Synthesis of some novel phosphorylated and thiophosphorylated benzimidazoles and benzothiazoles and their evaluation for larvicidal potential to Aedes albopictus and Culex quinquefasciatus

Article abstract of DOI:10.1016/j.bmcl.2014.04.082

Series of benzimidazole and benzothiazole linked phosphoramidates and phosphoramidothioates (5a-j) and benzimidazole linked phenylphosphoramidates and phenylphosphoramidothioates (10a-e) were synthesized. The title compounds were preliminary screened for mosquito larvicidal properties against Aedes albopictus and Culex quinquefasciatus at different concentration from 40 to 5 mg/L. Among the screened compounds three compounds revealed potential larvicidal effects with 100% mortality in the order of 10e > 5j > 5e. Compound 10e was found to be the most toxic compound to Ae. albopictus and Cx. quinquefasciatus. The LC₅₀ of 10e against Ae. albopictus was found to be 6.42 and 5.25 mg/L at 24 and 48 h, respectively, whereas it was 7.01 and 3.88 mg/L, respectively in Cx. quinquefasciatus. Temephos was used as positive control.

Full text of DOI:10.1016/j.bmcl.2014.04.082

Bioorganic & Medicinal Chemistry Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of some novel phosphorylated and thiophosphorylated
benzimidazoles and benzothiazoles and their evaluation for
larvicidal potential to Aedes albopictus and Culex quinquefasciatus
Prabal Bandyopadhyay a, Manisha Sathe a, Sachin N. Tikar b, Ruchi Yadav b, Pratibha Sharma c,
Ashok Kumar c, M. P. Kaushik a,
⇑
a Discovery Center, Process Technology Development Division, Defence Research & Development Establishment, Jhansi Road, Gwalior 474002, MP, India
b Vector Management Division, Defence Research & Development Establishment, Jhansi Road, Gwalior 474002, MP, India
c School of Chemical Sciences, Devi Ahilya University, Takshashila Campus, Khandwa Road, Indore 452001, MP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Series of benzimidazole and benzothiazole linked phosphoramidates and phosphoramidothioates (5a–j)
and benzimidazole linked phenylphosphoramidates and phenylphosphoramidothioates (10a–e) were
synthesized. The title compounds were preliminary screened for mosquito larvicidal properties against
Aedes albopictus and Culex quinquefasciatus at different concentration from 40 to 5 mg/L. Among the
screened compounds three compounds revealed potential larvicidal effects with 100% mortality in the
order of 10e > 5j > 5e. Compound 10e was found to be the most toxic compound to Ae. albopictus and
Cx. quinquefasciatus. The LC50 of 10e against Ae. albopictus was found to be 6.42 and 5.25 mg/L at 24
and 48 h, respectively, whereas it was 7.01 and 3.88 mg/L, respectively in Cx. quinquefasciatus. Temephos
was used as positive control.
Received 25 October 2013
Revised 6 April 2014
Accepted 21 April 2014
Available online xxxx
Keywords:
Phosphoramidate/phosphoramidothioate
Benzimidazole/benzothiazole
Larvicidal activity
Ó 2014 Elsevier Ltd. All rights reserved.
Aedes albopictus
Culex quinquefasciatus
Mosquitoes are one of the deadliest insects in this planet which
create biting nuisance and also transmit deadly diseases like
malaria, filariasis, yellow fever, dengue, chikungunya and Japanese
encephalitis, which contribute significantly to economic loss and
social debility in tropical countries, causing millions of death every
year.1 Mosquitoes in the genus Aedes are responsible for the
transmission of yellow fever, dengue, chikungunya and other
pathogenic arbo-viruses.2 Similarly, Culex quinquefasciatus com-
monly known as southern house mosquito and act as a primary
vector of lymphatic filariasis with worldwide distribution.3Cx.
quinquefasciatus commonly inhabit around human dwellings and
on aging prefer to bite humans than other mammals. It is an
important vector of lymphatic Filariasis caused by nematodes such
as Wuchereria bancrofti and Brugia malayi in humans in some parts
of India. Globally over 100 million individuals are affected due to
Filariasis annually. Out of which approximately 43 million Filariasis
cases results into serious disability and disfiguring of limbs.4
resistance, and undesirable effects on non-target organisms.5
These problems have highlighted the need of new strategies for
mosquito control.
