Comparative evaluation of new synergists containing a butynyl-type synergophore group and piperonyl butoxide derivatives

Article abstract of DOI:10.1002/1526-4998(200102)57:2<186::AID-PS290>3.0.CO;2-Z

Cross-substituted derivatives of piperonyl butoxide (PBO) and MB-599 (proposed common name: verbutin) were synthesized and investigated as carbofuran and permethrin synergists against housefly, Musca domestica L. The majority of PBO and MB-599 derivatives were significantly more potent synergists for carbofuran than for permethrin. PBO, the most important representative of this series was not the most potent synergist for carbofuran or for permethrin. Cleavage of the methylenedioxy ring of methylenedioxyphenyl (MDP) polyether compounds resulted in complete loss of synergistic activity with both insecticides, but it could be restored or even improved by incorporating an alkynyl ether moiety into the molecule. The improved synergistic activity was found to be closely associated with the 2-butynyloxymethyl side-chain, suggesting that this can be regarded as a characteristic synergophore group. MB-599, one of the most promising compounds bearing this group showed considerably higher activity with carbofuran (synergist ratio, SR=37.8) than with PBO (SR=6.4). There was no significant difference between synergistic activities of MB-599 (SR=4.6) and PBO (SR=4) for permethrin.

Full text of DOI:10.1002/1526-4998(200102)57:2<186::AID-PS290>3.0.CO;2-Z

Pest Management Science
Pest Manag Sci 57:186±190 (2001)
Comparative evaluation of new synergists
containing a butynyl-type synergophore group
and piperonyl butoxide derivatives
´
L a´ szl o´ Pap,* G e´ za Arvai, B e´ la Bert o´ k, Zsuzsanna Kuruczn e´ Ribai and
Ildik o´ Bakonyv a´ ri
Agro-Chemie Ltd, Budapest, H-1780, PO Box 49, Budapest, Hungary
Abstract: Cross-substituted derivatives of piperonyl butoxide (PBO) and MB-599 (proposed common
name: verbutin) were synthesized and investigated as carbofuran and permethrin synergists against
house¯y, Musca domestica L. The majority of PBO and MB-599 derivatives were signi®cantly more
potent synergists for carbofuran than for permethrin. PBO, the most important representative of this
series was not the most potent synergist for carbofuran or for permethrin. Cleavage of the
methylenedioxy ring of methylenedioxyphenyl (MDP) polyether compounds resulted in complete loss
of synergistic activity with both insecticides, but it could be restored or even improved by
incorporating an alkynyl ether moiety into the molecule. The improved synergistic activity was found
to be closely associated with the 2-butynyloxymethyl side-chain, suggesting that this can be regarded as
a characteristic synergophore group. MB-599, one of the most promising compounds bearing this
group showed considerably higher activity with carbofuran (synergist ratio, SR=37.8) than with PBO
(
SR=6.4). There was no signi®cant difference between synergistic activities of MB-599 (SR=4.6) and
PBO (SR=4) for permethrin.
2001 Society of Chemical Industry
#
Keywords: butynyl ether synergists; MB-599; piperonyl butoxide; carbofuran; permethrin
1
INTRODUCTION
The objective of the present study was to identify
and characterize the butynyl side-chain as a new
synergophore group. The synergist potency of related
MDP and 1,2-dimethoxybenzene homologues and the
in¯uence of increasing amounts of co-applied syner-
gists were investigated in house¯y using carbofuran
and permethrin insecticides.
Oxidative metabolism mediated by cytochrome-P450
monooxygenases is one of most important detoxi®ca-
1
tion routes of insecticides, and can be inhibited by the
methylenedioxyphenyl (MDP) synergists, which in-
2
clude piperonyl butoxide (PBO). A theoretical study
of the mode of action of PBO at molecular level has
3
been published recently.
