Biological evaluation of a series of benzothiazole derivatives as mosquitocidal agents

Article abstract of DOI:10.1515/chem-2019-0027

Aedes aegypti is associated with the transmission of numerous human and animal diseases, such as yellow fever, dengue fever, chikungunya, and more recently Zika virus. Emerging insecticide resistance has created a need to develop new mosquitocidal agents for effective control operations. A series of benzothiazole-piperidine derivatives (1-24) were investigated for their larvicidal and adulticidal effects on Ae. aegypti It was observed that compounds 2, 4, 6, 7, 8, 11 and 13 showed notable larvicidal activity. Furthermore, compounds 6 and 10 showed promising adulticidal activity. Based on the mosquitocidal properties of these compounds, docking studies were also carried out in the active site of the AeSCP2 enzyme to explore any insights into further in vitro enzyme studies. Docking results indicated that all these active compounds showed reasonable interactions with critical residues in the active site of this enzyme. This outcome suggested that these compounds might show their larvicidal and adulticidal effects via the inhibition of AeSCP2. According to in vitro and in silico studies, compounds 2, 4, 6, 7, 8, 10, 11 and 13 stand out as candidates for further studies.

Full text of DOI:10.1515/chem-2019-0027

Open Chem., 2019; 17: 288–294
Research Article
Belgin Sever, Mehlika Dilek Altıntop*, Ahmet Özdemir, Nurhayat Tabanca, Alden S. Estep,
James J. Becnel, Jeffrey R. Bloomquist
Biological evaluation of a series of benzothiazole
derivatives as mosquitocidal agents
https://doi.org/10.1515/chem-2019-0027
Keywords: mosquito control; Aedes aegypti;
received May 26, 2018; accepted December 26, 2019.
benzothiazole; piperidine; docking studies.
Abstract: Aedes aegypti is associated with the
transmission of numerous human and animal diseases,
such as yellow fever, dengue fever, chikungunya, and 1 Introduction
more recently Zika virus. Emerging insecticide resistance
has created a need to develop new mosquitocidal agents Mosquitoes are one of the most dangerous insect vectors
for effective control operations. A series of benzothiazole- and infectious disease carriers in developing countries
piperidine derivatives (1-24) were investigated for their [1]. Among mosquito species, Aedes aegypti L. transmits
larvicidal and adulticidal effects on Ae. aegypti. It was yellow fever, dengue fever, chikungunya, and more
observed that compounds 2, 4, 6, 7, 8, 11 and 13 showed recently, Zika virus [2]. Dengue is an endemic viral disease
notable larvicidal activity. Furthermore, compounds 6 found mainly in the tropical and subtropical regions
and 10 showed promising adulticidal activity. Based across the globe [3,4]. Dengue is characterized by fever,
on the mosquitocidal properties of these compounds, headache, muscle, and joint pain together with nausea
docking studies were also carried out in the active site of and vomiting [4-6]. Zika virus also causes severe brain
the AeSCP2 enzyme to explore any insights into further in defects and threatens the lives and health of adults and
vitro enzyme studies. Docking results indicated that all newborns from infected mothers [7].
these active compounds showed reasonable interactions
The battle against mosquitoes has become a crucial
with critical residues in the active site of this enzyme. environmental, economic and social health issue.
This outcome suggested that these compounds might Generally, chemical insecticides are considered as the
show their larvicidal and adulticidal effects via the first option for reducing vector-borne disease but evolving
inhibition of AeSCP2. According to in vitro and in silico resistance caused by cytochrome P450 monooxygenases
studies, compounds 2, 4, 6, 7, 8, 10, 11 and 13 stand out as (P450s), which are capable of metabolizing many
candidates for further studies.
insecticides, as well as decreases in target site sensitivity
can limit the success of insecticide treatment [8-10]. In
particular, overexpression of P450s such as the CYP9J32
gene in Ae. aegypti is associated with pyrethroid resistance
*
Corresponding author: Mehlika Dilek Altıntop, Department of
Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University,
6470 Eskişehir, Turkey, E-mail: mdaltintop@anadolu.edu.tr
[
11,12].