The best way to prevent outbreaks of mosquito-borne disease is
to control the vector at the grass root level. However, the control of
mosquito borne diseases is becoming increasingly difficult because
of effectiveness of vector control tools has declined due to the
development of resistance in mosquitoes against currently used
insecticides.6 Vector control strategy7 is an important part of the
global disease control programme. The objective behind this is to
reduce the levels of mortality and morbidity by reducing transmis-
sion of the disease. Therefore, the best way to prevent the out-
breaks of mosquito-borne disease is to control the mosquito
vector at the larval stage itself. Mosquitoes in the larval stage are
attractive targets for pesticides due to their stationary nature they
can be easily targeted in breeding habitats. Many organophospho-
rus (OP) compounds like reldan, temephos, fenthion, chlorpyrifos,
pirimiphos-methyl etc. have been in use for controlling Cx. quin-
quefasciatus, the vector of bancroftian filariasis in many countries.8
Recently, in the interest of developing a more effective insecticide
novel classes of organophosphorous compounds have been synthe-
sized and screened against their larvae and the adult mosquitos.9
The chemistry of organophosphorus (OP) compounds is a
rapidly developing area of research because of their importance
Repeated use of synthetic insecticides for mosquito control has
fostered several environmental and human health concerns,
including disruption of natural biological control systems, resur-
gences in mosquito populations, widespread development of
⇑
Corresponding author. Tel.: +91 751 2343972; fax: +91 751 2340042.
E-mail address: mpkaushik@rediffmail.com (M.P. Kaushik).
http://dx.doi.org/10.1016/j.bmcl.2014.04.082
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Bandyopadhyay, P.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.04.082

2
P. Bandyopadhyay et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
15% CuI
30%
I
I
HN
N
NH HN
NH2
NH2
4 eq Cs2CO3
N
H
H2N
DMA
3
1
2
150oC, 16 h
O
S
I2 (30 mol%)
N
NH2
H2N
NH2
S
H2O2 , PTSA
CH3CN, 80oC
3'
2'
1'
OR
Z
Z
P
P
N
X
N
X
Et3N
OR
OR
OR
NH
NH2
Cl
CH3CN, 50oC
4
5
3 / 3'
X = NH, S
Z= O, S
R= CH3, C2H5, C6H5
Scheme 1. Synthesis of O,O-disubstituted 1H-benzimidazol/benzothiazol-2-yl phosphoramidates/phosphoramidothioates (5a–j).
O
NH2
Al2O3-Fe2
CH3CN
N
3
OHC
NO2
NO2
N
H
NH2
60 o
C
8
6
7
Zn dust / H+
Et2O
[H]
N
NH2
N
H
9
Z
P
OR
OR
Et3N,
CH3CN, 50oC
Cl
Z= O, S
R= CH3, C2H5, C6H5
OR
RO
P
N
Z
NH
N
H
10
Scheme 2. Synthesis of O,O-disubstituted 4-(1H-benzimidazol-2-yl)phenylphosphoramidates/phenylphosphoramidothioates (10a–e).
