Biphenylmethyl Pyrethroids - American Chemical Society

17 Biphenylmethyl Pyrethroids

Downloaded by CALIFORNIA INST OF TECHNOLOGY on March 30, 2017 | http://pubs.acs.org Publication Date: June 26, 1984 | doi: 10.1021/bk-1984-0255.ch017

A Quantitative Structure-Activity Relationship Approach to Pesticide Design ERNEST L. PLUMMER FMC Corporation, Princeton, NJ 08540

A major portion of successful pesticide design comes from continued work in areas where there i s already a considerable body of knowledge. The probability of success for these programs can be improved s i g n i f i c a n t l y by adopting the systematic approach embodied i n current QSAR (Quantitative Structure A c t i v i t y Relationship) strategies. These strategies not only provide techniques for rapid optimization of leads but when applied to t h e i r f u l l e s t c a p a b i l i t i e s can provide models from which new lead areas can be generated. Synthetic pyrethroid insecticides represent a p a r t i c u l a r l y timely example of a mature pesticide area that has received continued interest well after the pioneering works of Michael Elliott and others had established seemingly complete structure-activity relationships (1,2). In 1976 our laboratory began a program aimed at finding and developing novel synthetic pyrethroid insecticides. Following basic QSAR strategies we were able to not only identify a novel lead area but to quickly optimize a c t i v i t y i n that area, and ultimately to identify additional novel structures that possess the broad spectrum i n s e c t i c i d a l and a c a r i c i d a l a c t i v i t y that differentiates this class of pyrethroid insecticides from other synthetic pyrethrin analogs. Our application of QSAR strategies to this problem is the subject of this report. F i r s t two important elements must be present for a QSAR strategy to succeed; accurate b i o l o g i c a l data and a readily accessible, easy to use data analysis system. 0097-6156/ 84/ 0255-0297S06.75/ 0 © 1984 American Chemical Society

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


298

PESTICIDE SYNTHESIS THROUGH RATIONAL APPROACHES

FMC i s p r i m a r i l y i n t e r e s t e d i n the development o f i n s e c t i c i d e s f o r a g r i c u l t u r a l a p p l i c a t i o n s . Since the l a r g e s t s i n g l e c l a s s of i n s e c t pests of a g r i c u l t u r e are the l e p i d o p t e r a n s we c h o s e a r e p r e s e n t a t i v e o f t h i s c l a s s , the southern armyworm, for development of our structure a c t i v i t y r e l a t i o n s h i p s . Although f o l i a r a p p l i c a t i o n and e v a l u a t i o n o f i n s e c t i c i d e s more accur a t e l y represents f i e l d c o n d i t i o n s , we f o u n d t h a t more r e l i a b l e d a t a c o u l d be o b t a i n e d u s i n g t o p i c a l a p p l i c a t i o n (Figure 1). Not o n l y i s the e x a c t amount o f compound a p p l i e d to the i n s e c t known i n t o p i c a l t e s t s but the amount r e a c h i n g the a c t i v e s i t e depends o n l y on i n t r i n s i c c h a r a c t e r i s t i c s o f the organism not on the i n t e r a c t i o n o f the compound w i t h the host p l a n t and i t s e n v i r o n m e n t n o r on how much t h e i n s e c t consumes b e f o r e i t d i e s . A l l t e s t s were run i n the presence o f a standard, permethrin, and the r e s u l t s are expressed as r e l a t i v e potency. T h i s value was converted to i t s negative l o g a r i t h m f o r r e g r e s s i o n a n a l y s i s . A l t h o u g h southern armyworms were used f o r the dev e l o p m e n t o f QSARs the o t h e r i n s e c t s l i s t e d i n F i g u r e 2 were used i n t o p i c a l or f o l i a r assays to monitor spectrum and performance under f i e l d c o n d i t i o n s . As t h i s study was i n p r o g r e s s we w e r e a l s o i n the process of d e v e l o p i n g the necessary data a n a l y s i s system. The computer based system t h a t appears i n F i g u r e 3 was d e v e l o p e d l a r g e l y as a r e s u l t o f the p y r e t h r o i d program and thus can be v i e w e d as a secondary product. T h i s s y s t e m was c o n s t r u c t e d on the c o n c e p t t h a t s t r u c t u r e a c t i v i t y studies are best performed by the s c i e n t i s t r e s p o n s i b l e for the design and synthesis o f t a r g e t p e s t i c i d e s . We f o u n d t h a t o n e o f t h e major impediments to the l a b o r a t o r y c h e m i s t ' s a p p l i c a t i o n o f a QSAR s t r a t e g y i s the tedium o f assembling p h y s i c o chemical parameters and b i o l o g i c a l data i n a form t h a t can be submitted to the a p p l i c a b l e s t a t i s t i c a l p r o gram. To o v e r c o m e t h i s b a r r i e r we h a v e w r i t t e n a simple computer process that a u t o m a t i c a l l y w r i t e s the necessary tables for submission to our s t a t i s t i c a l package, t h e U n i v e r s i t y o f C a l i f o r n i a ' s BMDP(3) S t a t i s t i c a l Software. M o l e c u l a r D e s i g n L i m i t e d ' s MACCS system(4) i s used to assemble a f i l e o f compounds o f i n t e r e s t . U s i n g FMC r e f e r e n c e numbers as keys t h i s f i l e i s used to c o n s u l t our b i o l o g i c a l data base f o r the r e q u i r e d data. The same MACCS f i l e i s used to search a separate chemical f i l e where substituents on FMC n u m b e r e d c o m p o u n d s a r e i d e n t i f i e d w i t h a simple Wisswesser L i n e N o t a t i o n code. T h i s l a t t e r i n f o r m a -


Design of Biphenylmethyl Pyrethroids


PLUMMER

Topical • 1 μΙ Acetone Solution • 24 Hour Mortality

Foliar • Plant Sprayed With Water/Acetone Solution • 48 Hour Mortality Relative Potency = «-Dso (LC50) FMC 33297 (Permethrin) LD50 (LC50) Test Compound

F i g u r e 1. biological

Evaluation response.

