Synthesis and molluscicidal structure - Activity relationships of some novel 1,2,4-triazole N-methyl carbamates

Article abstract of DOI:10.1002/ps.344

A new series of 1,2,4-triazole derivatives and their corresponding carbamates have been synthesized and screened for their molluscicidal activity against two types of terrestrial snail, Helix aspersa and Theba pisana, by two methods of application, either

Full text of DOI:10.1002/ps.344

Pest Management Science
Pest Manag Sci 57:707±712,2001)
DOI: 10.1002/ps.344
Synthesis and molluscicidal structure–activity
relationships of some novel 1,2,4-triazole
N-methyl carbamates
Mohamed A Radwan and Saad R El-Zemity*
Pesticide Chemistry Department, Faculty of Agriculture (Chatby), University of Alexandria, Alexandria, Egypt
Abstract: A new series of 1,2,4-triazole derivatives and their corresponding carbamates have been
synthesized and screened for their molluscicidal activity against two types of terrestrial snail, Helix
aspersa and Theba pisana, by two methods of application, either as contact or as bran baits. Several of
the tested compounds exhibited good molluscicidal activity, and T pisana was more sensitive than H
aspersa. Substitution at the o- and/or p-positions of the phenyl ring with chlorine or bromine gave
higher molluscicidal activity than the unsubstituted compound, with o,p-dichloro substitution being
optimum. In addition, compounds containing two triazole moieties showed higher molluscicidal
activity, particularly as stomach poisons, than the contact toxic effect of the corresponding compound
with one triazole ring. In general, carbamate derivatives were more active than their corresponding
1,2,4-triazole derivatives.
# 2001 Society of Chemical Industry
Keywords: carbamates; molluscicidal activity; structure-activity relationship; Theba pisana; Helix aspersa
1
INTRODUCTION
mates has been synthesized and tested in two
laboratory-based bioassays to evaluate their mollusci-
cidal potency. The molluscicidal structure-activity
relationships are discussed here.
Terrestrial snails are destructive agricultural pests
causing economic damage to a wide variety of plants
including vegetables, forage crops, tree fruits, shrubs,
¯owers, ground green cover and newly sown lawn-
grasses. Moreover, they play an important role in
transmitting and spreading diseases to cultivated
plants.1
2
EXPERIMENTAL METHODS
The use of speci®c molluscicides is considered to be
one of the most effective measures for terrestrial
mollusc control. Carbamates are a potent class of
molluscicide.2±5 The activity of carbamates against
terrestrial molluscs has been evaluated for aromatic
N-methyl carbamates, eg carbaryl, mexacarbate and
methiocarb.6±8 Methiocarb has been considered more
effective than the long-established molluscicide, me-
taldehyde, because methiocarb is little affected by
environmental conditions and its toxicity increases in
humid conditions which are favourable for terrestrial
gastropods.8
2.1 General experimental procedures
1H NMR spectra were recorded on a Varian spectro-
meter at 200MHz using tetramethylsilane as an
internal reference in hexadeuterodimethyl sulfoxide;
melting points were measured with a Ko¯er hot-stage
apparatus and were uncorrected. High resolution mass
measurements were performed on an AEL MS-30
mass spectrometer.
2.2 Synthesis
The sequence of the reactions leading to the synthesis
of o-,1H-1,2,4-triazol-ylmethyl)substituted phenols
and their corresponding N-methyl carbamate deriva-
tives is outlined in Fig 1. 1-Hydroxymethyl-1H-1,2,4-
triazole is readily obtained either by stirring a mixture
of 1,2,4-triazole with formalin in water at room
temperature for 5h or, preferably, by re¯uxing 1,2,4-
triazole with paraformaldehyde in the presence of a
catalytic amount of triethylamine.14 In the latter case,
a yield of 98% was achieved. The required compounds
were all prepared by heating under re¯ux a mixture of
the phenol or naphthol with one or two equivalent of
1,2,4-Triazoles constitute an important group of
heterocylic nitrogen derivatives showing a broad
spectrum of biological activity as herbicides, cotton
defoliants, growth regulators,9 insecticides10 and
fungicides.11 In our recent research, 2-[,1,2,4-tri-
azol-1-ylmethyl)amino]-3-methylpyridine, as well as
,1H-1,2,4-triazol-1-ylmethyl)anilines, N-alkylanilines
and N,N-dialkylanilines exhibited promising mollus-
cicidal activity.12,13 In an extension of these studies, a
new series of 1,2,4-triazole-based N-methyl carba-
* Correspondence to: Saad R El-Zemity, Pesticide Chemistry Department, Faculty of Agriculture (Chatby), University of Alexandria,
Alexandria, Egypt
(Received 15 May 2000; revised version received 26 February 2001; accepted 28 March 2001)
# 2001 Society of Chemical Industry. Pest Manag Sci 1526±498X/2001/$30.00
707