in industrial, agricultural, biochemical, and medicinal applica-
tions.10 OP compounds have found a wide range of applications
in the areas of industrial, agricultural, and medicinal chemistry,
owing to their biological and physical properties as well as their
utility as synthetic intermediates. It is interesting to note that
the variation in their physical, chemical, and biological properties
is governed by the selection of the group attached to phosphorus
atom. Phosphorous compounds containing the PAC bond are not
particularly abundant in nature; nevertheless they have diverse
biological activity, and as a consequence they have attracted the
attention of synthetic as well as medicinal chemists. Similarly,
other OP compounds, such as anhydrides (pyrophosphates) con-
taining the PAOAP linkage are known to have a rich history both
in terms of their synthetic utility as well as their biological impor-
tance.11 In particular, organophosphorus compounds (phospho-
ramidates) having the PANAC linkage have been reported as
insecticides, fungicides, herbicides, fire retardants, and lubri-
cants.12 Further, the development of phosphoramidate-substituted
nucleoside analogs has also become an area of intense interest due
to the anticancer, antiviral (anti-HIV), and spermicidal activities of
the nucleoside analogs. In addition, phosphoramidates play a sig-
nificant role in synthesis. One of the most important fields for dial-
kyl-, dibenzyl-, and diphenyl phosphoramidates is the protection
of amino groups. PAN bond-containing molecules have emerged
as an important class of compounds in modern organic chemistry,
with numerous applications as ligands in catalytic synthetic trans-
formations. There are several methods reported for the synthesis of
phosphoramidates (or, phosphoramidothioates) linked with benz-
imidazole nucleus in the literature. Phosphorylated and thi-
ophosphorylated compounds of 2-substituted benzimidazoles
were synthesized by the reaction of POCl3 and PSCl3 with 2-substi-
tuted benzimidazoles.13 The reaction of thiophosphorylated
bis-thiourea o-C6H4[NHC(S)NHP(S)(O-iPr)2]2 with iodine, KOH
and ClCH2C(O)OMe leads to O,O0-diisopropyl-1,3-dihydro-2H-
benzimidazol-2-ylideneamidothiophosphate formation.14,15 The
reaction of 2-aminobenzimidazole with diisopropyl phosphite
and carbon tetrachloride at a low temperature gave 1-diisoprop-
oxyphosphoryl-2-aminobenzimidazole, which on heating gave
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P. Bandyopadhyay et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
3
2-(diisopropoxyphosphoryl)-aminobenzimidazole.16
However,
reaction times, use of carcinogenic solvents, harsh reaction condi-
tions, tedious workup, and purification techniques are often used
to afford the compounds of desired purity. In continuation of our
work on new synthetic strategies,18 and as a part of our ongoing
research activities on bioactive compounds for mosquito control,19
herein, we describe the synthesis and mosquitocidal activity of
novel series of benzimidazole and benzothiazole linked phospho-
ramidates and phosphoramidothioates (Scheme 1) and benzimid-
azole linked phenylphosphoramidates and phenylphosphoramido
thioates (Scheme 2) for the first time. Results from this initial study
will be useful for guiding further work on phosphorylated and
thiophosphorylated benzimidazoles and benzothiazoles for the
development of novel efficacious insecticide which will effectively
manage organophosphorus resistant mosquitoes.
