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

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.


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



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.



hypermolecule


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.



16.

STERIMOL

TIPKER & VERLOOP


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 .


284


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 .


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 .


16.

TIPKER & VERLOOP

STERIMOL

& MTD

Steric Parameters in QSAR

285


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



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


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


TIPKER & VERLOOP

STERIMOL


H5C20-^~^-C


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.


288


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


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



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 .


290


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 .


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



TIPKER & VERLOOP

STERIMOL



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.


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.



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


/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


16.

TIPKER & VERLOOP

STERIMOL


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 )


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


294



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



16.

TIPKER & VERLOOP

STERIMOL


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.



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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,

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