Currently, PBO and a few closely related MDP
compounds (sesamex, sesamine, sesamoline, sulfox-
ide, propyl isome) are the most important insecticide
synergists. Synergists from other compound groups,
such as propynyl esters, propynyl ethers and the
substituted imidazoles, with inhibiting monooxygena-
tion activity have failed to achieve commercial
2
MATERIALS AND METHODS
2.1 Synthesis of synergists tested
Safrol and methyleugenol were hydrogenated over
9,10
10% Pd±C
in methanol to yield the corresponding
4-propyl-1,2-methylenedioxy- and 1,2-dimethoxy-
benzenes (1 and 11), respectively. Benzyl propargyl
ethers 10 and 20 were prepared according to a method
4
success.
We have recently reported a new family of alkynyl
synergists having butynyl side-chains as the synergo-
11
described in the literature. The structures of the
synergists studied are shown in Table 1. Syntheses of
other benzyl ether derivatives have been published
5±7
phore group. High synergist potency with a number
of active ingredients characterizes these compounds.
They are supposed to be particularly effective in
preventing resistance evolution and controlling resis-
12,13
elsewhere.
8
tant populations. The ®eld performance of MB-599
(proposed common name: verbutin), one of the most
2.2 Insecticide and synergist standards
Technical grade carbofuran (>95%, Chinoin) and
permethrin (>95%, with 40:60 ratio of cis:trans
isomers, Chinoin) were used as insecticides. Analytical
effective members of this series, is currently under
evaluation.
*
Correspondence to: L a´ szl o´ Pap, Agro-Chemie Ltd, Budapest, H-1780, Po Box 49, Budapest, Hungary
(
Received 26 June 2000; revised version received 29 September 2000; accepted 1 November 2000)
#
2001 Society of Chemical Industry. Pest Manag Sci 1526±498X/2001/$30.00
186

New synergists containing butynyl-type synergophore group
Table 1. Structures of tested synergists
1
2
a
Structure number
Aromatic ring
R
R
Reference
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
B
B
B
n-C H7
H
9
3
H
H
CH O(CH ) O(CH ) O(CH ) CH
3
22
2
2 2
2 2
2 3
CH(CH )O(CH ) O(CH ) O(CH ) CH
23, 24
3
2 2
2 2
2 3
3
3
n-C H7
CH O(CH ) O(CH ) O(CH ) CH
2 2 2 2 2 2 3 3
3
n-C H7
CH(CH )O(CH ) O(CH ) O(CH ) CH
3 2 2 2 2 2 3
3
H
H
CH OCH CꢀCCH
2
2
3
CH(CH )OCH CꢀCCH
3
2
3
3
n-C H7
n-C H7
CH OCH CꢀCCH
3
2
2
3
CH(CH )OCH CꢀCCH
3
3
2
1
1
1
1
1
1
1
1
1
1
2
H
CH OCH CꢀCH
25, 26, 27
10
2
2
n-C H7
H
3
H
H
CH O(CH ) O(CH ) O(CH ) CH
2 2 2 2 2 2 3 3
CH(CH )O(CH ) O(CH ) O(CH ) CH
3
2 2
2 2
2 3
3
3
n-C H7
CH O(CH ) O(CH ) O(CH ) CH
2 2 2 2 2 2 3 3
3
n-C H7
CH(CH )O(CH ) O(CH ) O(CH ) CH
3 2 2 2 2 2 3
3
H
H
CH OCH CꢀCCH
2
2
3
CH(CH )OCH CꢀCCH
3
2
3
3
n-C H7
n-C H7
CH OCH CꢀCCH
3
2
2
3
CH(CH )OCH CꢀCCH
3
3
2
H
CH OCH CꢀCH
28, 11
2
2
a
Unless otherwise noted, the synergists are here reported for the ®rst time.
grade (>98%) PBO was obtained from Riedel±de
Haen, Seelze, Germany.
mi n si xe tc ut ir ce i .d e alone to that of the insecticide‡synergist
2.3 Bioassay
The synergistic potency of the putative synergists was
studied on house¯y (Musca domestica L, WHO/NTT)
3 RESULTS
3.1 Synergist potency
Tables 2 and 3 show the synergist potencies of MDP
compounds with carbofuran and permethrin in com-
parison with those of the related 1,2-dimethoxy-
benzene (veratryl) analogues.