Phosphorylated and thiophosphorylated benzimidazoles and
benzothiazoles 5a–j could be prepared from 2-aminobenzimidaz-
oles/benzothiazoles. Initially, 2-aminobenzimidazole20/2-amino-
benzothiazole21 have been prepared by reported methods with
slight modification. 2-Aminobenzimidazole 3 was synthesized in
one-step by a direct CuI/N,N0-dimethylethylenediamine catalyzed
the synthesis of phosphoramidates/phosphoramidothioates
linked with benzimidazole/benzothiazole starting from 2-amino
benzimidazole/benzothiazole and dialkyl/diaryl chlorophosphate
have not been explored so far and to best of our knowledge
phenylphosphoramidates/phenylphosphoramidothioates linked
with benzimidazole have not been reported elsewhere. Benzimid-
azole and benzothiazole, ‘privileged’ structures, are important
classes of compounds for the pharmaceutical industry. The
benzimidazole and benzothiazole moieties are found in various
synthetic pharmaceuticals, displaying a broad spectrum of biolog-
ical activities including anti-ulcer, anti-tumour, anti-hypertensive,
anti-viral, anti-fungal, anti-bacterial, immunosuppressive, anti-
inflammatory, analgesic effects.17 The biological significance of
these class of compounds inspired us to develop a rapid and effi-
cient synthetic procedure for the synthesis of benzimidazole and
benzothiazole linked phosphoramidates and phenylphosphorami-
dates. Perusal of the literature revealed that reported methods
for the synthesis of phosphoramidates and phenylphosphorami-
dates are associated with several drawbacks, such as longer
Table 1
Synthesized benzimidazole linked phosphoramidates and phosphoramidothioates (5a–j)
Entry
a
Chloro phosphate/phosphothionate
Product (5)
Yield* (%)
68
O
O
O
O
O
P
N
Cl
Cl
P
O
NH
N
H
O
P
O
O
O
O
P
NH
N
b
c
O
63
61
N
H
O
P
O
Cl
O
O
P
N
O
O
NH
N
H
S
P
O
S
O
O
P
N
Cl
Cl
O
d
e
69
64
NH
N
H
S
P
O
O
O
S
P
N
O
NH
N
H
O
P
O
O
O
O
P
N
S
Cl
Cl
O
f
67
68
NH
O
P
O
O
O
O
P
N
S
g
O
NH
O
P
O
Cl
O
O
h
i
63
O
P
N
S
O
NH
O
S
P
S
O
O
P
NH
N
S
Cl
Cl
O
65
62
S
P
O
O
O
S
P
N
S
j
O
NH
*
Isolated yield.
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4
P. Bandyopadhyay et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
double amination reaction of 1,2-di-iodobenzenes 1 with guani-
dines 2. Likewise, in order to access the 2-aminobenzothiazole 30
as the precursor substrates, a metal-free process was taken for
the synthesis of 2-aminobenzothiazole from cyclohexanone 10
and thiourea 20 in presence of catalytic iodine and hydrogen perox-
ide as the external oxidant under mild conditions (Scheme 1). The
compound 3 (or, 30) was treated with dialkyl/diaryl chlorophos-
phate/ chlorothiophosphate 4 in presence of triethylamine (Et3N)
base in acetonitrile, yielding the title compounds, viz., O,O-disub-
stituted 1H-benzimidazol/benzothiazol-2-yl phosphoramidates/
phosphoramidothioates (5a–j).22 The yields of products (5a–j)
were ranging from 61% to 69%. The purity of the compounds was
checked on silica coated TLC plate using hexane/ethyl accetate
(8:2, v/v) as mobile phase. The compounds (5a–j) were character-
ized by 1H, 13C, 31P NMR, ESI-MS, and elemental analysis (see
Supplementary information).
The synthetic route of the designed benzimidazole and benzo-
thiazole linked phosphoramidates and phosphoramidothioates
(5a–j) is summarized in Scheme 1.
When the reaction was carried out with 1,2-phenylendiamine 6
and 4-nitro benzaldehyde 7 in 1:1 M ratio using mesoporous
23
mixed metal oxide nanocrystals of Al2O3–Fe2O3 as heterogenous
catalyst in acetonitrile at 60 °C, then mono-substituted product,
i.e., 2-(4-nitrophenyl)-1H-benzimidazole 8 is formed with excel-
lent yield (82%). The compound 8 thus formed was reduced24
further with the help of zinc dust under acidic condition in etharial
solution to get the product 2-(4-aminophenyl)-1H-benzimidazole
(9). The compound 9, was further treated with dialkyl/diaryl chlo-
rophosphate/chlorothiophosphate 4 in presence of triethylamine
(Et3N) to access the target compounds O,O-disubstituted
4-(1H-benzimidazol-2-yl)phenylphosphoramidates/phenylphosph-
oramidothioates (10a–e)25 with yields ranging from 60% to 64%. An
overview of synthetic highlights delineating the synthesis of benz-
imidazole linked phenylphosphoramidates and phenylphosph-
oramidothioates (10a–e) is depicted in Scheme 2.
