Insecticidally Active Conformations of Pyrethroids

6 Insecticidally ActiveConformationsof Pyrethroids MICHAEL ELLIOTT, ANDREW W. FARNHAM, NORMAN F. JANES, PAUL H . N E E D H A M , and DAVID A. PULMAN Downloaded by UNIV OF ARIZONA on March 9, 2017 | http://pubs.acs.org Publication Date: June 1, 1974 | doi: 10.1021/bk-1974-0002.ch006

Rothamsted Experimental Station, Harpenden, Hertfordshire, AL5 2JQ, England

The most active pyrethroids are effective at 0.03 mg/kg insect bodyweight (0.002 mg/kg with synergist), and small changes in structure and configuration greatly affect their potency. Therefore, the mechanism of their action as insecticides must involve very specific interference with the biological system. The information available on the nature of the site of action from a study of molecular conformations of active compounds is reviewed. The factors considered are (a) the essential requirements for activity (b) how modifications of substituents affect activity and speed of action (c) the influence of polarity (d) the influence of asymmetric substituents. Many powerful toxicants act by interfering with a specific component essential for normal functioning of the organism. Effectiveness at doses less than 25 mg/kg i s considered to indicate such specificity (1). Table 1 shows the range of concentrations at which some mammalian poisons and insecticides act. The diversity of organisms and routes of administration necessarily limits the value of such comparisons but the figures i l l u s t r a t e that, as a group, pyrethroids are at least as active as other insecticides. Further, some recently developed pyrethroids, discussed here, are more potent than other insecticides, of whatever class, under our test conditions and act at concentrations comparable with other categories of outstandingly active poisons. The lethal action of a toxic compound may be interpreted as a dynamic process at the target, i n which an important factor i s the strength of bonding with the receptor. This depends on the extent to which the chemical and stereochemical features of the poison and site of action complement one another. Knowing the conformation of very active biological 80 Kohn; Mechanism of Pesticide Action ACS Symposium Series; American Chemical Society: Washington, DC, 1974.

Downloaded by UNIV OF ARIZONA on March 9, 2017 | http://pubs.acs.org Publication Date: June 1, 1974 | doi: 10.1021/bk-1974-0002.ch006

β.

ELLIOTT

ET AL.

Active Conformations of Pyrethroids

81

agents should help locate and identify such sites of action. The purpose of this communication i s to discuss these factors for the pyrethroids, especially the most potent members of the class. To compare results from many different tests, insecticide! potency i s here expressed relative to bioresmethrin, given the value of 100, as standard. The relative potency of different pyrethroids depends particularly on the insect species tested, so that generalised structure-activity relationships cannot be deduced from tests against one species. Therefore, here broad trends are indicated by approximate relative a c t i v i t i e s to both houseflies (HF) (Musca domestica L.) and mustard beetles (MB) (Phaedon cochleariae Fab.) determined by topical application of measured drops i n acetone, as described i n detail elsewhere (2)· The results are appropriately considered with reference to pyrethrins I and II, (Figure 1) the most important constituents of pyrethrum extract (£, k) · Both these compounds contain the basic structural features required for the most active compounds. These are methyl groups held by the carboxylic ester function of the cyclopropane ring and the cyclopentenolone i n the required steric relation to an unsaturated centre (in pyrethrins I and II, the conjugated double bonds) i n the alcohol side chain. In every instance investigated so far, removing any of these features decreases a c t i v i t y (£). A variety of groups and structures c i s and trans to the carboxyl function, some greatly enhancing activity, can replace the isobutenyl side chain of chrysanthemic acid, and so direct involvement of this group i n precise f i t at the site of action i s unlikely. However, these side chains influence the overall properties, including polarity, of the molecules, and i n the active conformations of the esters are oriented so as not to impede interaction of the dimethyl group with the site of action when the unsaturated side chain i s correctly positioned. Recently, (6) many of the most active pyrethroids, including pyrethrin I, have been found to have polarities (expressed by their octanol-water partition coefficients) within a narrow range of values. An important contribution of the acid side chain, therefore, appears to be to influence the polarity of the molecule from this s t e r i c a l l y unobtrusive position. This concept i s illustrated by comparing pyrethrin I with pyrethrin II, i n which a methoxycarbonyl group replaces methyl, where shown. Pyrethrin II i s more polar than pyrethin I, having a partition coefficient similar to other pyrethroids which are effective knockdown agents (£). K i l l i n g power to most species i s diminished by the substitution.

