l o n g as phenoxy, p h e n y l and t h e p h e n y l e t h o x y s j u s t discussed, are s t i l l quite active. I t appears t h a t t h i s p o s i t i o n c a n be d e s c r i b e d as a b a l l a s t p o s i t i o n ; one t h a t c a n be s u b s t i t u t e d f r e e l y without d r a m a t i c a l l y changing the a c t i v i t y i n vitro. The i d e n t i f i c a t i o n o f such a p o s i t i o n has c o n s i d e r a b l e advantage f o r d e s i g n s i n c e such p o s i t i o n s c a n be u s e d t o b u i l d i n properties that favor i n vivo a c t i v i t y . As i n d i c a t e d e a r l i e r , i t a l s o h a s some i m p l i c a t i o n s w i t h r e g a r d t o t h e mechanism o f a c t i o n o f t h e s e compounds. E a r l y s t u d i e s s u g g e s t t h a t d i f l u b e n z u r o n and i t s a n a l o g s a r e stomach p o i s o n s , l a c k i n g s i g n i f i c a n t a c t i v i t y i f they a r e n o t ingested. However, when one extends t h e b a l l a s t groups t o s u b s t i t u e n t s w i t h h i g h l i p o p h i l i c i t y , i t becomes a p p a r e n t t h a t t h i s i s only a p h y s i c a l b a r r i e r . Penetration o f the i n s e c t c u t i c l e i s q u i t e e f f e c t i v e when t h e l i p o p h i l i c i t y i s s u f f i c i e n t l y h i g h . I n c o n c l u s i o n , we w i s h t o once a g a i n emphasize t h e v a l u e o f the c o n t e x t t h a t s u r r o u n d s t h e a p p l i c a t i o n o f QSAR s t r a t e g i e s i n s y n t h e s i s p l a n n i n g and i n a n a l y s i s o f b i o l o g i c a l d a t a i n c l u d i n g i n s i g h t s r e l a t i v e t o mode o f a c t i o n s t u d i e s . I f the f i r s t steps o f e x p e r i m e n t a l d e s i g n a r e done p r o p e r l y t h e b e n e f i t s c a n i n c l u d e a c t i v i t y o p t i m i z a t i o n as w e l l as e f f e c t i v e o v e r a l l p r o j e c t execution.

Literature Cited 1.

Cruse, W. B. T. Acta. Cryst. 1978, B34, 2904-2906.

2.

Darvas, F.

3.

Gammon, D. W.; Brown, M. A.; Casida, J . E. Pestic. Biochem. Physiol. 1981, 15, 181-191.

4.

Gijswijt, M. J.; Deul, D. H.; Dejong, B. J . Pestic. Biochem. Physiol. 1979, 12, 87-94.

5.

Hansch, C.; Unger, S.; Forsythe, A. B. J . Med. Chem. 1973, 16, 1217.

6.

Neuman, R.; Guyer, W. Pestic. Sci. 1987, 20, 147-156.

7.

Plummer, E. L. ACS Symposium Series 255, P.S. Magee, G. K. Kohn and J. J . Menn, Editors, 1984, 297-320.

8.

Reynolds, S. E. Pestic. Sci. 1987, 20, 131-146 and references therein cited.

9.

Verloop, A.; Hoogenstraaten, W.; Tipker J . Drug Design, 1976, 7, 165-206.

J . Med. Chem. 1974, 17, 799-804.

RECEIVED August 2, 1989


Contribution of Quantitative Agrochemical Design Strategies to

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