MA Radwan, SR El-Zemity
1-hydroxymethyl-1H-1,2,4-triazole in acetic acid for
4±72h ,see Table 1).
compounds 3a±b and 4h in the case of compounds
5a±b). The solvent was then removed under reduced
pressure, and to the residue was added aqueous
sodium hydrogen carbonate solution ,10M, 30ml).
The solution was extracted with diethyl ether
,3Â100ml), washed with water ,50ml) and dried
over magnesium sulfate. Evaporation of the solvent
gave a residue which was puri®ed by column chroma-
tography using hexane ‡ ethyl acetate ,5‡1 by
volume) as eluent. The physical properties of the
products are given in Tables 1, 2and 3.
This reaction can be considered as an extention of
the Mannich reaction, in which the primary or
secondary amine is replaced by hydroxymethyl-1,2,4-
triazole and the phenol or naphthol provides the
activated proton. Compounds 1 and 3 were easily
converted into their corresponding carbamate deriva-
tives, 2 and 4, respectively, by reaction with methyl
isocyanate in the presence of a catalytic amount of
triethylamine.15
2.2.1 General procedure for the synthesis of
o-!1H-1,2,4-triazol-1-ylmethyl)phenols !1a±k),
2.2.2 General procedure for the synthesis of
o-!1H-1,2,4-triazol-l-ylmethyl)phenyl N-methyl
carbamate !2a±h) and o,p-di-!1H-1,2,4-triazol-1-
ylmethyl)phenyl N-methyl carbamate !4a±b)
A mixture of methyl isocyanate ,1.3ml, 0.023mol) in
anhydrous diethyl ether ,10ml) with the correspond-
ing o-,1H-1,2,4-triazol-1-ylmethyl)phenol ,1a and
1d±j in the case of compounds 2a±h) or o,p-di-,1H-
1,2,4-triazol-1-ylmethyl)phenol ,0.02mol) ,3a±b in
the case of compounds 4a±b) and three drops of
o,p-di-!1H-1,2,4-triazol-1-ylmethyl)phenols !3a±b)
and !1H-1,2,4-triazol-1-ylmethyl)naphthols !5a±b)
A mixture of 1-hydroxymethyl-1H-1,2,4-triazole14
,25mmol, in the case of compounds 1a±k, 5a±b and
50mmol in the case of compounds 3a±b) and the
corresponding phenol or naphthol ,25mmol) in acetic
acid ,25ml) was heated under re¯ux for 4±72h ,12h in
the case of compounds 1a±k, 72h in the case of
Figure 1. Overall synthetic routes to
o-(1H-1,2,4-triazol-1-ylmethyl)
substituted phenols and their
corresponding N-methyl carbamate
derivatives. (tri)=hydroxymethy-1H-
1,2,4-triazole.
708
Pest Manag Sci 57:707±712,2001)