Kohn; Mechanism of Pesticide Action ACS Symposium Series; American Chemical Society: Washington, DC, 1974.

82

MECHANISM OF

PESTICIDE

The most direct evidence about the structural features of the pyrethroids important for high activity, and concerning their conformations at the site of action, comes from bioassay results with esters of symmetrical alcohols such as 5-benzyl3-furylmethyl alcohol (8, £) 3-phenoxy-benzyl alcohol (£, 10) (Figure 2). Esters such as pyrethrin I, and S-bioallethrin, of the asymmetric alcohols pyrethrolone and allethrolone (11) give results more d i f f i c u l t to interpret, especially when only houseflies, atypical i n their response to pyrethroids, are considered. Steric requirements for the acid components of the esters are c l a r i f i e d by considering esters of [IB]- and [IS]-2, 2-dimethylcyclopropane carboxylic acids (Figure 3) which have similar insecticidal a c t i v i t y . Replacing either hydrogen atom at C-3 i n the [1R], but not i n the [IS] form with an isobutenyl substituent gives much more potent esters (2); this substitution i s possibly at a location remote from the region on the receptor accessible to the unsaturated alcoholic side chain and the methyl groups on the cyclopropane ring. The overall properties of the ester are thus modified to give improved insecticidal efficiency without interfering with the essential access to the methyl groups. In contrast, by similar operations on the [IS] ester access to the methyl groups i s impeded and insecticidal a c t i v i t i e s are much decreased. Only unsaturated side chains i n the [1R, trans] esters give high a c t i v i t y (Figure k). The isobutyl compound i s much less potent. Re-arranging the isobutenyl (natural) group to but-l(Z)-enyl increases potency and, with appropriate alcohols, the butadienyl acid gives almost the most potent esters known (12)· A l l these changes are variations of a C-4 unit and i l l u s t r a t e the great influence of diverse types of substituent at this position in the molecule. An ester (not shown) with an isobutenyl side chain, but no methyl groups on the cyclopropane ring, i s completely inactive. This evidence supports the conclusion that the dimethyl group i s an essential feature of the conformation of very active pyrethroids. This group i s also present i n the six-carbon side chain of the ethanochrysanthemate RU 11,679 ( ϋ ) and i n the halovinyl compounds (12) (Figure 5)· Here, with appropriate alcohols, exceptional insecticidal activity i s attained, greater than i n any other compound reported so far (Ik). As i n the previous series described [1R] stereochemistry at C-l i s important· The steric relationship of the methyl groups on the cyclopropane ring with respect to the alcohol i n the potent conformations w i l l now be considered. In the esters of Figure 2, pyrethrolone, 5-benzyl-3-furylmethyl alcohol and a n d


ACTION


6.


ELLIOTT E T AL.

various

gem-

side-chains dimethyl effective

group

planar

unsaturated

spacer

side-chain

1 1


C

|

s i _

/ CH

1 C H 3

°^'' \ / \ S 1 -' CO.OT H

3

83

1

^° ^

^

PYRETHRIN

H

acid : alcohol CH 0 C> 3

2

N

,„/ Figure 1.

^

"

Structural requirements for activity in pyrethroid insecticides

i l CH

3

PYRETHRIN II

i

Cft/H,

l

.0

,

w

v

,

_

_

PYRETHRIN I

Relative

Potencies

_ H £

M§_

2

160

CH

3

-Ο

π

π

r

κ

S-BIOALLETHRIN

10

BIORESMETHRIN

100

PHENOTHRIN

(30)

rans)

Figure 2.