Sterol carrier protein-2 (SCP-2),
2
a
nonspecific
Belgin Sever, Mehlika Dilek Altıntop, Ahmet Özdemir: Department
of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu
University, 26470 Eskişehir, Turkey
intracellular lipid carrier, is expressed throughout the
animal kingdom including insects. Moreover, single SCP-2
domain genes have also been proven to be expanded in
mosquitoes [13]. Cholesterol is crucial for insects in order
to grow, develop and reproduce, but they are not capable
of synthesizing cholesterol de novo [14,15]. The mosquito
SCP-2, Ae. aegypti SCP-2 (AeSCP2), has been reported to be
involved in cholesterol and fatty acid uptake in the midgut
in both larval and adult mosquitoes [16]. A small number
of studies have focused on developing new insecticides
that prevent cholesterol biosynthesis targeting AeSCP2
Nurhayat Tabanca: USDA-ARS, Subtropical Horticulture Research
Station, 13601 Old Cutler Road, Miami, FL 33158, USA
Nurhayat Tabanca, Jeffrey R. Bloomquist: Department of Entomology
and Nematology, Emerging Pathogens Institute, University of
Florida, Gainesville, FL 32610, USA
Alden S. Estep: Navy Entomology Center of Excellence, Research
&
Development Department, 1700 SW 23rd Drive, Gainesville, FL
3
2608, USA
Alden S. Estep, James J. Becnel: USDA-ARS, Center for Medical,
Agricultural, and Veterinary Entomology, 1700 SW 23rd Drive,
Gainesville, FL 32608, USA
Open Access. © 2019 Belgin Sever et al., published by De Gruyter.
Attribution alone 4.0 License.
This work is licensed under the Creative Commons
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Biological evaluation of a series of benzothiazole derivatives as mosquitocidal agents
ꢀ289
[
17-19]. Fifty seven compounds were identified in silico as Table 1: Structures of compounds 1-24 [29].
possible inhibitors of the cholesterol-binding capacity
of SCP-2 from the library of 16000 compounds [20].
Therefore, targeting this cholesterol transport pathway
associated with AeSCP2 could be an alternative target for
the development of specific mosquitocidal agents.
N
O
R'
N
R
S
N
H
Benzothiazole (BT) is a privileged bicyclic ring
system present in a wide variety of synthetic and natural
products. BT and its derivatives play a distinctive role
in medicinal chemistry due to their diverse biological
activities such as antiprotozoal, antimicrobial,
anticancer, antischizophrenia, antihypertensive, anti-
inflammatory, and antiviral activities [21-25]. Venugopala
et al. 2013 [26], also screened benzothiazole analogs for
their mosquitocidal and repellent properties against
Anopheles arabiensis by mosquito feeding-probing
assay, cone bio-assay and standard World Health
Organization (WHO) larvicidal assay. Similarly, piperidine
is a strong base mainly found in several natural alkaloid
skeletons [27]. Diversely substituted piperidines are
the leading heterocycles in the structure of several
important pharmaceuticals such as bupivacaine,
troxipide, tofacitinib, fexofenadine, astemizole, fentanyl,
haloperidol, loperamide, trimeperidine, etc. [28].
On the basis of these findings, benzothiazole-
piperidine derivatives, which had been reported
previously for their antimicrobial effects on pathogenic
bacteria and Candida species by our research group [29],
were evaluated for their insecticidal activities against
Ae. aegypti. In addition, molecular docking studies were
performed for the most effective compounds within
the active site of AeSCP2 (PDB code: 1PZ4) to provide a
mechanistic approach for further studies [30].