14
by a standard topical method described previously.
Dose-mortality tests were carried out for synergized
and unsynergized insecticides and assessed by probit
15
analysis. Carbon dioxide anaesthetized adult female
ies (3- to 4-day-old, 17±21mg body-weight) were
¯
treated topically by applying insecticide or insecticide
plus synergist in cellosolve (2-ethoxyethanol; 0.2ml) to
the dorsal surface of the thorax with a micro-applicator
3.1.1 MDP compounds
SR values indicate that PBO (4) cannot be considered
an optimum structure either with carbofuran or with
permethrin. The structure of the molecule can be ®ne-
tuned even among the polyether series by removing the
6-propyl group and/or substitution in the benzylic
position. Exchanging the polyether chain for an
alkynyl ether does not cause a profound improvement
in activity with permethrin (Table 3). The best poly-
ethers (3, 5) and alkynyl ethers (9) are within a narrow
range of SR=5±6 which does not differ signi®cantly
from that of PBO (4, SR=4).
(Microlab P, Hamilton, Reno NV). Control ¯ies were
treated with the solvent only. The treated ¯ies were
kept in normal laboratory conditions (temperature
2
2(Æ2)°C, relative humidity 60(Æ10)%, 12:12h
light:dark). Mortality was assessed after 24h. Two
replicates of 10 ¯ies were tested for each dose level of
insecticide or insecticide‡synergist. Each test was
repeated three times. Synergists were co-administered
with insecticides. Synergist activity was screened by
application of a constant amount of synergist, 1000ng
per ¯y. To investigate the effect of synergist dose on
insecticidal activity, various quantities of synergist,
MDP alkynyl ethers (6±10) of any substitution
pattern are superior to the corresponding polyethers
(1±5) when tested with carbofuran (Table 2). Syner-
gist potency is signi®cantly affected by structural
variation and the tendency is similar within the
corresponding series (2±5 vs 6±9). The most active
compound 6 (piperonyl 2-butynyl ether) shows an SR
2
50, 500, 1000, 2000 and 5000ng per ¯y, were ad-
ministered. The tested synergists caused no mortality
alone even at the highest dose applied, so the synergist
ratio (SR) was calculated as the ratio of the LD50 of the
Pest Manag Sci 57:186±190 (2001)
187

L Papa et al
LD50
FL 95%
ng per ¯y
Carbofuran alone 480 169.9 143.0 200.4 1.81 0.55 2.713
a
b
2
w
c
Treatment
n
Slope ÆSE
df SR
4
5
5
4
3
3
3
2
3
3
2
4
4
3
4
3
2
3
4
3
4
Ð
1
2
3
4
5
6
7
8
9
0
1
2
380
420
360
300
300
300
220
300
280
240
27.0
15.8
16.6
26.4
31.1
4.3
22.6
12.6
10.6
22.3
19.5
3.7
32.1 2.12 0.47 6.783
19.3 1.73 0.58 3.856
24.8 2.66 0.37 12.809
30.8 2.57 0.39 1.080
47.1 2.61 0.38 7.168
4.9 2.84 0.27 0.581
5.9 4.46 0.53 2.913
8.9 3.27 0.39 4.738
12.9 3.21 0.31 9.045
9.8 3.60 0.42 0.823
6.3
10.7
10.2
6.4
(PBO)
5.5
40.0
32.7
22.1
20.2
19.8
0.7
5.2
4.6
7.7
6.5
8.4
4.2
1
1
1
8.6
7.4
300 259.6 215.2 317.0 2.00 0.50 7.370
300 261.4 219.9 313.7 2.24 0.23 4.060
380 237.3 204.1 274.4 2.34 0.21 2.154
300 204.9 175.0 240.0 2.58 0.25 4.802
300 170.7 115.1 255.5 2.70 0.25 6.516
0.7
13
14
15
16
1
1
1
2
0.7
0.8
1.0
220
260
360
280
360
6.4
4.5
2.4
4.0
12.6 3.67 0.41 5.549
5.2 3.97 0.43 3.216
17.1 2.46 0.23 3.270
65.3 2.73 0.28 2.522
23.5 2.13 0.19 5.097
26.6
37.8
11.6
3.0
7 (MB-599)
8
9
0
14.6
56.1
19.8
12.3
47.9
16.5
8.6
a
b
c
Treatments were performed as described in Section 2.3.
