Use of STERIMOL, MTD, and MTD* Steric ... - ACS Publications

STERIMOL & MTD Steric Parameters in QSA R. 289 the MTD and MTD* methods. The Equations 10-13 are related to the series o f the R-analogs and 14-17 to ...
0 downloads 0 Views 1MB Size
16 Use of STERIMOL, MTD, and MTD* Steric Parameters in Quantitative Structure-Activity Relationships J. TIPKER and A. VERLOOP

Downloaded by EMORY UNIV on June 29, 2014 | http://pubs.acs.org Publication Date: June 26, 1984 | doi: 10.1021/bk-1984-0255.ch016

Biochemistry Department, DUPHAR B.V., 's Graveland, The Netherlands

STERIMOL and MTD (Minimum Topological Difference) steric parameters to account for steric influences in QSAR of pesticides have been described and applied in the literature. We have recently developed an improved version of the Simon MTD method, i.e. MTD* parameters. The MTD and MTD* methods will be described. The scope and limitations of the STERIMOL, MTD and MTD* approaches will be discussed and compared using QSAR of insecticidal benzoylphenylureas, DDT-type analogs and benzylchrysanthemates, herbicidal benzonitriles and nitrophenols, and plant-growth regulating phenoxypropionic acids. In 1976 we have p u b l i s h e d t h e STERIMOL a p p r o a c h (1_); i n c l u d i n g a t a b l e c o n t a i n i n g 5 s u b s t i t u e n t c o n s t a n t s o f a b o u t 250 d i f f e r e n t g r o u p s w h i c h c o u l d be u s e d i n QSAR s t u d i e s where s t e r i c e f f e c t s were e x p e c t e d . R e c e n t l y t h i s method h a s been d e v e l o p e d f u r t h e r , w i t h a " s e c o n d g e n e r a t i o n " s e t o f STERIMOL p a r a m e t e r s a s a r e s u l t (2). T h e s e STERIMOL p a r a m e t e r s have been compared w i t h o t h e r s t e r i c c o n s t a n t s , s u c h a s E s ( 1 ) , m o l a r r e f r a c t i v i t y (3) and t h e MSD (minimum s t e r i c d i f f e r e n c e j method o f Simon ( £ ) . From t h e s e s t u d i e s i t c o u l d be c o n c l u d e d t h a t t h e p r e d i c t i v e power o f t h e MSD method was l e s s w i t h r e g a r d t o t h e STERIMOL a p p r o a c h . I n g e n e r a l i t c o u l d be s t a t e d t h a t STERIMOL p a r a m e t e r s were preferable i n describing s t e r i c e f f e c t s i f a great variation i n the s u b s t i t u e n t s e x i s t s ; v a r i a t i o n i n t h e sense o f d e v i a t i o n s f r o m s p h e r i c s h a p e (2>.5)* MTD and MTD* a p p r o a c h e s In 1976 Simon d e v e l o p e d a new method t o d e s c r i b e s t e r i c e f f e c t s i n QSAR (6»). He d e f i n e d t h e minimum s t e r i c d i f f e r e n c e (MSD) 0097-6156/ 84/ 0255-0279506.00/ 0 © 1984 American Chemical Society

In Pesticide Synthesis Through Rational Approaches; Magee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

Downloaded by EMORY UNIV on June 29, 2014 | http://pubs.acs.org Publication Date: June 26, 1984 | doi: 10.1021/bk-1984-0255.ch016

280

PESTICIDE SYNTHESIS THROUGH RATIONAL APPROACHES

between a m o l e c u l e and t h e n a t u r a l s u b s t r a t e o f a b i o l o g c a l r e c e p t o r a s t h e n o n - o v e r l a p p i n g volume o f t h e c o n f o r m a t i o n s w h i c h a l l o w o f a maximum s p a t i a l o v e r l a p o f t h e 2 m o l e c u l e s . In p r a c t i c e the planar s t r u c t u r a l formulae o f t h e molecules a r e super-imposed and t h e u n s u p e r p o s a b l e atoms a r e c o u n t e d . An example i s g i v e n i n F i g u r e 1. The MSD p a r a m e t e r s m i g h t be c h a r a c t e r i z e d as p r o v i d i n g a r o u g h measure o f t h e d e v i a t i o n f r o m " i d e a l " b u l k . O f c o u r s e some problems immediately a r i s e , i . e . : 1. The s u p e r p o s i t i o n o f t h e m o l e c u l e s i s o f t e n r a t h e r s u b j e c t i v e and i t t a k e s h a r d l y i n t o a c c o u n t t h e f l e x i b i l i t y o f t h e molecules studied. 2. The n a t u r a l s u b s t r a t e i s unknown i n many s t u d i e s o f QSAR. Simon e t a l . adopt i n t h o s e c a s e s t h e most a c t i v e m o l e c u l e o f a s e r i e s as t h e s t a n d a r d , a s s u m i n g t h a t i t s shape i s c l o s e s t to the " n a t u r a l " substrate. 3. The g r e a t e s t p r o b l e m o f t h e MSD a p p r o a c h i s t h a t i t d o e s n o t d i s c r i m i n a t e between d i f f e r e n c e s i n shape o f t h e p a r t s o f t h e m o l e c u l e s d i r e c t e d t o t h e w a l l s o f t h e r e c e p t o r w h i c h would be r e l e v a n t , and d i f f e r e n c e s i n shape t o w a r d s t h e o u t e r r e g i o n w h i c h would b e i r r e l e v a n t . B a l a b a n e t a l . (7) r e c e n t l y p u b l i s h e d a method w h i c h p a r t l y o v e r c o m e s t h e a b o v e - m e n t i o n e d p r o b l e m s . T h i s MTD (minimum t o p o l o g i c a l d i f f e r e n c e ) a p p r o a c h i s t r y i n g t o d e v e l o p an o p t i m a l s t a n d a r d m o l e c u l e by s y s t e m a t i c a l l y a n a l y z i n g t h e s h a p e s o f t h e members i n a s e r i e s i n r e l a t i o n t o t h e i r b i o l o g i c a l a c t i v i t i e s . The method c a n be b r i e f l y d e s c r i b e d a s f o l l o w s . 1. A s o - c a l l e d h y p e r m o l e c u l e i s d e v e l o p e d , w h i c h c a n b e considered as t h e assembly o f a l l atomic p o s i t i o n s o f a l l m o l e c u l e s i n t h e s e r i e s . F i g u r e 2 and 3 show t h e p r o c e d u r e f o r 32 s u b s t i t u t e d b e n z o n i t r i l e s . 2. A n i n i t i a l s t a n d a r d m o l e c u l e i s c h o s e n , f o r example t h e most a c t i v e member, and t h e MTD v a l u e s o f a l l t h e members a r e c a l c u l a t e d i n t h e same way as i n t h e Simon method. Now a l l t h e p o s i t i o n s i n t h e h y p e r m o l e c u l e a r e c h a n g e d one by one i n s u c h a way t h a t n o t o n l y f a v o u r a b l e and u n f a v o u r a b l e p o s i t i o n s are taken i n t o account, but a l s o i n d i f f e r e n t p o s i t i o n s , which do n o t c o n t r i b u t e t o t h e MTD v a l u e a t a l l . A f t e r e v e r y change t h e o b t a i n e d MTD v a l u e s a r e c o r r e l a t e d w i t h t h e b i o l o g i c a l a c t i v i t y and t h e c o r r e l a t i o n c o e f f i c i e n t i s o p t i m i z e d by t h e s o - c a l l e d s t e e p e s t a s c e n t method. I f no s i n g l e change i n t h e f i n a l s t a n d a r d c a n d e l i v e r MTD v a l u e s w h i c h c o r r e l a t e b e t t e r w i t h t h e b i o l o g i c a l a c t i v i t y , an o p t i m a l s t a n d a r d i s d e r i v e d . 3. T o a v o i d t h e f i n d i n g o f o n l y a l o c a l optimum o f t h e s t a n d a r d , the procedure i s repeated several times, s t a r t i n g from d i f f e r e n t other i n i t i a l standards, e.g. t h e t o t a l hyper­ m o l e c u l e , o r i n i t i a l s t a n d a r d s w h i c h a r e g e n e r a t e d a t random, u n t i l most o p t i m i z a t i o n s have l e d t o t h e same s t a n d a r d . In t h e B a l a b a n MTD a p p r o a c h t h e a d d i t i o n a l i n f l u e n c e o f e l e c t r o n i c and h y d r o p h o b i c e f f e c t s i s a c c o u n t i n g f o r by a d d i n g e . g . π and σ