Compound
R
R’
ꢀ
ꢁ
3
ꢂ
5
6
7
ꢃ
ꢄ
H
ꢁ-methyl
H
ꢂ-methyl
H
ꢃ,ꢄ-dimethyl
ꢂ,ꢅ-dimethyl
ꢁ-methyl
H
Cl
Cl
ꢂ-methyl
Cl
ꢃ,ꢄ-dimethyl
ꢂ,ꢅ-dimethyl
ꢁ-methyl
Cl
CHꢂ
CHꢂ
CHꢂ
ꢀ
ꢀ
ꢀ
0
ꢀ
ꢁ
ꢂ-methyl
ꢃ,ꢄ-dimethyl
ꢂ,ꢅ-dimethyl
ꢁ-methyl
CHꢂ
ꢀ3
OCHꢂ
OCHꢂ
OCHꢂ
OCHꢂ
ꢀ
ꢀ
ꢂ
5
ꢂ-methyl
ꢃ,ꢄ-dimethyl
ꢂ,ꢅ-dimethyl
ꢁ-methyl
ꢀ6
ꢀ
ꢀ
ꢀ
7
ꢃ
ꢄ
OC H
ꢃ
ꢅ
ꢅ
ꢅ
ꢅ
OC H
ꢂ-methyl
ꢃ
OC H
ꢃ,ꢄ-dimethyl
ꢂ,ꢅ-dimethyl
ꢁ-methyl
ꢃ
ꢁ0
OC H
ꢃ
ꢁ
ꢁ
ꢁ
ꢁ
ꢀ
ꢁ
3
ꢂ
NOꢃ
NOꢃ
NOꢃ
NOꢃ
ꢂ-methyl
2
Experimental
ꢃ,ꢄ-dimethyl
ꢂ,ꢅ-dimethyl
2
.1 Chemistry
2
-Chloro-N-(benzothiazol-2-yl)acetamide derivatives were 2.2 Biological assays
synthesized via the reaction of 2-aminobenzothiazoles
withchloroacetylchlorideinthepresenceoftriethylamine. 2.2.1 Mosquitoes
N-(Benzothiazol-2-yl)-2-(piperidin-1-yl)acetamide derivatives
(
1-24) (Table 1) were obtained by the nucleophilic The Orlando 1952 strain (ORL1952) of Ae. aegypti is a
substitution reaction of 2-chloro-N-(benzothiazol-2-yl) laboratory susceptible colony that has been without
acetamides with piperidine derivatives in the presence of wildtype supplementation for over seventy years. The
potassium carbonate. The synthetic protocol and spectral strain was originally collected near Orlando Florida, USA
data of the compounds were reported previously by our and has been maintained by the USDA ARS Center for
research group [29].
Medical, Agricultural and Veterinary Entomology (CMAVE)
in Gainesville, Florida (previously the Insects Affecting
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29ꢅꢀ
Belgin Sever et al.
Man Laboratory). Insecticide susceptibility of this strain 2.2.4 LDꢇꢅ and LCꢇꢅ calculation
has been characterized for a large number of common
pesticides [31,32]. Colony maintenance and organism Median lethal doses were calculated using SigmaPlot (v13).
rearing for bioassays were described previously [31].
Raw mortality counts from each dose of each replicate
were converted to percentage mortality and plotted. Curve
fitting of dose and mortality data was performed using a
four parameter logistic model with constrained minimum
and maximum values of 0 and 100, respectively.
2.2.2 Larvicidal activity
The larval bioassay was described in detail previously
31]. Briefly, ORL1952 eggs were hatched overnight in
[
approximately 100 mL of deionized water. Five first instar 2.ꢆ Molecular docking studies
larvae were transferred into the wells of 96-well flat-
bottom tissue culture plate in 188 µL of deionized water. Molecular docking studies were carried out to understand
Ten microliters of a 2% solution of finely ground alfalfa the relationship between protein structures and
powder were added to each well.
substrates, which can provide reasonable explanations
Compounds 1-24 were dissolved in DMSO to produce for substrate specificities and differences in the active
a 100 mg/µL stock solution. Dilutions of each stock site of the target structure. As previously mentioned,
solution were created by adding 2, 1, 0.5, or 0.2 microliters inhibition of AeSCP2 can reduce the uptake of cholesterol
to the wells containing larva and food media for the initial and lead to death in both larval and adult mosquitoes.