Figure 1. Larvicidal activity of synthesized phosphorylated and thiophosphorylated
benzimidazoles and benzothiazoles (5a–j and 10a–e) to Ae. albopictus.
chlorophosphate/chlorothiophosphate. No by-products such as
phosphoramidic acids and polymerized products have been
The reaction was monitored by TLC using hexane/ethyl accetate
(8:2, v/v) and GC to determine the consumption of dialkyl/diaryl
Table 2
Synthesized benzimidazole linked phenylphosphoramidates and phenylphosphoramidothioates (10a–e)
Entry
a
Chloro phosphate/phosphothionate
Product (10)
Yield* (%)
60
O
O
O
O
O
P
N
Cl
Cl
P
O
NH
N
H
O
P
O
O
O
O
P
N
b
64
62
O
NH
N
H
O
P
Cl
O
O
O
c
O
P
N
O
NH
N
H
S
P
O
S
O
O
Cl
Cl
P
N
O
d
62
63
NH
N
H
S
P
O
O
O
S
P
N
e
O
NH
N
H
*
Isolated yield.
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P. Bandyopadhyay et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
5
Table 3
Larvicidal activity (LC50 and LC90) of synthesized O,O-diethyl 4-(1H-benzimidazol-2-
yl) phenylphosphoramidothioate (10e) to Ae. albopictus
10e
Ae. albopictus
24 h
48 h
LC50
F.L.
LC90
F.L.
X2
*
*
6.42
5.14–8.02
19.58
12.21–31.39
0.455
5.25
4.38–6.29
13.82
9.81–19.48
4.98
S.E.
Y=
0.401
2.85 + 2.64
0.405
2.8 + 3.04
⁄
LC50 and LC90 in mg/L.
Table 4
Larvicidal activity (LC50 and LC90) of synthesized O,O-diethyl 4-(1H-benzimidazol-2-
yl)phenylphosphoramidothioate (10e) to Cx. quinquefasciatus
10e
Cx. quinquefasciatus
24 h
48 h
LC50
F.L.
LC90
F.L.
X2
*
*
7.01
5.64–8.72
25.15
16.21–39.04
5.23
3.88
3.17–4.75
12.9
9.26–17.96
7.48
S.E.
Y=
0.361
3.04 + 2.31
0.29
3.55 + 2.45
⁄
LC50 and LC90 in mg/L.
for a compound to remain effective against the insect larvae. It also
evident from Table 3 the presence of P@S found to be more
effective in contrast to P@O compound. These results evidently
suggested that compounds (10e, 5j and 5e) containing
[NHAP(@S)(OEt)2] group exhibited better larvicidal activity profile
in compare to their methyl and phenyl analogues. The log dose
probit (LDP) assay of 10e to Ae. albopictus and Cx. quinquefasciatus
were performed at different concentrations (Figs. 1 and 2), data
revealed that 10e was most toxic to Ae. albopictus with the
LC50 of 6.42 and 5.25 mg/L at 24 and 48 h. whereas to Cx.
quinquefasciatus it was 7.01 and 3.88 mg/L, respectively.
In summary, a number of novel phosphorylated and thi-
ophosphorylated benzimidazole and benzothiazole derivatives
were synthesized and their larvicidal activities were evaluated
against Ae. albopictus and Cx. quinquefasciatus. To the best of our
knowledge, this is the first Letter wherein benzimidazole and ben-
zothiazole linked to phosphoramidates and phosphoramidothio-
ates and benzimidazole linked to phenylphosphoramidates and
phenylphosphoramidothioates showing larvicidal activity against
the mosquito species Ae. albopictus and Cx. quinquefasciatus. The
results based on larval bioassay indicated that, amongst 15 tested
compounds, 10e exhibited better mosquitocidal activity to both Ae.
albopictus and Cx. quinquefasciatus. In addition, compound 5j dis-
played moderate mosquitocidal activity to Ae. albopictus and good
activity to Cx. quinquefasciatus. Moreover, the compounds 10b, 5e
and 5d also demonstrated larval mortality to Cx. quinquefasciatus.