Novel 1,2,4-triazole N-methyl carbamate molluscicides
Table 1. Physical data for 1H-1,2,4-triazoles and their corre-
sponding N-methyl carbamate derivatives
Table 3. Physical data for 1- and 2-(1H-1,2,4-triazol-1-ylmethyl) substituted
naphthol derivatives
Compound
R
Tri ꢀposition) a
Yield ꢀ%)
mp ꢀ°C)
Compound
R
R1
R2
Yield ꢀ%) mp ꢀ°C)
5a
5b
2-OH
1-OH
1
2
70
68
226±227
222±223
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
CH3
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
65
66
68
75
70
67
80
63
66
72
55
81
93
90
95
95
80
81
89
140±141
110±112
160±161
122±123
196±198
185±186
200±203
179±180
180±183
173±175
205±206
140±141
124±125
100±101
122±123
132±133
112±113
163±164
156±157
a
Tri=hydroxymethyl-1H,1,2,4-triazole.
CH3
H
Cl
H
H
H
Cl
Cl
H
basis of their wide geographical distribution and the
economic importance of the crops they damage, and
were identi®ed according to the key given by Godan.1
Adult animals were fed on bran bait ad libitum and
allowed to acclimatize to the laboratory conditions for
3 weeks.
Cl
Br
H
Br
Br
NO2
H
1j
Br
H
1k
2a
2b
2c
2d
2e
2f
H
Cl
H
H
2.3.2 Test chemicals
H
Stock solutions of each tested compound, including
methiocarb ,4-methylthio-3,5-dimethylphenyl N-
methylcarbamate) as a reference, were prepared in
dimethyl sulfoxide ,DMSO), which causes little
distress to slugs and has been shown to be the most
appropriate solvent for topical application,16 and
serially diluted with the same solvent to achieve the
desired concentrations.
H
Cl
Cl
H
Cl
Br
H
2g
2h
Br
Br
Br
triethylamine, in a small glass-stoppered ¯ask was
allowed to stand for 1 week at room temperature. The
solvent was removed under reduced pressure and the
desired product obtained as white needles after
recrystallization. The yield and melting points are
presented in Tables 1 and 2.
2.3.3 Bioassay techniques
2.3.3.1 Topical application !contact toxicity). The
method of Hussein et al. 17 was used because it is
easy, reproducible and allows rapid screening of large
numbers of chemicals that may be used as spray
application. Preliminary experiments were carried out
to establish the effective range of the tested chemicals.
Six different concentrations, ranging from 2.5 to
25g litreÀ1, for each compound were prepared and
three replicates ,10 animals for each) were kept in 0.5-
litre glass jars covered with cloth netting and secured
with a rubber band to prevent snails from escaping.
The tested dose was gently applied on the surface of
the snail body inside the shell using a micropipette
containing 30ml in the case of H aspersa and 5ml in the
case of T pisana. Snails were provided with lettuce
leaves to feed on 24h after treatment. Dead animals
were detected 24, 48 and 72h after treatment by loss of
response to a thin stainless steel needle according to
the WHO procedure.18 Methiocarb ,Mesurol, Bayer
Co) and DMSO were included as standards for
comparison.
2.3 Molluscicidal tests
2.3.1 Test animals
Specimens of the herbivorous snails, Theba pisana
,Muller) and Helix aspersa ,Muller) were collected
during autumn 1999 from untreated nursery plants
and farms in Alexandria Governorate, Egypt. The
snail species used in these studies were selected on the
Table 2. Physical data for 1H-1,2,4-triazoles and their corre-
sponding N-methyl carbamate derivatives
Compound
R
R1
Yield ꢀ%)
mp ꢀ°C)
2.3.3.2 Toxic baits !stomach toxicity). Bran baits
containing 5 and 10g kgÀ1 of the tested compounds
were used for trials, after preliminary tests had
revealed that more than 10g kgÀ1 baits discouraged
snails feeding. The preparation of bran baits was
3a
3b
4a
4b
Cl
H
H
Cl
H
53
60
80
71
179±180
230±231
130±131
145±146
Cl
H
Cl
Pest Manag Sci 57:707±712,2001)
709