In Pesticide Synthesis Through Rational Approaches; Magee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

Downloaded by EMORY UNIV on June 29, 2014 | http://pubs.acs.org Publication Date: June 26, 1984 | doi: 10.1021/bk-1984-0255.ch016

TIPKER & VERLOOP

STERIMOL

& MTD Steric Parameters in QSAR

"natural" agonist

without hydrogens

* m i s s i n g ; MSD=1

# t o o much; MSD=1

MSD=2

MSD=3

F i g u r e 1. C a l c u l a t i o n o f t h e o r i g i n a l MSD p a r a m e t e r , a c c o r d i n g t o t h e method o f Simon.

In Pesticide Synthesis Through Rational Approaches; Magee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

PESTICIDE SYNTHESIS THROUGH RATIONAL APPROACHES

hypermolecule

Downloaded by EMORY UNIV on June 29, 2014 | http://pubs.acs.org Publication Date: June 26, 1984 | doi: 10.1021/bk-1984-0255.ch016

structure

F i g u r e 2. C o n s t r u c t i o n o f t h e h y p e r m o l e c u l e o f 31 substituted benzonitriles.

In Pesticide Synthesis Through Rational Approaches; Magee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

Downloaded by EMORY UNIV on June 29, 2014 | http://pubs.acs.org Publication Date: June 26, 1984 | doi: 10.1021/bk-1984-0255.ch016

16.

STERIMOL

TIPKER & VERLOOP

& MTD Steric Parameters in QSAR

283

a l l t h e compounds c a n be c o v e r e d b y t h e h y p e r m o l e c u l e , none o f t h e positions i s superfluous. structure H 2-CI 2 , 6 - F ; 2,6-C"l2; 2 , 6 - B r ; 2 , 6 - I 2-F.6-C1; 2-CI.6-0H; 2 , 6 - ( C H ) 2-Cl,6-Br; 2-CI,6-CH ; 4-CI 3-CI 2-OCH3 2-CF ,6-Cl 2-0C H ,6-Cl 2,6-(0CH ) 2,4,6-Cl ; 2,6-Cl ,4-0H 2 , 4 - C l ; 2-Cl,4-CH 2,6-Cl ,4-0CH 2,6-Cl ,3-0CH 2,6-Cl ,3-0C0CH 2,3,6-Cl 2,3,5,6-Cl4 2,5-(0C H ) 3,4,5-Cl 2,3,4-Cl 2,3,4,5,6-Cl 3,4-Cl 2,4,5-C1 2

2

3

3

3

2

5

3

2

3

2

2

3

2

3

2

3

2

3

3

2

5

2

2

3

5

2

3

2

2

positions 1 1 2 1 2 3 1 2 3 1 2 3 1 8 1 10 1 2 4 1 2 3 45 6 1 2 3 4 12 1 2 3 47 1 2 3 8 1 2 8 1 2 3 8 9 1 2 3 10 12 1 2 3 4 1 0 12 1 2 3 10 1 2 3 10 11 1 2 4 7 11 12 1 8 10 11 1 2 8 10 1 2 3 8 10 11 1 8 10 1 2 8 11

F i g u r e 3. A t o m i c p o s i t i o n s i n t h e h y p e r m o l e c u l e o f 31 s u b s t i t u t e d b e n z o n i t r i l e s .

In Pesticide Synthesis Through Rational Approaches; Magee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

284

PESTICIDE SYNTHESIS THROUGH RATIONAL APPROACHES

t e r m s t o t h e r e g r e s s i o n a f t e r t h e d e v e l o p m e n t o f t h e optimum s t a n d a r d . We c o n s i d e r e d t h a t a b e t t e r a p p r o a c h would be t o i n c l u d e h y d r o p h o b i c and e l e c t r o n i c p a r a m e t e r s a l r e a d y i n t h e p r o c e d u r e t o o b t a i n t h e optimum s t a n d a r d (8). T h e r e s u l t i n g s t e r i c p a r a m e t e r s are i n d i c a t e d as MTD* v a l u e s . O p t i o n s i n t h e p r o c e d u r e make i t p o s s i b l e t o connect t h e f a v o u r a b l e atomic p o s i t i o n s t o each o t h e r and t o t h e b a s i c s t r u c t u r e .