Species Southern Army worm (Spodoptera Eridania)

(SAW)

Cabbage Looper (Trichoplusia Ni)

(CL)

Tobacco Budworm (Heliothis Virescens)

(TBW)

Mexican Bean Beetle (Epilachna Varivestis)

(MBB)

Large Milkweed Bug (Oncopeltus Fasciatus)

(MWB)

Twospotted Spider Mite (Tetranychus Urticae)

(TSM)

Pea Aphid (Acyrthosiphon Pisum)

(PA)

Figure

2.

Evaluation of b i o l o g i c a l

response.




QUALITATIVE ANALYSIS

QUANTITATIVE ANALYSIS

Figure

3.

QSAR

system.


17.

PLU M MER


301


t i o n i s used to c o n s u l t a table o f p h y s i o c o c h e m i c a l parameters. I n t h i s t a b l e we s t o r e data for p i , s i g m a , F , R, a n d MR f r o m H a n s c h ' s t a b u l a t i o n s ( 5 ) and the STERIMOL p a r a m e t e r s L , B l and B4 ( 6 ) . T h i s data is used to generate a t a b l e that i n c l u d e s parameter data f o r each p o s i t i o n on an aromatic r i n g , the sum of parameters f o r one o r more r i n g s when appropriate and the relevant b i o l o g i c a l response data. Q u a n t i t a t i v e and q u a l i t a t i v e a r e a v a i l a b l e t h r o u g h t h e BMDP p a b i l i t i e s o f o u r d a t a managment D a t a R e t r i e v a l S y s t e m ( D R S ) (7). c u l a r l y important to have the p l ly a v a i l a b l e since t h i s i s , as I s e v e r a l examples, an important f of s t r u c t u r e - a c t i v i t y data.

a n a l y s i s f a c i l i t i e s rograms and the capsystem, the A . D . M . We f i n d i t p a r t i o t t i n g programs r e a d i w i l l i l l u s t r a t e by i r s t step i n a n a l y s i s

• We h a v e a l s o a d d e d t h e c a p a b i l i t i e s o f D r . H o p f i n g e r ' s CHEMLAB package{8) w h i c h can be used to g e n e r a t e new p a r a m e t e r s f o r a n a l y s i s o r c a n be u s e d i n a more q u a l i t a t i v e f a s h i o n f o r c o n f o r m a t i o n a l a n a l y s i s based on m o l e c u l a r mechanics. Our s e a r c h f o r a new l e a d i n the p y r e t h r o i d area s t a r t e d w i t h a simple p r o p o s i t i o n : It has been suggested t h a t f o r a p y r e t h r o i d e s t e r to be a c t i v e i t must have an a l c o h o l w i t h the s p e c i f i c feature o f two c e n t e r s o f u n s a t u r a t i o n separated by a b r i d g i n g group (1/2.) (Figure 4). In the case o f a l l e t h r i n and r e s methrin the b r i d g i n g atom i s a methylene group. In permethrin i t i s an oxygen atom. I f t h i s i s a r e quirement, one s h o u l d be a b l e t o express i t w i t h some physicochemical parameter or set o f parameters. In the i n i t i a l p h a s e o f o u r w o r k we p r e p a r e d a set of b e n z y l e s t e r s of the 3 - ( 2 , 2 - d i c h l o r o e t h e 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) w h i c h were monosubstituted i n the meta p o s i t i o n . The s u b s t i tuents were chosen to cover a broad spectrum o f p h y s i cochemical parameter space by s e l e c t i n g them from Hansch's c l u s t e r sets (9). In a d d i t i o n , substituents w i t h no b r i d g i n g group, one atom and two atom bridges were i n c l u d e d to probe the need f o r a b r i d g i n g atom. A s we h a v e p r e v i o u s l y r e p o r t e d ( 1 0 ) r e g r e s s i o n anal y s i s o f the data f o r a l l compounds gave poor c o r r e l a t i o n s on a l l our tabulated parameters. But on examina t i o n o f the p l o t ( F i g u r e 5) o f l i p o p h i l i c i t y versus s o u t h e r n a r m y w o r m a c t i v i t y we f o u n d t h a t , w i t h t h e exc e p t i o n o f four two-atom bridged compounds, t h i s param e t e r c o u l d e x p l a i n u p t o 86% o f t h e v a r i a t i o n i n the b i o l o g i c a l data. A t t h i s p o i n t we c o n s i d e r e d t h e two atom b r i d g e d substituents o u t l i e r s , p r i m a r i l y because of t h e i r common f e a t u r e . B y d o i n g so we h a d a u s e f u l model from which to continue our d e s i g n work.




302

Cl

Cl

Permethrin Figure

4.

Bridging

atoms o f p y r e t h r o i d

alcohols.


PLU M MER



17.

(

Biphenylmethyl Pyrethroids - American Chemical Society

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