Some active pyrethroids


4

100

70

84

MECHANISM OF PESTICIDE ACTION

Potency

Potency

C

CH, CH, moderate

H

*\^\yH H "

^3

'"COjR

b

>=\ZV

1R

^ '

1R,trans H

high

(natural form)

COjR

sidechain replacing H o r H a

CH ,CH

Q J

b

enhances a c t i o n

y^ CH

3

3 3 5

''

1R,c

3

high

CQz"

3

Cft ,CH

3


ÇH3 CH moderate

"ν/Ν,^Ρ***

3

is.trans

very l o w

1S,cis

very low

H ^/\JCOfcR. b

H.'

*H 1S

sidechain replacing H o r H a

blocks Figure 3.

action

b

CH, ^3

CH

3

.CH,

Η

Effect of introducing C-3 substituent

Relative 5-Benzyl-3~furylmethyl

Figure 4.

esters

HF

Potencies MB

Various C-3 sidechains



6.

ELLIOTT ET AL.


85

3-phenoxy-benzyl alcohol have i n common an unsaturated centre (pentadienyl, benzyl, or phenoxy) held by the cyclopentenolone ring i n pyrethrolone, the 3»5-substituted furan or the msubstituted benzene ring i n a very similar relationship to the alcohol link and thence, v i a the cyclopropane carboxylate function, to the dimethyl groups. There i s evidence that an important feature of a l l three alcohols, and of others giving potent esters, i s the a b i l i t y of the unsaturated side chain to adopt a conformation not coplanar with the ring (Figure 6). For example, the ester of the xanthene alcohol i s quite inactive. Rotation about the bond shown i n 3-phenoxybenzyl alcohol, and at corresponding positions i n 5-benzyl-3-furylmethyl alcohol and i n pyrethrolone can occur freely, but i s precluded i n the xanthene. To gain further insight into the structural requirements for effective alcoholic components, numerous substituted 5-benzyl-3-furylmethyl and 3-phenoxybenzy1 alcohols were investigated. Nearly a l l nuclear substituents on both alcohols decreased a c t i v i t y , as dido£-methyl (Figure 7) ando^-cyano groups on 5-benzyl-3-furylmethyl and 5-benzylfurfuryl esters (Figure 8). However, increased activity of the o(-cyano-3phenoxybenzylchrysanthemate prompted an examination of esters of this cyanohydrin with other effective acids, and with the [UR, cis]dibromovinyl acid i t was possible to compare the esters of the two optical enantiomers (Figure 9)· One of the cyanohydrins was obtained by addition of hydrogen cyanide to the aldehyde i n the presence of the enzyme D-oxynitrilase, and was thus available for esterification. The crystalline ester of the other enantiomer separated on standing (Figure 10)· The 5-benzyl-3-furylmethyl and 3-phenoxybenzyl esters of this acid were themselves more potent than the chrysanthemates, but the crystalline ester (NRDC l6l,Figure 11) was quite exceptional and much more active than the liquid enantiomer. The latter was l i t t l e , i f any,more active than the unsubstituted compound, so the remarkable increase i n a c t i v i t y i s produced by replacing one of the prochiral hydrogen atoms of the ©(-methylene group, whilst substituting the other has l i t t l e influence on toxicity. The absolute configuration of the crystalline isomer has been tentatively deduced to be S. On a molar basis the crystalline isomer i s 20-30 times more active than bioresmethrin, i t s e l f more potent than many other established insecticides. From the considerations discussed at the beginning of this communication, such a c t i v i t y should indicate a very specific interaction with a receptor s i t e , which other work suggests i s probably i n the central nervous system of the insect (1£). This compound may therefore be the most effective agent yet available to investigate the mechanism of action of this group of


86

MECHANISM

O F PESTICIDE ACTION

Relative Potencies of Isomers to houseflies


C

^

=

C

H

^V

C H

*

1R,trans

"C0 CH 2

2fï

j,

f^^j|

^C=CH

1S,trans

1R,cis

100

0.5

40

250

3

260

110

-

170

α ^C=CH

Br

Figure 5. Replacement of methyl by halogen

(1R, trans )-chrysanthemates


1%cis low

14

6.