It has been observed that, P@S containing compounds are more
toxic than that containing P@O. Moreover, it has also been
observed that compounds (10e, 5j and 5e) containing
[NHAP(@S)(OEt)2] group exhibited better activity profile (toxicity)
than the other. These mosquitocidal results indicated that struc-
tural factors, such as type of substitution in the ring and water sol-
ubility of the target compounds could further enhance their
toxicity. The results obtained from this study suggested that the
compounds 10e, 5j and 5e could be the new addition in the list
of OP larvicidal molecules.
Figure 2. Larvicidal activity of synthesized phosphorylated and thiophosphorylated
benzimidazoles and benzothiazoles (5a–j and 10a–e) to Cx. quinquefasciatus.
formed, which are generally obtained by the use of other classical
methods. Easy workup, excellent yields of the products and mild
reaction conditions encouraged us to apply this method for the
synthesis of variety of benzimidazole and benzothiazole linked
phosphoramidates and phosphoramidothioates (Table 1) and
benzimidazole linked phenylphosphoramidates and phen-
ylphosphoramidothioates (Table 2). All the synthesized com-
pounds 5a–j and 10a–e were characterized by 1H, 13C, 31P NMR,
ESI-MS and elemental analyses (see Supplementary information).
The larvicidal activity26 of ten synthesized benzimidazole and
benzothiazole linked phosphoramidates and phosphoramidothio-
ates (5a–j) and five synthesized benzimidazole linked phen-
ylphosphoramidates and phenylphosphoramidothioates (10a–e)
tested against mosquito species Aedes albopictus and Cx. quinque-
fasciatus at different concentrations (40–5 mg/L). Amongst them,
three compounds 10e, 5j and 5e exhibited promising larvicidal
activity (Figs. 1 and 2). 10e elicited comparatively better larvicidal
activity to both the mosquito species (Tables 3 and 4). Temephos
was used as positive control.
Screening of synthesized compounds revealed that 10e was the
most toxic amongst all giving 100% larval mortality to Ae. albopic-
tus at 10 mg/L, whereas 65% larval mortality to Cx. quinquefasciatus.
To see the effect of N-phosphorylation of –NH2 group at 2-position
of benzimidazole and benzothiazole ring on larvicidal activity,
2-amino benzimidazole/benzothiazole and representative com-
pounds of dialkyl/diaryl chlorophosphates/chlorothiophosphates
were also screened and no substantial activity was observed. From
this study it was understood that phosphorylation of 2-amino
group of benzimidazole and benzothiazole ring was significant
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P. Bandyopadhyay et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
Benzimidazoles and Congeneric Tricyclic Compounds, Part 2; John Wiley & Sons:
Acknowledgements
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We are thankful to Defence Research
Organization (DRDO), New Delhi, India for providing financial
support for the research project (ERIP/ER/0703685/M/01/1091).
& Development
We thank the Director, Defence Research
& Development
Establishment (DRDE), Gwalior, India for taking keen interest and
encouragement and giving support. P.B. is thankful to DRDO,
New Delhi, India, for a Senior Research Fellowship. Thanks to
Mr. Ajay Pratap and Mr. Ashish Shrivastav for recording the NMR
and mass spectra, respectively.
Supplementary data
20. Deng, X.; McAllister, H.; Mani, N. S. J. Org. Chem. 2009, 74, 5742.
21. Zhao, J.; Huang, H.; Wu, W.; Chen, H.; Jiang, H. Org. Lett. 2013, 15, 2604.
Supplementary data (general experimental information, detail
experimental procedures, spectral characterization data, and copies
of ESI-MS spectra of phosphorylated and thiophosphorylated benz-
imidazole and benzothiazole derivatives are given in supplementary
information) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.bmcl.2014.04.082.