Downloaded by EMORY UNIV on June 29, 2014 | http://pubs.acs.org Publication Date: June 26, 1984 | doi: 10.1021/bk-1984-0255.ch016

C o m p a r i s o n o f STERIMOL, MTD and MTD* The r e s u l t s o f t h e s t u d i e s w i l l b e summarized. D e t a i l s o f t h e QSAR a n a l y s e s a r e o r w i l l be p u b l i s h e d e l s e w h e r e , i n c l u d i n g i n t e r c o r r e l a t i o n m a t r i c e s o f t h e s t e r i c parameters mentioned. But r e l e v a n t c o n c l u s i o n s f r o m e . g . i n t e r c o r r e l a t i o n s w i l l be d i c u s s e d . A t t h i s moment t h e STERIMOL method h a s been a p p l i e d s u c c e s s f u l l y i n a b o u t 50 p u b l i c a t i o n s ; o f t e n w i t h b e t t e r r e s u l t s t h a n o t h e r s t e r i c a p p r o a c h e s , i n c l u d i n g MTD and MTD*, e s p e c i a l l y i n s e r i e s w i t h f e w s u b s t i t u e n t p o s i t i o n s . A r e c e n t example i s o u r s t u d y o f DDT a n a l o g s . Brown e t a l . ( £ ) a n a l y s e d a s e r i e s o f 21 d e r i v a t i v e s u s i n g t h e v a n de Waals (Vw) volumes a s s t e r i c p a r a m e t e r s . I n T a b l e I t h e e q u a t i o n s a r e g i v e n i n which t h e s t e r i c parameters are compared. The MSD a p p r o a c h gave no s i g n i f i c a n t r e s u l t s . A d d i t i o n o f σ* t o E q u a t i o n 1-3 d i d n o t i m p r o v e t h e c o r r e l a t i o n s i g n i f i c a n t l y . STERIMOL gave t h e b e s t r e s u l t s and MTD and MTD* were c o m p a r a b l e w i t h Vw. T h e o b t a i n e d o p t i m a l s t a n d a r d f r o m t h e p r o c e d u r e t h a t gave E q u a t i o n 4 i s shown i n F i g u r e 4, and i t i n d i c a t e s t h a t d i - s u b s t i t u t e d c a r b o n atoms gave t h e b e s t f i t . The STERIMOL a p p r o a c h however, h a s a l s o some weaknesses and l i m i t a t i o n s [2). One a s p e c t i s t h a t 5 STERIMOL p a r a m e t e r s a t e a c h s u b s t i t u t i o n p o s i t i o n m i g h t a b s o r b t o o many d e g r e e s o f f r e e d o m s o t h a t t h e problem o f "chance c o r r e l a t i o n s " might a r i s e , e s p e c i a l l y when many s u b s t i t u e n t p o s i t i o n s a r e i n v o l v e d . T h i s was one o f t h e r e a s o n s f o r d e c r e a s i n g t h e number o f STERIMOL p a r a m e t e r s t o 3 i n t h e " s e c o n d g e n e r a t i o n " STERIMOL a p p r o a c h . S t i l l t h e method i s d i f f i c u l t t o u s e when t h e number o f o b s e r v a t i o n s i s s m a l l i n r e l a t i o n t o t h e number o f s u b s t i t u t i o n p o s i t i o n s , s o t h a t o t h e r s t e r i c methods would be needed, e . g . t h e MSD and MTD a p p r o a c h e s . An example i s t h e QSAR s t u d y o f t h e h e r b i c i d a l a c t i v i t y o f s u b s t i t u t e d b e n z o n i t r i l e s . O u r f i r s t a n a l y s i s u s i n g t h e STERIMOL p a r a m e t e r s showed s t e r i c e f f e c t s t o be v e r y i m p o r t a n t , b u t b e c a u s e o f t h e l a r g e number o f 5 s u b s t i t u e n t p o s i t i o n s many p a r a m e t e r s , sometimes e v e n i n q u a d r a t i c f o r m were n e c e s s a r y , w h i c h r e s u l t e d i n an e q u a t i o n o f t o o low s t a t i s t i c a l s i g n i f i c a n c e . The b i o l o g i c a l a c t i v i t y i s expressed as t h e i n h i b i t i o n o f r o o t g r o w t h o f Panicurn m i l i a c e u m grown on a g a r . T h e b i o l o g i c a l and p h y s i c o - c h e m i c a l d a t a a r e p u b l i s h e d e l s e w h e r e ( 5 ) and t h e r e s u l t i n g e q u a t i o n s when a p p l y i n g MTD and MTD* p a r a m e t e r s are shown i n T a b l e I I .

In Pesticide Synthesis Through Rational Approaches; Magee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

16.

TIPKER & VERLOOP

STERIMOL

& MTD

Steric Parameters in QSAR

285

Downloaded by EMORY UNIV on June 29, 2014 | http://pubs.acs.org Publication Date: June 26, 1984 | doi: 10.1021/bk-1984-0255.ch016

T a b l e I . C o m p a r i s o n o f Vw, MSD, MTD, MTD* and STERIMOL p a r a m e t e r s i n a s e r i e s o f 21 DDT a n a l o g s w i t h a c t i v i t y a g a i n s t Culex f a t i g a n s .

H5C2

oC2H5

°OiO~

-log LC

5 0

t = +0.500 VwX 5.40 - 0 . 0 0 6 ( V w X ) 5.26 -0.859

r 0.789

s 0.513

F 14.82

= - 0 . 2 9 MSD* +1.44

2.04

0.424

0.735

4.17 ( 2 )

= -1.33 MTD +0.95

4.76

0.731

0.554

21.85 ( 3 )

= - 1 . 1 3 MTD* +0.31, σ* +0.93

4.96 2.52

0.782

0.520

14.19 ( 4 )

(1)0

2

-log L C

5 0

-log L C

5 0

-log L C

5 0

-log L C

5 0

= +20.21 B l 8.86 0.921 0.345 22.37 ( 5 ) -4.68 ( B l ) 2 8.86 -0.96 B5 3.67 +0.44 σ* 5.19 -17.35 MSD v a l u e s c a l c u l a t e d f r o m t h e most a c t i v e member; X=CH(C2H5)N02 β E q u a t i o n 1 a c c o r d i n g t o Brown e t a l . (9)

a

In Pesticide Synthesis Through Rational Approaches; Magee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

PESTICIDE SYNTHESIS THROUGH RATIONAL APPROACHES

286

Table I I .