MA Radwan, SR El-Zemity
carried out according to the method of El-Sebae et
al,19 and they were tested for their molluscicidal
activity against T pisana snails. For each treatment,
three glass jars ,0.5 litre) containing 10 adult snails per
jar, and tightly covered with cloth netting secured with
a rubber band were used. Three jars were also pre-
pared for the control group containing bran bait free
from chemicals. Two millilitres of water were added
daily into each jar to provide suitable humidity for snail
activity. Mortality counts were recorded daily up to 7
days, and dead snails were removed.
ity, particularly against T pisana. Mono-substitution of
the 1,2,4-triazole moiety with a methyl ,1b and 1c),
nitro ,1k) or chloro ,1d±f) group did not improve the
activity over the unsubstituted compound ,1a) against
the two tested snails. However, conversion of these
1,2,4-triazole derivatives into N-methyl carbamates
,2b±d) led to an obvious increase in their molluscicidal
activity. Furthermore, the position of chlorine sub-
stituent in carbamate derivatives played an important
positive role in their potency in the order meta > ortho
> para. Moreover, it was found that disubstitution of
chlorine in o,p-positions resulted in a further increase
in molluscicidal activity ,1g versus 1a or 2e versus 2a).
Thus, molluscicidal activity reached the highest level
in compound 2e, which is superior to methiocarb
against T pisana snails.
2.3.3.3 Statistical procedure. Percentage mortality was
corrected by Abbott's formula.20 LD50 ,mg per snail)
values with ®ducial limits for each treatment were
determined by the probit analysis method of Finney.21
Although chloro-substitution in the synthesized
carbamates containing two 1,2,4-triazole moieties in
their structure increased the molluscicidal action, the
ortho-substituted compound ,4a) was more active than
the meta-substituted one ,4b) against the two tested
snails. A fact which demonstrates the steriospeci®city
of action of the carbamates was seen in that com-
pounds containing two triazole moieties in their
structure ,4a±b) proved to be more potent than those
containing one triazole moiety ,2b±c).
3
RESULTS AND DISCUSSION
The molluscicidal properties for the new series of
1,2,4-triazole derivatives and their corresponding
carbamates against two tested snails by the topical
application method are shown in Table 4. Many of the
tested compounds exhibited good molluscicidal activ-
Substitution with bromine on the aryl ring ,1h±i)
had little effect on molluscicidal activity, but an effect
was obtained with the ortho-bromo-substituted carba-
mate derivative ,2f). However, the 2,4-dichloro com-
pound ,2e) was more active than the 2,4-dibromo
compound ,2h) and both of these were more active
than the unsubstituted compound.
Table 4. Molluscicidal activity of the test compounds
against Helix aspersa and Theba pisana snails by topical
application method
LD50 ꢀmg per snail) at 48h with
95% ®ducial limits a
Compound
H aspersa
T pisana
1a
1b
1c
1d
1e
1f
1g
1h
1i
>750
>750
>750
>750
>750
>750
>750
>750
The results of 7 days of screening in the bait test
against T pisana, presented in Table 5, indicate that
methyl substitution at the ortho-position ,1b) displays
better activity than that at the para position ,1c).
Interestingly, compound 1b was superior to the
standard ,methiocarb) at a concentration of 5g kgÀ1
in the bait. In contrast, chloro-substituted derivatives
,1d±f and 2b±d) were inactive as bran baits. However,
the 2,4-dichlorosubstituted compound ,2e) gave high
molluscicidal activity compared with the standard in
the 5g kgÀ1 bran baits. Conversion of compounds 1h
and 1j into their carbamates increased the activity
above that of the standard in a 5g kgÀ1 bait ,2f and
2h). The 2,4-dibromo compound ,2h) was more
active than the 2,4-dichloro compound ,2e) as a
5g kgÀ1 bait, which is the opposite trend to that found
in the topical test ,Table 4). Ortho-chloro substitution
in a compound containing two 1,2,4-triazole moieties
,3a) and its corresponding carbamate compound ,4a)
showed higher activity than in their meta analogues ,3b
and 4b). Compound 4a was the most active in the
series, including the standard, achieving 78% and 94%
mortality in 5 and 10g kgÀ1 bran baits, respectively.
The b-naphthol derivative ,5a) showed superior
activity to the a-naphthol derivative ,5b), indicating
that replacing the phenol in 1,2,4-triazole derivatives
with naphthol enhanced the molluscicidal activity
701 &506±862)
>750
>750
695 &534±805)
432 &279±668) 251 &302±407)
716 &493±941) 601 &399±730)
>750
>750
1j
675 &513±889) 420 &239±756)
688 &387±926) 592 &492±701)
1k
2a
2b
2c
2d
2e
2f
2g
2h
3a
3b
4a
4b
5a
5b
>750
495 &436±562)
374 &267±407) 245 &205±288)
331 &299±367) 221 &194±251)
412 &285±684) 248 &177±294)
212 &170±271) 101 &83±123)
392 &354±435) 235 &186±293)
>750
308 &277±401) 125 &97±146)
>750 >750
555 &487±632)
716 &578±873) 625 &337±963)
216 &177±260) 143 &110±185)
436 &388±661) 384 &329±448)
414 &381±578) 276 &217±350)
>750
>750
Methiocarb 211 &189±245) 107 &88±124)
Control
0.0
0.0
a
Average based on three replicates &n =3),10 animals
each.
710
Pest Manag Sci 57:707±712,2001)

Novel 1,2,4-triazole N-methyl carbamate molluscicides
Table 5. Molluscicidal activity of the test compounds
against Theba pisana snails by ingestion assays
aryl N-methyl carbamate represent a new class of
potent compounds against terrestrial snails, which
were comparable or superior to methiocarb in both
topical and bran bait tests.
Mortality of snails exposed to
bran bait ꢀ%) ꢀÆSE) a
Compound 5g kgÀ1 bait 10g kgÀ1 bait
1a
1b
1c
1d
1e
1f
1g
1h
0.00
16 &Æ0.84)
47 &Æ1.2)
18 &Æ1.2)
13 &Æ0.43)
18 &Æ1.0)
18 &Æ1.0)
33 &Æ0.51)
13 &Æ0.47)
0.00
ACKNOWLEDGEMENTS
The authors are grateful to Prof Dr AH El-Sebae and
Prof Dr N Bakry for advice throughout this work.
79 &Æ0.76)
37 &Æ0.19)
0.00
13 &Æ0.58)
0.00
13 &Æ0.63)
0.00
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