screening bioassay. Negative control wells were prepared For this purpose, compounds 2, 4, 6, 7, 8, 10, 11 and 13
with 2 microliters of DMSO and positive control wells were docked to the active site of AeSCP2 due to their in
contained permethrin. Bioassay plates were covered and vitro mosquitocidal potencies. Ligands were sketched
maintained on the benchtop at 22-23°C. Mortality was and cleaned in Maestro molecular modeling workspace
scored at 24 hours and the assay was repeated on three followed by energy minimization in ligand preparation
separate days. Additional dilutions (to 0.01 mg/µL; 0.005 program of Schrödinger’s Maestro molecular modeling
mg/µL for compound 11) of active compounds (>80% package (Schrödinger Release 2016-2: Schrödinger,
mortality at 0.1 mg/µL) were tested to determine the full LLC, New York, NY, USA) using Optimized Potential
dose response curve and allow calculation of LC values. Liquid Simulations (OPLS_2005) force field. The X-ray
50
crystallographic structure of the AeSCP2 complex with
palmitic acid (PDB code: 1PZ4) [30] was retrieved from the
Protein Data Bank (PDB) server and optimized for docking
analysis in protein preparation module of Schrödinger
2.2.ꢆ Adulticidal activity
Three to seven-day post-emergence female Ae. aegypti software. In molecular docking simulations, Glide/
were sorted into groups of 10 in TK35 plastic cups after XP docking protocols were applied for the prediction
one hour of chilling at 4°C. Compound stock solutions of topologies of active compounds in the active site of
in DMSO (100 µg/µL) were diluted in acetone to produce AeSCP2.
a 10 mg/µL solution. Five hundred nanoliters of the
Ethical approval: The conducted research is not
compound solution were applied to the thorax of each related to either human or animal use.
mosquito using a repeating syringe with a blunt tip needle
(
Hamilton PB600 with 7100 syringe). Cups containing
treated mosquitoes were capped with tulle mesh and ꢆ Results and Discussion
mosquitoes were allowed to recover with access to 10%
sucrose saturated cotton balls. Mortality was recorded Compounds 1-24 were investigated for their larvicidal
at 24 hours and the assay was repeated at least three and adulticidal activities against Ae. aegypti. Initial
times. Acetone was used as a negative control, whereas screening of the first instar larvae was completed at
permethrin (mixture of 46.1% cis and 53.2% trans isomers four concentrations (1.0, 0.5, 0.25, 0.1 mg/µL) with seven
(
Chemservice, West Chester, PA, USA)) was used as a compounds producing more than 80% mortality at the
positive control. Additional dilutions (from 5 ug/mosq 0.1 mg/µL dose (Table 2). Compounds 6 and 10 produced
to 0.5 ug/mosq) and assays of active compounds were more than 80% mortality in initial screening of adult
performed to calculate LD values. Specific details of the Ae. aegypti females (Table 2). LC50 or LD50 values were
5
0
adult topical bioassay were published previously [33].
subsequently determined for compounds that produced
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Biological evaluation of a series of benzothiazole derivatives as mosquitocidal agents
ꢀ291
Table 2: Twenty-four hour larval and adult topical mortality of compounds 1-24 against the susceptible Orlando (ORL1952) strain of Ae.
aegypti.