22. In
a
two-neck round-bottomed flask, 2-aminobenzimidazole 3/2-
aminobenzothiazole 30 (10 mmol, 1 equiv) was added slowly with constant
stirring by magnetic stirrer in CH3CN (10 mL) solvent and the whole reaction
setup was placed on a ice-bath. To this, triethylamine (Et3N) (1.5 mL, 15 mmol,
1.5 equiv) was added dropwise and keep the stirring for 10 min. Then dialkyl/
diaryl chlorophosphate/chlorothiophosphate
4 (15 mmol, 1.5 equiv) was
added dropwise by a syringe (5 mL) through rubber septum, (attached to the
side-neck of the RB). Stirring was going on in the ice-bath for another half an
hour and then after coming to room temperature, the reaction mixture was
refluxed at 70 °C on a sand-bath. The reaction progress was monitored by TLC
using hexane: ethyl accetate (8:2, v/v) and GC to determine the consumption of
dialkyl/diaryl chlorophosphate/chlorothiophosphate 4. After the reaction was
completed, from the reaction mixture excess of solvent was removed under
reduced pressure and the resulting reaction mixture was extracted with water
and ethyl acetate. The base Et3N will go to aquous layer as Et3NꢀHCl. Due to this
reason, the organic layer was washed with brine solution several times to
break the emulsion formed. The organic layer was then washed with aqueous
NaOH solution so as to remove unreacted dialkyl/diaryl chlorophosphate/
chlorothiophosphate, if available. The organic extract was dried over
anhydrous sodium sulfate and excess of solvent was removed under reduced
pressure so as to obtain the product. It was then purified by column
chromatography over silica gel using hexanes/EtOAc (9:1, v/v) as the eluting
solvent system, yielding the pure products (5a–j).
References and notes
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25. The compound 9, that is 2-(4-aminophenyl)-1H-benzimidazole(10 mmol,
1 equiv) was treated with dialkyl/diaryl chlorophosphate/chlorothiophosphate 4
(15 mmol, 1.5 equiv) in presence of triethylamine (Et3N) (1.5 mL, 15 mmol,
1.5 equiv) and CH3CN (10 mL) to get the title compounds (10a–e) by the same
procedure as described for the synthesis of 5 from 3 (or, 30). The reaction
progress was monitored by TLC using hexane: ethyl accetate (8:2, v/v) and
GC to determine the consumption of dialkyl/diaryl chlorophosphate/
chlorothiophosphate 4. It was then purified by column chromatography over
silica gel using hexanes/EtOAc (9:1, v/v) as the eluting solvent system, yielding
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method27 to both the mosquito species (susceptible laboratory strain maintained
at Vector Management Division, DRDE, Gwalior). Late third to early fourth instar
larvae were sorted and twenty larvae were transferred into disposable 200 mL
plastic cups containing 99 mL of dechlorinated tap water. The compounds
were dissolved in DMSO and dilutions were prepared (final concentration
ranging from 40 to 5 mg/L). One milliliter of DMSO dissolved serially diluted
compound was dispensed with an automated micropipette in the water cup.
Temephos was used as positive control. Dried Brewers yeast powder was
provided as larval diet. Mortality was recorded after 24 and 48 h. Moribund
larvae (presenting tremours, rigidity or mobility to reach water surface on
touch) were considered as dead. Test was rejected for control mortality >20% or
pupation >10%. All rearing and bioassay were performed at 12:12 (Light:Dark)
h, at 27 2 °C and 70–80% relative humidity. Experiment was replicated twice
for compounds exhibiting larvicidal effect. The LC50 and LC90 values were
determined as per Probit Analysis28 using INDOSTAT statistical software.
27. World Health Organization document: WHO/VBC/81.806, 1981.
28. Finney, D. Probit Analysis; Cambridge University Press: Cambridge, United
Kingdom, 1971.
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Please cite this article in press as: Bandyopadhyay, P.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.04.082