I n h i b i t i o n o f r o o t growth of Panicum miliaceum u n d e r t h e i n f l u e n c e o f 31 b e n Z O M t r M l f -

t

Downloaded by EMORY UNIV on June 29, 2014 | http://pubs.acs.org Publication Date: June 26, 1984 | doi: 10.1021/bk-1984-0255.ch016

pC

pC

5 0

5 0

(pCso)

r

s

= +1.37 = +1.37 Iπ. -0.36 *2 +0.16 σ -1.50

2.32 2.35 0.26

0.454

0.886

2.33

(6)

= - 0 . 5 9 MTD +0.27

5.36

0.705

0.680

28.73

(7)

= +1.21 = +1.21 π π - 0 . 4 2 ir2 +0.67 σ - 0 . 6 2 MTD -0.51

3.45 4.34 1.84 5.02

0.856

0.524

17.82

(8)

3.66 5.98 5.83 9.87

0.913

0.414

32.35

(9)

0

PC5Q = = +1.02 +1.02 -0.46 +1.95 -0.70 +0.31

π tr2 σ MTD*

F

W i t h o u t s t e r i c p a r a m e t e r s E q u a t i o n 6 was o b t a i n e d , w h i c h was o f no s i g n i f i c a n c e . The MTD v a l u e s used i n E q u a t i o n 7 and o b t a i n e d a f t e r o p t i m i s a t i o n were added t o t h e v a r i a b l e s f r o m E q u a t i o n 6, r e s u l t i n g i n E q u a t i o n 8. I f t h e o p t i m i s a t i o n t o o k p l a c e i n t h e p r e s e n c e o f t h e p h y s i c a l p a r a m e t e r s (MTD* a p p r o a c h ) t h e b e s t r e s u l t was a c h i e v e d , shown i n E q u a t i o n 9. E l e c t r o n w i t h d r a w i n g g r o u p s i n c r e a s e t h e a c t i v i t y a t an o p t i m a l π - v a l u e o f about 2. The s t e r i c r e q u i r e m e n t s a r e g i v e n i n F i g u r e 5, s h o w i n g t h a t d i o r t h o s u b s t i t u t i o n gave the b e s t f i t . A n o t h e r e x a m p l e o f t h e use o f t h e MTD and MTD* a p p r o a c h e s c a n b e found i n a s e r i e s o f o p t i c a l l y a c t i v e α-phenoxypropionic a c i d s w i t h a u x i n - l i k e a c t i v i t y , p a r t l y p u b l i s h e d i n (5>). The R - s t e r e o i s o m e r s a r e much more a c t i v e t h a n t h e S - a n a l o g e s . B o t h s e r i e s were a n a l y z e d by L i e n e t a l . (10) and a c o r r e l a t i o n w i t h π , π , σ and t h e Van d e r W a a l s volume was f o u n d . The P f e i f f e r r u l e i s e x p l a i n e d i n terms o f d i f f e r e n t s t r u c t u r a l requirements f o r the s u b s t i t u e n t s a s m e a s u r e d b y π and van d e r W a a l s v o l u m e . A n a l y s i n g t h e s e r i e s u s i n g STERIMOL d e l i v e r e d e q u a t i o n s c o n t a i n i n g t o o many p a r a m e t e r s . In T a b l e I I I t h e e q u a t i o n s a r e g i v e n a s a r e s u l t o f 2

In Pesticide Synthesis Through Rational Approaches; Magee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

TIPKER & VERLOOP

STERIMOL

Downloaded by EMORY UNIV on June 29, 2014 | http://pubs.acs.org Publication Date: June 26, 1984 | doi: 10.1021/bk-1984-0255.ch016

H5C20-^~^-C

& MTD Steric Parameters in QSAR

0C2H5

• favourable • unfavourable A indifferent F i g u r e 4. S t a n d a r d used i n E q u a t i o n 4 t o o b t a i n MTD* v a l u e s i n a s e r i e s o f DDT a n a l o g s .

• favourable • unfavourable A indifferent

F i g u r e 5. S t a n d a r d used i n E q u a t i o n 9 t o o b t a i n MTD* values i n a series of bezonitriles.

In Pesticide Synthesis Through Rational Approaches; Magee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

288

PESTICIDE SYNTHESIS THROUGH RATIONAL APPROACHES

T a b l e I I I . A u x i n - a c t i v i t y o f p h e n o x y p r o p i o n i c a c i d s (PC50) H

R

H00C-C-X«-^~^ CH t

r

1.84 2.15 1.28

0.475

0.941

1.94

24

(10)

pC50 = = - 0 . 8 8 MTD MTD 5.80 +8.10

0.778

0.641

33.66

24

(11)

pC

5 0

= +2.18 +2.18 π = π -0.45 *2 +0.98 σ +3.69

Downloaded by EMORY UNIV on June 29, 2014 | http://pubs.acs.org Publication Date: June 26, 1984 | doi: 10.1021/bk-1984-0255.ch016

3

s

F

η

= +2.04 = +2.04 -0.38 +0.31 -0.84 +5.38

π π *2 σ σ MTD MTD

2.86 2.96 0.65 5.97 5.97

0.855

0.569

12.90

24

(12)

= +1.62 = +1.62 -0.43 +1.14 -0.78 +7.32

π π *2 σ MTD*

2.81 4.22 3.06 8.16

0.910

0.455

22.89

24

(13)

5.24 5.09 3.93

0.865

0.269

16.79

21

(14)

0..6 62 2 MTD MTD 5.48 pC o = = --0 +5.40

0.783

0.315

30.07

21

(15)

= +1.41 +1.41 pC o = -0.26 +0.66 -0.32 +3.01

0.910

0.229

19.19

21

(16)

0.949

0.175

36.09

21

(17)

pC

5 0

pC

5 0

= +1.84 +1.84 ir π pC o = -0.33 *2 π +1.02 σ σ +1.92 5

2

5

SH 5

π 4.21 π *2 ir2 4.20 σ σ 2.56 MTD MTD 2.72

π pC Q = = +1.77 ir -0.25 *2 +0.35 σ -0.28 MTD* +1.95 5

ο X=0

7.76 5.57 1.62 4.96

or S

In Pesticide Synthesis Through Rational Approaches; Magee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

Downloaded by EMORY UNIV on June 29, 2014 | http://pubs.acs.org Publication Date: June 26, 1984 | doi: 10.1021/bk-1984-0255.ch016

16.