st
Larvicidal activity against ꢀ instar Ae. aegypti*
Adulticidal activity against adult female
#
Ae. aegypti**
ꢀ
0.5
mg/µL
0.ꢁ5
mg/µL
0.ꢀ
mg/µL
LC ± SE
IC
Rꢁ
5 mg/
LD ± SE
LD
50
Rꢁ
5
0
50
(µM)
50
mg/µL
(mg/µL)
mosquito (mg/mosq.) (µM)
ꢀ
ꢁ
ꢆꢂ ± ꢇꢃ
ꢇꢊꢊ
ꢈꢉ ± ꢇꢃ
ꢇꢊꢊ
ꢇꢊꢊ
ꢇꢊꢊ
ꢉꢂ ± ꢂꢇ
ꢇꢊꢊ
-
-
ꢄꢁ ± ꢄ
ꢁꢉ ± ꢄ
-
-
-
-
ꢊ.ꢊꢆꢄ ±
ꢊ.ꢊꢊꢅ
ꢂꢂꢃ.ꢃ
ꢊ.ꢆꢈꢁ
3
ꢂ
ꢉꢂ ± ꢇꢃ
ꢇꢊꢊ
ꢁꢊ ± ꢃꢊ
ꢇꢊꢊ
ꢊ
ꢊ
-
-
ꢁꢉ ± ꢃꢆ
ꢄꢊ ± ꢃꢉ
-
-
-
-
ꢇꢊꢊ
ꢈꢉ ± ꢃꢂ
ꢊ.ꢊꢄꢅ ±
ꢊ.ꢊꢇꢇ
ꢃꢇꢁ.ꢅ
ꢊ.ꢉꢆꢁ
5
6
ꢇꢊꢊ
ꢇꢊꢊ
ꢆꢂ ± ꢇꢃ
ꢇꢊꢊ
ꢈꢉ ± ꢃꢂ
ꢇꢊꢊ
ꢄꢊ ± ꢅꢂ
ꢇꢊꢊ
-
-
ꢉꢉ ± ꢃꢇ
ꢈꢂ ± ꢇꢃ
-
-
ꢊ.ꢊꢅꢂ ±
ꢊ.ꢊꢇꢇ
ꢇꢄꢂ.ꢈ
ꢂꢉꢆ.ꢃ
ꢂꢄꢁ.ꢁ
ꢊ.ꢄꢁꢂ
ꢃ.ꢊꢈꢁ ±
ꢊ.ꢂꢂꢈ
ꢄꢁꢁꢃ.ꢊ
ꢆꢉꢉꢅ.ꢄ
ꢊ.ꢆꢃꢄ
7
ꢃ
ꢇꢊꢊ
ꢇꢊꢊ
ꢇꢊꢊ
ꢇꢊꢊ
ꢆꢂ ± ꢇꢃ
ꢇꢊꢊ
ꢆꢂ ± ꢇꢃ
ꢈꢉ ± ꢃꢂ
ꢊ.ꢇꢃꢈ ±
ꢊ.ꢊꢇꢆ
ꢊ.ꢈꢊꢂ
ꢊ.ꢆꢈꢇ
ꢁꢉ ± ꢃꢆ
ꢄꢂ ± ꢇꢃ
-
-
-
-
-
ꢊ.ꢇꢃꢂ ±
ꢊ.ꢊꢇꢅ
ꢄ
ꢀ
ꢁꢉ ± ꢁꢃ
ꢇꢊꢊ
ꢁꢉ ± ꢁꢃ
ꢈꢉ ± ꢇꢃ
ꢂꢂ ± ꢂꢇ
ꢈꢊ ± ꢃꢊ
ꢂꢂ ± ꢅꢈ
ꢄꢉ ± ꢇꢃ
-
-
-
-
ꢉꢊ
-
0
ꢀ
ꢈꢂ ± ꢄ
ꢃ.ꢆꢄꢃ ±
ꢊ.ꢄꢉꢊ
ꢊ.ꢅꢂꢂ
ꢀ
ꢇꢊꢊ
ꢇꢊꢊ
ꢇꢊꢊ
ꢇꢊꢊ
ꢊ.ꢊꢂꢁ ±
ꢊ.ꢊꢊꢂ
ꢇꢊꢉ.ꢂ
ꢂꢊꢉ.ꢃ
ꢊ.ꢄꢁꢉ
ꢁꢊ ± ꢇꢉ
-
-
ꢀ
ꢀ
ꢁ
3
ꢇꢊꢊ
ꢇꢊꢊ
ꢈꢉ ± ꢃꢂ
ꢇꢊꢊ
ꢉꢂ ± ꢁꢄ
ꢇꢊꢊ
ꢄꢉ ± ꢅꢈ
ꢇꢊꢊ
-
-
ꢅꢉ ± ꢇꢅ
ꢄꢉ ± ꢃꢅ
-
-
-
-
ꢊ.ꢊꢆꢈ ±
ꢊ.ꢊꢊꢇ
ꢊ.ꢆꢅꢈ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢂ
5
6
7
ꢃ
ꢄ
0
ꢀ
ꢁ
3
ꢂ
ꢇꢊꢊ
ꢇꢊꢊ
ꢇꢊꢊ
ꢉꢂ ± ꢃꢂ
ꢇꢅ ± ꢉ
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
ꢅꢊ ± ꢂꢄ
ꢉꢂ ± ꢇꢃ
ꢅꢂ ± ꢇꢃ
ꢄꢂ ± ꢇꢅ
ꢂꢉ ± ꢄ
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
ꢅꢅ ± ꢃꢃ
ꢇꢊꢊ
ꢁꢊ ± ꢊ
ꢇꢊꢊ
ꢃꢅ ± ꢉ
ꢉꢂ ± ꢁꢄ
ꢁꢉ ± ꢅꢊ
ꢈꢉ ± ꢃꢂ
ꢈꢊ ± ꢂꢅ
ꢂꢊ ± ꢇꢁ