Number of ¯ies on which each probit analysis was based.
Table 2. Synergist potency of tested compounds
with carbofuran on housefly
SR, synergist ratio: LD50 of unsynergized divided by LD50 of synergized treatment.
value twice as high as that of the known propargyl
homologue 10.
loss of activity in the polyether series (either with
carbofuran or with permethrin) as expected from the
structure-activity relationship studies by Wilkinson et
al. Potency is, however, retained by incorporating
the alkynyl ether moiety, which con®rms that the
16
3.1.2 1,2-Dimethoxybenzene compounds
Opening the methylenedioxy ring results in complete
LD50
FL 95%
ng per ¯y
a
b
2
w
c
Treatment
n
Slope ÆSE
df SR
Permethrin alone 300 198.9 169.3 232.5 2.56 0.39 5.604
340 111.7 80.2 162.8 2.86 0.39 9.561
3
4
4
4
3
4
3
2
3
3
4
3
3
3
3
3
4
4
3
4
3
Ð
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
1.8
4.0
5.8
4.0
5.4
3.8
3.2
4.1
6.0
2.9
0.9
0.9
0.9
1.0
1.1
2.7
4.6
3.4
2.5
2.1
360
360
300
360
300
240
300
300
360
49.9
34.4
50.2
37.2
51.8
62.5
48.6
33.4
68.5
43.2
29.4
32.0
26.1
45.3
57.7 2.85 0.35 6.729
40.2 2.50 0.40 2.79
79.0 2.65 0.38 7.819
53.1 2.62 0.38 2.774
59.1 3.39 0.30 2.907
(PBO)
27.3 126.7 3.08 0.33 5.211
41.8
28.8
59.6
56.6 2.68 0.37 3.755
38.6 2.98 0.34 0.352
78.7 3.04 0.33 2.014
1
1
1
1
1
1
1
1
1
1
2
300 221.9
19.8 256.3 2.91 0.34 3.811
300 225.6 195.9 259.4 3.06 0.33 3.341
300 223.8 193.4 258.6 2.90 0.35 1.206
300 203.8 178.8 232.0 3.51 0.29 2.381
300 189.9 165.7 217.0 2.28 0.30 0.806
340
360
280
340
300
72.8
44.5
58.9
81.3
94.3
63.1
38.3
51.8
70.3
84.1 2.91 0.34 2.014
51.4 2.79 0.36 3.791
66.7 3.81 0.26 5.568
94.2 2.85 0.35 6.111
7 (MB-599)
8
9
0
82.9 107.1 3.61 0.28 1.337
a
b
c
Treatments were performed as described in Section 2.3.
Table 3. Synergistic potency of tested compounds
Number of ¯ies on which each probit analysis was based.
with permethrin on housefly
SR, synergist ratio: LD50 of unsynergized divided by the LD50 of synergized treatment.