TIPKER & VERLOOP

STERIMOL

& MTD Steric Parameters in QSA R

289

t h e MTD and MTD* m e t h o d s . T h e E q u a t i o n s 10-13 a r e r e l a t e d t o t h e s e r i e s o f t h e R - a n a l o g s and 14-17 t o t h e S - d e r i v a t i v e s . E q u a t i o n 10 shows t h a t t h e p h y s i c a l p a r a m e t e r s π and σ c a n n o t d e s c r i b e t h e a c t i v i t y s i g n i f i c a n t l y . MTD a l o n e g i v e s a l r e a d y b e t t e r r e s u l t s a s shown b y E q u a t i o n 11 and c o m b i n i n g t h e M T D - v a l u e s w i t h π and σ r e s u l t s i n E q u a t i o n 12, i n w h i c h t h e σ p a r a m e t e r d o e s n ' t g i v e a significant contribution ( s e e t - v a l u e ) . T h e b e s t r e s u l t s were o b t a i n e d w i t h t h e MTD* a p p r o a c h shown i n E q u a t i o n 13. E l e c t r o n w i t h d r a w i n g s u b s t i t u e n t s w i t h a π-optimum o f 1.9 a r e f a v o u r a b l e . T h e i d e a l s t a n d a r d i s g i v e n i n F i g u r e 6. W i t h t h e compounds h a v i n g a S - c o n f i g u r a t i o n a good c o r r e l a t i o n c o u l d a l r e a d y b e o b t a i n e d w i t h o u t s t e r i c p a r a m e t e r s a s shown i n E q u a t i o n 14. I n d e e d , t h e a d d i t i o n o f t h e MTD p a r a m e t e r ( E q u a t i o n 15-16) o r MTD* ( E q u a t i o n 17) d i d i m p r o v e t h e c o r r e l a t i o n b u t t h e d i f f e r e n c e was n o t a s p r o n o u n c e d a s w i t h t h e R - s t e r e o i s o m e r s . The e x p l a n a t i o n f o r t h i s d i f f e r e n c e i n s t e r i c i n f l u e n c e m i g h t be t h e f a c t t h a t t h e R - a n a l o g s f i t e x c e l l e n t l y a t t h e r e c e p t o r and s m a l l c h a n g e s i n t h e m o l e c u l e d i s t u r b t h i s f i t r a t h e r e a s i l y , i n c o n t r a s t w i t h t h e S-compounds w h i c h d o n o t f i t w e l l s o t h a t t h e same c h a n g e s have o n l y a s m a l l e f f e c t o n t h e a l r e a d y p o o r f i t . A l s o i n t h i s example MTD* gave b e t t e r r e s u l t s t h a n MTD, e s p e c i a l l y i n t h e R s e r i e s . When l e s s s u b s t i t u e n t p o s i t i o n s a r e p r e s e n t STERIMOL c a n be used but i n t h o s e c a s e s t h e r e i s o f t e n h a r d l y a n y d i f f e r e n c e i n r e s u l t s i f compared w i t h t h e MTD* method. T h i s i s i l l u s t r a t e d b y o u r v e r s i o n o f t h e QSAR o f t h e i n s e c t i c i d a l a c t i v i t y a g a i n s t A m e r i c a n c o c k r o a c h e s o f 36 s u b s t i t u t e d b e n z y l chrysanthemates. The b i o l o g i c a l d a t a were p u b l i s h e d b y Nakagawa e t a l . (11) and we used f o r t h i s example t h e minimum m o l a r d o s e t o c a u s e d e a t h (MLD) w i t h o u t a d d i t i o n o f s y n e r g i s t s . T h e a u t h o r s s p l i t up t h e s e r i e s i n o r t h o , meta and p a r a s u b s t i t u t e d s u b s e r i e s and t h e y f o u n d t h a t t h e b i o l o g i c a l a c t i v i t i e s c o u l d be c o r r e l a t e d w i t h t h e Van d e r W a a l s volume i n a way w h i c h was d e p e n d e n t o n t h e s u b s t i t u t i o n p o s i t i o n . We have p u t a l l t h e compounds t o g e t h e r and compared t h e d i f f e r e n t s t e r i c a p p r o a c h e s . T h e r e s u l t s a r e summarized i n T a b l e IV.

HOOC-C-X-

• f avourable •unfavourable A indifferent

F i g u r e 6. S t a n d a r d s used i n E q u a t i o n 13 ( l e f t ) and i n E q u a t i o n 17 ( r i g h t ) t o o b t a i n MTD* v a l u e s i n a s e r i e s of stereo isomers o f phenoxypropionic a c i d s .

In Pesticide Synthesis Through Rational Approaches; Magee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

290

PESTICIDE SYNTHESIS THROUGH RATIONAL APPROACHES

T a b l e IV. I n s e c t i c i d a l a c t i v i t y a g a i n s t American cockroaches of 36 s u b s t i t u t e d b e n z y l c h r y s a n t h e m a t e s .

Downloaded by EMORY UNIV on June 29, 2014 | http://pubs.acs.org Publication Date: June 26, 1984 | doi: 10.1021/bk-1984-0255.ch016

C00CH2-^~^

l o g ( l / M L D ) = +0.44 +0.62 +0.86 -0.14 +4.98

t dVw o r t h o 6.28 dVw meta 12.56 4.88 dVw p a r a dVw p a r a 3.21

-0.40 MTD +9.62

r 0.915

s 0.377

F 40.21 ( 1 8 )

0.896

0.409

43.61 ( 1 9 )

0.902

0.386

2

l o g ( l / M L D ) = +0.41 B5 o r t h o 5.50 +0.63 B5 meta 1 1 . 3 4 +0.46 L p a r a 4.83 +3.09 log(l/MLD)

R

12.19

148.5

(20)