Εΐυοττ ET AL.

87


Relative HF

MB


(1R trans)-chrysanthemates

Potencies

Figure 8.

Effect of a-cyano group


88



R-form:

Selective destruction

of S - i s o m e r

with D-oxynitrilase, then S-form:

esterification

C r y s t a l l i s a t i o n f r o m m i x t u r e of e s t e r s

Figure 9.

Synthesis of isomeric cyano-esters

Relative

Potencies

( b i o r e s m e t hr i η = 100) ( 1R, cis)-dibromovinyl

esters

m.p.100 Figure 10.

HF

0

M B

170

190

220

160

350

3 8 0

2300

1600

1 0 0 %

Effect of cyano group in each a position



ELLIOTT E T AL.


CH ,.CH 3

3

y-— ='

CO

Br'

NRDC 161

M.Wt

505

M.p.

100°

[o|

.15.6°

o

LD (jJg/insect) 50

Mustard beetles

0.0003

Houseflies

0.0003

Houseflies pretreated with synergist

0.00002

Figure 11.

(^0.03mg/kg) »

»

Properties of most active compound


90


insecticides, and to indicate their active conformations and hence the nature of their site of action. Acknowledgements: We thank Dr. I· J . Graham-Bryce for encouragement and c r i t i c a l interest and the National Research Development Corporation for financial support*


Table 1 COMPARISON OF SOME TOXICANTS

Test species

LD-^img/kg)

Mammalian poisons: Cyanide Curare Tetrodotoxin Tetrachlorodioxin

10

Mice

0·5

"

0.008

11

Guinea pigs

0.0006

Houseflies

7-H

Insecticides: DDT & analogues Lindane

11

2

Parathion

11

2

Dieldrin

11

1

Zectran

Bees

0·6

Dimethoate

Houseflies

0.5

Pyrethroids

11

down to

0.03


β.

ELLIOTT E T AL.

Active Conformations of

Pyrethroids

91


Literature Cited 1.

O'Brien, R. D., i n "Insecticides: Action and Metabolism", p. 1. Academic Press, New York and London, 1967.

2.

Barlow, F., Elliott, M., Farnham, A. W., Hadaway, A.B., Janes, N. F., Needham, P. H., and Wickham, J. C., Pesticide Science, (1971) 2, 115·

3.

Crombie, L., and Elliott, M., Fortsch. Chem. Org. Naturst., (1961) 19, 120.

4. Natural

E l l i o t t , M., and Janes, N. F. i n "Pyrethrum, the Insecticide," p. 56. J . E. Casida, Ed., Academic Press, New York and London, 1973.

5.

E l l i o t t , Μ., B u l l . Wld. Hlth Org. (1971) 44, 315.

6.

Briggs, G. G., E l l i o t t , M., Farnham, A. W., Janes, N.F., Needham, P. Η., and Young, S. R., unpublished results.

7.

Briggs, G. G., E l l i o t t , M., Farnham, A. W., and Janes, N. F., Pesticide Science, (1974), i n the press.

8.

E l l i o t t , M., Farnham, A. W., Janes, N. F., Needham, P. H., and Pearson, B. C., Nature (1967) 213, 493.

9.

E l l i o t t , M., Janes, N. F., and Pearson, B. C., Pesticide Science (1971) 2, 243.

10.

British Patent 1,243,858 (1971) to Sumitomo Chemical Company Limited.

11.

E l l i o t t , Μ., Chem. and Ind. (1969), 776.

12.

E l l i o t t , M., Farnham, A. W., Janes, N. F., Needham, P. H., and Pulman, D. Α., Nature (1973) 244, 456.

13·

Velluz, L., Martel, J . , and Nominé, G., C. R. Acad. S c i . (Paris), (1969) 268, 2199.

14.

E l l i o t t , M., Farnham, A. W., Janes, N. F., Needham, P. H., and Pulman, D. Α., Nature (1974) 248, 710.

15.

Burt, P. E., Pesticide Science (1970) 1, 88.


Insecticidally Active Conformations of Pyrethroids

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