188
Pest Manag Sci 57:186±190 (2001)

New synergists containing butynyl-type synergophore group
Within the MDP series, carbamate synergists more
potent than PBO have already been reported. When
tested on susceptible house¯y, isosafrol, safrol and
3
1
,4-methylenedioxyphenyl 2-propynyl ether (RO 7-
366) proved to be better synergists of carbaryl and
17
isolan than did PBO. Similarly, myristicin, isosafrol
and 1-nitro-3,4-methylenedioxybenzene were more
ef®cient synergists for carbaryl than PBO in the
18
house¯y.
A similar superiority of some closely
related propynyl aryl ethers over PBO as carbaryl
synergists, particularly at lower synergist doses, has
been demonstrated on such important crop pests as
brown planthopper (Nilaparvata lugens Stal), green
leafhopper (Nephotettix cincticeps Uhler) and tobaco
Figure 1. Relationship of synergist ratio (SR) to doses of 4 (PBO) and 17
MB-599) co-administered with carbofuran in housefly.
(
19
2
-butynyloxymethyl side-chain is a characteristic
caterpillar (Spodoptera litura Fab).
synergophore group. With permethrin, the synergistic
effectiveness of analogous MDP and 1,2-dimethoxy-
benzyl alkynyl compounds (6±8 vs 16±18 and 10 vs 20)
does not differ signi®cantly. With carbofuran, the
effect of substitution pattern on potency is the greatest.
The most active representative among veratryl alkynyl
ethers (17, MB-599) possesses an SR value more than
four times that of the closely related propargyl ether
With the exception of compound 5, all tested MDP
derivatives were found to be much more ef®cient
synergists for carbofuran than for permethrin (Tables
2 and 3). In accordance with the results found with the
MDP compounds, 1,2-dimethoxybenzene com-
pounds, particularly 16, 17, 18 and 20, showed sig-
ni®cantly higher synergistic action with carbofuran
than with permethrin. From a theoretical point of view
this variance can be attributed either to different
potencies of the synergists in inhibiting an identical
metabolic process and/or to distinct metabolic routes
actually involved in permethrin and carbofuran
detoxi®cation.
20.
3.2 Effect of dose of compounds 4 (PBO) and 17 on
synergist ratio
The effect of different quantities of the PBO (4) and
compound 17 on the activity of carbofuran are
presented in Fig 1. Increasing synergist doses generally
resulted in higher SRs in both cases, although the
increase of insecticide potency of carbofuran was
signi®cantly higher at each dose with 17 than with
PBO. On increasing the synergist dose from 250 to
A striking difference was observed between PBO
and 17 in responding to increasing amounts of
synergist co-applied with carbofuran, but not with
permethrin. Accordingly, it is postulated that PBO and
17 inhibit similar metabolic processes of both carbo-
furan and permethrin. While carbofuran is metab-
olized almost exclusively via a single enzyme system,
5
000ng per ¯y, the SR was enhanced from 1.3 to 14.5
20
for PBO and from 11.3 to 65.6 for 17. The ®tted line
for 17 is much steeper (b =13.8, r =0.991) than was
obtained for PBO (b =2.45, r =0.906). The synergis-
tic activities of both PBO and 17 showed signi®cantly
lower dose-dependence with permethrin (b =1.25,
r =0.988 and b =1.15, r =0.946, respectively, Fig 2).
the cytochrome-P450 monooxygenases, permethrin
can alternatively be degraded by different classes of
21
detoxi®cation enzymes that cannot be suppressed by
either PBO or 17.
In conclusion, the results presented con®rm that the
co-applied insecticide and the insecticide±synergist
ratio inherently in¯uence the observed synergistic
potency. Under our test conditions we found benzyl
butynyl ethers to be superior to PBO-type benzyl
polyethers. MB-599 (17), the most promising candi-
date of butynyl ethers, potentiates carbofuran at
extremely low insecticide±synergist ratios, which is
preferable in the ready-mix formulations used in
agriculture. The ®eld performance of MB-599 (17)
with various insecticides is currently being evaluated.
4
DISCUSSION
PBO was one of the less effective carbofuran synergists
amongst the MDP compounds tested (Table 2).
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