ꢂꢂ ± ꢅꢈ
ꢂꢂ ± ꢅꢈ
ꢃꢉ ± ꢁꢄ
ꢆꢂ ± ꢇꢃ
ꢄꢉ ± ꢅꢈ
ꢄꢉ ± ꢅꢈ
ꢁꢉ ± ꢂꢇ
ꢄꢉ ± ꢂꢇ
ꢇꢅ ± ꢉ
ꢇꢊꢊ
ꢉꢂ ± ꢂꢇ
ꢆꢂ ± ꢇꢃ
ꢆꢂ ± ꢇꢃ
ꢁꢅ ± ꢉ
ꢅꢂ ± ꢅꢊ
ꢅꢂ ± ꢅꢊ
ꢃꢊ ± ꢃꢊ
ꢇꢊꢊ
ꢇꢊꢊ
ꢇꢊꢊ
ꢄꢉ ± ꢇꢃ
ꢅꢊ ± ꢇꢊ
ꢅꢊ ± ꢂꢊ
ꢄꢂ ± ꢄ
ꢄꢅ ± ꢃꢇ
ꢆꢂ ± ꢇꢃ
ꢆꢂ ± ꢇꢃ
ꢂꢂ ± ꢂꢇ
ꢇꢊꢊ
ꢂꢂ ± ꢅꢈ
ꢂꢂ ± ꢅꢈ
ꢉ ± ꢇꢃ
ꢉꢂ ± ꢇꢃ
ꢉꢂ ± ꢇꢃ
ꢄꢉ ± ꢂꢇ
*
*
Positive control permethrin at 3.0 pg/µL resulted in 26.7 ± 23.1 ꢋ mortality. Negative control solvent control (DMSO) had 0ꢋ mortality.
* The average mortality in the two permethrin positive controls of 0.1935 and 0.4772 ng/mosquito was 63.3 ± 15.3 and 100, respectively.
Acetone controls had 0ꢋ mortality.
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292ꢀ
Belgin Sever et al.
A
B
Figure: 1: Docked poses of compounds 2, 4, ꢈ, ꢉ, 8, 1ꢅ, 11 and 1ꢆ (Yellow dashes: Hydrogen bonding; Blue and green dashes: π-π
interactions) (A) and interactions of compound ꢈ in the active site of AeSCP2 (B).
>
80% mortality at the discriminating dose in either or activity positively as observed in compounds 6 and 10. In
both bioassays by further subdilutions and additional general, the loss of larvicidal activity was detected with
assays (Table 2). Compounds 11, 6, 4, 2, 13, 8, and 7 6-ethoxy and 6-nitro substitutions on the benzothiazole
showed the highest larvicidal activity with LC5 values ring as observed in compounds 17-24.