E q u a t i o n s 18-20 g i v e a b o u t t h e same r e s u l t s and t h e s t a n d a r d o b t a i n e d i n t h e p r o c e d u r e t h a t l e d t o E q u a t i o n 20 i s shown i n F i g u r e 7. S i n c e t h e s e e q u a t i o n s c o n t a i n o n l y s t e r i c p a r a m e t e r s , t h e p i c t u r e o b t a i n e d f r o m t h e MTD method c a n d i r e c t l y be used t o compare t h e b i o l o g i c a l a c t i v i t y o f t h e compounds. MTD* and MTD a r e i n p r i n c i p l e t h e same i n t h i s example b e c a u s e no e l e c t r o n i c and h y d r o p h o b i c p a r a m e t e r s a r e i n v o l v e d . However, e x t r a p o l a t i o n outside t h e hypermolecule i s not p e r m i s s i b l e . A n o t h e r example i s t h e h e r b i c i d a l a c t i v i t y o f s u b s t i t u t e d n i t r o p h e n o l s , expressed as t h e i n h i b i t i o n o f t h e H i l l r e a c t i o n . In a s e r i e s o f 28 compounds w i t h 3 s u b s t i t u t i o n p o s i t i o n s , MTD MTD* a n d STERIMOL were compared ( 5 ) . T h e b i o l o g i c a l v a l u e s were t a k e n f r o m t h e work o f T r e b s t and D r a b e r ( 1 2 ) and t h e r e s u l t s a r e summarized i n T a b l e V. T h e r e i s a l r e a d y a s i g n i f i c a n t c o r r e l a t i o n w i t h π a l o n e , a s c a n be seen f r o m E q u a t i o n 2 1 , b u t i t c a n be improved by a d d i n g B l t e r m s f o r b o t h o r t h o s u b s t i t u e n t s . E q u a t i o n 22 shows t h e r e s u l t . T h e more s t e r i c h i n d r a n c e o f t h e h y d r o x y l g r o u p , t h e more t h e i n h i b i t i o n i n c r e a s e s . The MTD* a p p r o a c h l e d t o E q u a t i o n 23 and i t i s s t a t i s t i c a l l y as good a s E q u a t i o n 2 2 . T h e s t a n d a r d o b t a i n e d w i t h t h i s p r o c e d u r e i s shown i n F i g u r e 8. O p t i m i z a t i o n i n t h e a b s e n c e o f π y i e l d e d E q u a t i o n 2 4 . The MTD v a l u e s used i n E q u a t i o n 24 t u r n e d t o be h i g h l y c o r r e l a t e d with t h e π v a l u e s (r=0.924), so t h a t combination o f t h e parameters gave no s i g n i f i c a n t improvement i n E q . 2 5 . The i n t e r c o r r e l a t i o n

In Pesticide Synthesis Through Rational Approaches; Magee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

Downloaded by EMORY UNIV on June 29, 2014 | http://pubs.acs.org Publication Date: June 26, 1984 | doi: 10.1021/bk-1984-0255.ch016

TIPKER & VERLOOP

STERIMOL

& MTD Steric Parameters in QSAR

• favourable • unfavourable A indifferent

F i g u r e 7. S t a n d a r d used i n E q u a t i o n 20 t o o b t a i n MTD values i n a s e r i e s of benzyl chrysanthemates.

• favourable • unfavourable A indifferent

F i g u r e 8. S t a n d a r d used i n E q u a t i o n 23 t o o b t a i n MTD* values in a series of nitrophenols.

In Pesticide Synthesis Through Rational Approaches; Magee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

PESTICIDE SYNTHESIS THROUGH RATIONAL APPROACHES

292

o f π and MTD* i n E q u a t i o n 23 however i s v e r y low (r=0.001). So, we c o n c l u d e t h a t i f a v a r i a b l e ( i n t h i s example π ) i s a l r e a d y c o r r e l a t e d w i t h t h e b i o l o g i c a l a c t i v i t y , a MTD o p t i m i z a t i o n w i t h o u t t h i s v a r i a b l e o f t e n p r o d u c e s a MTD p a r a m e t e r t h a t i s i n t e r c o r r e l a t e d w i t h t h a t v a r i a b l e . On t h e o t h e r hand an o p t i m i z a t i o n i n t h e p r e s e n c e o f t h i s v a r i a b l e (MTD*) w i l l r e d u c e t h e r e s i d u a l sum o f s q u a r e s and w i l l p r e v e n t a n i n t e r c o r r e l a t i o n . T a b l e V.

I n h i b i t i o n H i l l r e a c t i o n by 28 n i t r o p h e n o l s

Downloaded by EMORY UNIV on June 29, 2014 | http://pubs.acs.org Publication Date: June 26, 1984 | doi: 10.1021/bk-1984-0255.ch016

/Rl

t pl50 -

+

0.98 π +3.38

+

pl50 = 0 . 6 3 π +0.88 Β1

r

s

8.61

0.860

0.589

F 74.15

(21)

7.37

0.958

0.344

89.75

(22)

0.942

0.396

98.28

(23)

o r t h o R l 4.22 +1.34 B l o r t h o R2 6.82

+0.23 +

pl50 = 0 . 9 8 π

-0.75

12.80

MTD*

5.70

= -1.22 MTD +7.83

9,40

0.879

0.551

88.42

(24)

1.36 2.38

0.888

0.542

46.60

(25)

+6.37 pl

5 0

pl50 - +0.37 π -0.80 MTD +6.21

When t h e number o f o b s e r v a t i o n s i n c r e a s e s and more v a r i a b l e s a r e a l l o w e d , STERIMOL a p p e a r s t o be b e t t e r b e c a u s e o f i t s more p r e c i s e d e s c r i p t i o n o f t h e s h a p e o f s u b s t i t u e n t s . A QSAR a n a l y s i s o f t h e l a r v i c i d a l a c t i v i t y o f 61 s u b s t i t u t e d b e n z o y l u r e a s i s a n example o f t h i s . T h e a c t i v i t y a g a i n s t P i e r i s b r a s s i c a e i s e x p r e s s e d a s LD5Q ( i n ppm) and t h e s e v a l u e s a r e p u b l i s h e d b y W e l l i n g a e t a l . (13). T h e QSAR r e s u l t s a r e g i v e n i n T a b l e V I . E q u a t i o n 26 shows t h a t o n l y t h e i n d i c a t o r p a r a m e t e r D l , w h i c h d i s c r i m i n a t e s between t h e 2,6-C12 and t h e 2,6-F2 d e r i v a t i v e s , gives a s i g n i f i c a n t contribution t o the regression i f s t e r i c p a r a m e t e r s a r e o m i t t e d . MTD on i t ' s own g i v e s o n l y a p o o r c o r r e l a t i o n w h i c h c a n b e s e e n f r o m E q u a t i o n 27. C o m b i n a t i o n w i t h

In Pesticide Synthesis Through Rational Approaches; Magee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

16.

TIPKER & VERLOOP

STERIMOL

& MTD Steric Parameters in QSAR

293

T a b l e V I . L a r v i c i d a l e f f e c t a g a i n s t P i e r i s b r a s s i c a e o f 61 s u b s t i t u t e d benzoyl phenyl ureas.

(CH )

Downloaded by EMORY UNIV on June 29, 2014 | http://pubs.acs.org Publication Date: June 26, 1984 | doi: 10.1021/bk-1984-0255.ch016

3

t 1.34 1.67 6.75 0.93

r 0.710

s 0.805

14.27 ( 2 6 )

4.61

0.515

0.956

21.28 ( 2 7 )

- l o g ( L D ) = -0.68 MTD +0.52 Σ π +0.48 oR +1.56 D l -0.44 D2 +0.25

7.02 5.01 1.82 7.34 1.91

0.862

0.585

31.84 ( 2 8 )

- l o g ( L D ) = -0.64 MTD* +0.55 Σ π +0.37 oR +1.56 D l -0.50 D2 +0.18

7.10 5.15 1.41 7.33 2.13

0.861

0.589

31.56 ( 2 9 )

4.86 2.87 8.63 7.16 6.50 7.60 2.58

0.899

0.514

32.08 ( 3 0 )

- l o g ( L D ) == +0.17 Σ π +0.60 oR +1.91 D l * -0.30 D2e -0.88 5 0

= -0.61 MTD +1.09 5 0

5 0

2

• l o g ( L 0 ) == -0.03 L p a r a -0.20 B5 p a r a -1.31 L meta +0.82 Σ π +1.76 oR +1.48 D l -0.53 D2 +2.57 5 0

δ D1=0 f o r 2.6-C12 compounds a n d D l = l f o r 2.6-F2 d e r i v a t i v e s ε D2=0 f o r N(H) and D2=l f o r N(CH ) compounds 3

In Pesticide Synthesis Through Rational Approaches; Magee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

294

PESTICIDE SYNTHESIS THROUGH RATIONAL APPROACHES

Downloaded by EMORY UNIV on June 29, 2014 | http://pubs.acs.org Publication Date: June 26, 1984 | doi: 10.1021/bk-1984-0255.ch016

t h e v a r i a b l e s used i n E q u a t i o n 26 l e a d s t o an improved r e s u l t : E q u a t i o n 2 8 . T h e MTD* p r o c e d u r e g i v e s no b e t t e r c o r r e l a t i o n , f o r t h e E q u a t i o n s 28 and 29 a r e a b o u t t h e same. T h e main r e a s o n f o r t h e l a c k o f d i f f e r e n c e between MTD and MTD* i s f o u n d i n t h e low i n t e r c o r r e l a t i o n s between t h e s e p a r a m e t e r s and t h e o t h e r p h y s i c a l p a r a m e t e r s . E q u a t i o n 30 shows t h e r e s u l t o f t h e STERIMOL a p p r o a c h . B o t h i n d i c a t o r p a r a m e t e r s and t h e σ t e r m g i v e a s i g n i f i c a n t c o n t r i b u t i o n t o t h e r e g r e s s i o n and i t c a n b e concluded t h a t e l e c t r o n withdrawing groups with a l i p o p h i l i c c h a r a c t e r and s u b s t i t u t e d a t t h e p a r a p o s i t i o n a r e p r e f e r a b l e . When t h e s u b s t i t u e n t s become t o o l a r g e , t h e s q u a r e o f L becomes more i m p o r t a n t , w h i c h r e s u l t s i n a d e c r e a s e i n a c t i v i t y . T h e 2,6-F2 compounds a r e f a r more a c t i v e t h a n t h e c h l o r o a n a l o g s . N-methylation causes a s l i g h t decrease i n a c t i v i t y . D i s c u s s i o n and C o n c l u s i o n s We t r i e d t o summarize t h e QSAR s t u d i e s d i c u s s e d i n a r o u g h way i n Table VII T a b l e V I I . Comparison parameters. Series

o f u s e f u l n e s s o f MTD, MTD* and STERIMOL Number o f

members s u b s t i t u t i o n positions DDT a n a l o g s 21 1 5 31 Benzonitriles 5 P h e n o x y p r o p i o n i c a c i d s 21/24 Benzyl chrysanthemates 36 3 Nitro-phenols 28 3 61 2 Benzoylphenylureas

Relative quality of equation with MTD MTD* STERIMOL -

±

+

±

+ +

-

+

+ + +

± +

( ) +

±

±

T h e s e r e s u l t s g i v e some i n s i g h t i n t h e s c o p e and l i m i t a t i o n s o f t h e MTD, MTD* and STERIMOL p a r a m e t e r s . L e t us f i r s t compare t h e MTD and MTD* m e t h o d s . I n t h e example o f t h e b e n z y l c h r y s a n t h e m a t e s t h e r e g r e s s i o n e q u a t i o n s have o n l y s t e r i c t e r m s , s o t h a t t h e r e i s no d i f f e r e n c e between t h e two methods i n p r i n c i p l e . In t h e case o f t h e benzoylphenyl ureas t h e i n t e r c o r r e l a t i o n between t h e MTD v a l u e s and t h e o t h e r p a r a m e t e r s i s v e r y low, s o i t i s u n d e r s t a n d a b l e t h a t t h e r e i s h a r d l y any d i f f e r e n c e . B u t i n t h e f o u r o t h e r s t u d i e s t h e r e was much more i n t e r c o r r e l a t i o n between t h e MTD v a l u e s on t h e o n e hand and t h e e l e c t r o n i c a n d / o r h y d r o p h o b i c p a r a m e t e r s o n t h e o t h e r hand, and i n t h e s e c a s e s t h e MTD * method g i v e s s l i g h t l y b e t t e r r e s u l t s . Our p r e l i m i n a r y c o n c l u s i o n f r o m t h e e x a m p l e s d i s c u s s e d , i s t h a t t h e MTD* i s t h e p r e f e r a b l e o n e , b o t h f r o m f u n d a m e n t a l and

In Pesticide Synthesis Through Rational Approaches; Magee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

Downloaded by EMORY UNIV on June 29, 2014 | http://pubs.acs.org Publication Date: June 26, 1984 | doi: 10.1021/bk-1984-0255.ch016

16.