0
of 0.034 (107.3 µM), 0.053 (163.8 µM), 0.065 (214.5 µM),
According to docking results, compounds 2, 4, 6,
0
.096 (332.2 µM), 0.098 (307.2 µM), 0.123 (364.4 µM), and 7, 8, 10, 11, and 13 showed high affinity and substrate-
0
.128 (379.2 µM) µg/µL, respectively. Compounds 6 and 10 specific interactions in the active site of AeSCP2 [30,34]
exhibited the highest adulticidal activity with LD values (Figure: 1). Benzothiazoles of compounds 2, 6, 7, 10, 11,
50
of 2.084 (6442.0 µM) and 2.962 (9775.6 µM) µg/mosquito, and 13 presented π-π interactions with Arg15 and Phe105
respectively. Compounds 1, 3, 5, 9, 12, 14-24 did not show residues of the binding site of AeSCP2. The methoxy
strong larvicidal or adulticidal activity.
substitution on the benzothiazole ring of compound
Generally, 4-methyl substitution on the piperidine 13 could account for all interactions of this compound.
ring and 6-methoxy substitution on the benzothiazole Piperidines of compounds 4, 6, 7, 8, 10 and 11 displayed
ring, apart from compound 13, caused the loss of cation-π interaction with the Arg15 residue and only
larvicidal activity. On the other hand, 6-chloro substituted 4-methyl substitution on the piperidine ring did not have a
benzothiazoles (6, 7 and 8) displayed reasonable positive influence. All interactions of compounds 4 and 8
larvicidal activity; only compound 5 did not possess any were related to 3,5-dimethyl substitution on the piperidine
antimosquito properties related to 4-methyl substitution ring. Moreover, the acetamido moieties of compounds 2
on the piperidine ring. This outcome indicated the and 10 served as H-bond donors for the in pocket residue
importance of the chloro substitution at the sixth position Leu102. The docking score, glide gscore and glide emodel
of the benzothiazole scaffold. Among nonsubstituted results of compounds 2, 4, 6, 7, 8, 10, 11, and 13 are also
benzothiazoles (1-4), only 3-methyl substituted given in Table 3. The emodel score is appropriate for
piperidine-based compound
2
and 3,5-dimethyl the comparison of different conformations of the same
showed ligand, but the docking score is generally used for the
substituted piperidine-based compound
4
significant larvicidal activity, indicating that the methyl comparison of different ligands [35]. The docking scores
substitution at the third position of the piperidine ring of the compounds were determined to range between -8.19
enhanced the larvicidal activity. The presence of 3-methyl and -8.95 kcal/mol as similar to each other.
moiety on piperidine ring also influenced adulticidal
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Biological evaluation of a series of benzothiazole derivatives as mosquitocidal agents
ꢀ29ꢆ
Table ꢆ: Docking score (kcal/mol), glide gscore (kcal/mol) and glide
emodel (kcal/mol) results of compounds 2, 4, ꢈ, ꢉ, 8, 1ꢅ, 11 and 1ꢆ
for AeSCP2 (PDB code: 1PZ4).
of Defense. USDA is an equal opportunity provider and
employer.
Conflict of interest: The authors declare that they have
no conflict of interest.
Compound
Docking score Glide gscore
Glide emodel
ꢁ
ꢂ
6
7
ꢃ
-ꢈ.ꢂꢊ
-ꢈ.ꢁꢄ
-ꢈ.ꢈꢇ
-ꢈ.ꢇꢆ
-ꢈ.ꢃꢇ
-ꢈ.ꢆꢅ
-ꢈ.ꢆꢃ
-ꢈ.ꢃꢃ
-ꢈ.ꢂꢈ
-ꢈ.ꢅꢂ
-ꢈ.ꢈꢅ
-ꢈ.ꢃꢁ
-ꢈ.ꢃꢉ
-ꢈ.ꢆꢈ
-ꢈ.ꢆꢆ
-ꢈ.ꢃꢅ
-ꢅꢉ.ꢅꢇ
-ꢁꢈ.ꢃꢊ
-ꢅꢂ.ꢄꢁ
-ꢄꢇ.ꢂꢅ
-ꢅꢄ.ꢉꢊ
-ꢄꢉ.ꢊꢃ
-ꢁꢉ.ꢁꢃ
-ꢂꢃ.ꢄꢄ
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