TIPKER & VERLOOP

STERIMOL

& MTD Steric Parameters in QSAR

295

p r a c t i c a l p o i n t o f view. We e x p e c t t h a t t h i s c o n c l u s i o n w i l l b e c o n f i r m e d i n o t h e r QSAR s t u d i e s . The c h o i c e b e t w e e n t h e STERIMOL and MTD* a p p r o a c h e s i s d e p e n d e n t o n some p r o p e r t i e s o f t h e s e r i e s s t u d i e d , e . g . t h e number o f members i n r e l a t i o n t o t h e number o f s u b s t i t u t i o n p o s i t i o n s I n t h o s e c a s e s where t h e r e s u l t i n g d e g r e e s o f f r e e d o m a r e s u f f i c i e n t , t h e STERIMOL a p p r o a c h g i v e s t h e most s a t i s f a c t o r y r e s u l t s ( e . g . i n t h e s t u d i e s o n t h e DDT a n a l o g s and t o a l e s s e r e x t e n t i n b e n z o y l p h e n y l u r e a s ; T a b l e V I I ) . But i n o p p o s i t e c a s e s , i . e . t h e QSAR's o f t h e b e n z o n i t r i l e s and t h e p h e n o x y p r o p i o n i c a c i d s , t h e STERIMOL p a r a m e t e r s c a n n o t b e u s e d . The s t u d i e s o n t h e c h r y s a n t h e m a t e s and t h e n i t r o p h e n o l s a r e o f an i n t e r m e d i a t e c h a r a c t e r . B u t i n s u c h c a s e s t h e STERIMOL a p p r o a c h i s o f t e n s t i l l p r e f e r a b l e b e c a u s e o f i t s h i g h e r p r e d i c t i v e power; we have i l l u s t r a t e d t h a t i n an e a r l i e r s t u d y on t h e p l a n t g r o w t h regulating a c t i v i t y of substituted phenoxyacetic acids (4). This phenomenon i s p r o b a b l y c a u s e d by t h e f a c t t h a t t h e STERIMOL parameters a r e independent geometric measures, i n c o n t r a s t t o t h e MTD* p a r a m e t e r s w h i c h a r e i n i t i a t e d by t h e b i o l o g i c a l d a t a and t h u s n o t i n d e p e n d e n t . B e s i d e s t h e MTD* v a l u e s a r e o b t a i n e d a f t e r an o p t i m i z a t i o n w i t h many r e g r e s s i o n a n a l y s e s w h i c h m i g h t more e a s i l y g i v e r i s e t o chance c o r r e l a t i o n s o r o v e r r a t i n g o f t h e s t a t i s t i c a l c r i t e r i a . T h e r e f o r e r a n d o m i z a t i o n o r s p l i t t i n g up t h e d a t a i n a t r a i n i n g and a n e v a l u a t i o n s e t a r e needed t o v e r i f y a MTD* a p p r o a c h ( 8 ) . B u t i f t h e o b t a i n e d r e s u l t s a r e s i g n i f i c a n t , the standard molecule can help t o v i s u a l i z e the s t e r i c aspects o f QSAR. The c h o i c e between t h e MTD* and STERIMOL a p p r o a c h e s i s i n f l u e n c e d b y s t i l l o t h e r f a c t o r s such as t h e r e p r o d u c i b i l i t y and t h e c o m p u t e r t i m e needed (5J. Our t e n t a t i v e c o n l u s i o n i s t h a t t h e STERIMOL a p p r o a c h has t h e g r e a t e s t a d v a n t a g e s p r o v i d e d t h a t t h e chemical s e r i e s s t u d i e d allows i t s a p p l i c a t i o n . I f that i s not t h e c a s e t h e n t h e MTD* method c a n be u s e f u l , n o t w i t h s t a n d i n g i t s r e s t r i c t e d a p p l i c a b i l i t y o f p r e d i c t i v e purposes.

Literature Cited 1. Verloop, Α.; Hoogenstraaten, W.; Tipker, J., in "Drug Design" Ariens, E. J . Ed.; Academic Press: New York, 1976, Vol. VII, pp. 165-207. 2. Verloop, Α., in proc. 5th Int. Congress of Pest. Chem., Miyamoto, J.; Kearney, P. C . , Eds.; Pergamon Press, Oxford 1983, vol 1, pp 339-344 3. Verloop, Α.; Tipker, J., in "Biological Activity and Chemical Structure"; Keverling Buisman, J . Α., Ed.; Elsevier: Amsterdam, 1977; pp. 63-81. 4. Verloop, Α., Phil. Trans. R. Soc. Lond. 1981, B295, pp. 45-55. 5. Verloop, Α.; van den Berg, G.; Tipker, J., in "Recent Advances in Weed Research."; Fletcher, W. W., Ed.; Common Wealth Agricultural Bureaux. England; Slough, 1983; pp. 79-103.

In Pesticide Synthesis Through Rational Approaches; Magee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

Downloaded by EMORY UNIV on June 29, 2014 | http://pubs.acs.org Publication Date: June 26, 1984 | doi: 10.1021/bk-1984-0255.ch016

296

PESTICIDE SYNTHESIS

T H R O U G H RATIONAL

APPROACHES

6. Simon, Z.; Chiriac, Α.; Motoc, I.; Holban, S.; Ciubotaru, D.; Szabadai, Z. Stud. Biophys. 1976, 55, pp. 217-226. 7. Balaban, A. T.; Chiriac, Α.; Motoc, I.; Simon, Z. in LECTURE NOTES IN CHEMISTRY, Berthier, G. et a l . Eds. vol. 15, Springer-Verlag: Berlin, 1980. 8. Hoogenstraaten, W; Tipker, J. to be published. 9. Brown, D. B.; Metcalf, R. L . ; Sternburg, J . G.; Coats, J. R. Pestic. Biochem. Physiol. 1981, 15, pp. 43-57. 10. Lien, E. J.; Rodrigues de Miranda, J. F . ; Ariens, E. J . Mol. Pharmacol. 1976, 12, pp. 598-604. 11. Nakagawa, S.; Okajima, N.; Kitahaba, T.; Nishimura, K.; Fujita, T.; Nakajima, M. Pestic. Biochem. Physiol. 1982, 17, pp. 243-258. 12. Trebst, Α.; Draber, W., in "Advances in Pesticide Science"; Geissbuhler, G. T. et a l . Eds. Pergamon Press: Oxford, 1979, pp. 223-234. 13. Wellinga, K.; Mulder, R.; Van Daalen, J. J. J. Agric. Food Chem., 1973, 21, 993. RECEIVED December 23,

1983

In Pesticide Synthesis Through Rational Approaches; Magee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.