Identification of naphthol derivatives as novel antifeedants and insecticides. 1

Article abstract of DOI:10.1021/jf501705u

A series of β-naphthol-derived 2-aminobenzothiazolomethylnaphthol derivatives (4a-4q) were synthesized and purified in excellent yields (86-94%) using green protocols and screened for their antifeedant and toxic activities against tobacco caterpillar (Spo

Full text of DOI:10.1021/jf501705u

Article
pubs.acs.org/JAFC
Identification of Naphthol Derivatives as Novel Antifeedants and
Insecticides. 1
Praveen Kumar Kalavagunta,† Rajasekharreddy Pala,‡ Usha Rani Pathipati,‡ and Narender Ravirala*,†
‡
†Crop Protection Chemicals Division and Biology and Biotechnology Division, CSIR-Indian Institute of Chemical Technology,
Taranaka, Hyderabad 500 007, India
S
* Supporting Information
ABSTRACT: A series of β-naphthol-derived 2-aminobenzothiazolomethylnaphthol derivatives (4a−4q) were synthesized and
purified in excellent yields (86−94%) using green protocols and screened for their antifeedant and toxic activities against tobacco
caterpillar (Spodoptera litura) and castor semilooper (Achaea janata) using no-choice leaf disk and topical bioassay methods. Four
of them, 4d, 4f, 4i, and 4j, were identified to be potent antifeedants with ED50 values of 16.4, 19.3, 7.0, and 5.2 μg/cm2 against S.
litura and 13.9, 17.2, 10.2, and 7.7 μg/cm2 against A. janata, respectively, and the mortality rate is >95% for 4i and 4j in the case
of S. litura and 4j in case of A. janata at a dosage of 0.2 μg/insect. Compounds 4d, 4i, and 4m are moderately toxic to A. janata
only. Overall, this study identified a novel class of synthetic compounds that do not belong to organochlorides,
organophosphates, carbamates, or neonicotinoids as strong antifeedants as well as insecticides.
KEYWORDS: β-naphthol, 2-aminobenzothiazole, Spodoptera litura, Achaea janata, antifeedant activity, insecticidal activity
death.10 However, its potential environmental effects are not
well understood.
INTRODUCTION
■
The enormous increase of population necessitates the need for
Several natural products such as azadirachtin, gossypol,
growing more food, which depends not only on good
quercetin, and rutin are potent insecticides/pesticides. Very few
cultivation practices but also on the control of pests and
of them are known to have a naphthalene ring in their structure.
diseases of the crops before as well as after harvest. Many novel
Even though they are fewer in number, most of them are
known to possess a 2-hydroxynaphthalene-1-carbaldehyde
skeleton in their basic structure. The natural products
hemigossypol and methoxyhemigossypol are currently being
used as components of insect bait composition11 and also
showing antifungal activity.12 On the other hand, gossypol
(Figure 1), which is a dimer of hemigossypol, a defensive
chemical present in cotton, also shows antioxidative,13
and alternate methods of pest control have been suggested in
recent years, but it appears that the routine use of chemical
pesticides is inevitable to curtail crop losses. The major reason
for the inability of these newly devised methods to protect
crops from insect pests is that they are developing resistance in
a rapid manner. Hence, a need occurs for the invention of
newer pesticides that can manage pest populations in the field,
leaving beneficial species unaffected. Conventional pesticides,
most of which are either organochlorides such as DDT,
endosulfan, and pentachlorophenol or organophosphates such
as chlorpyrifos, monocrotophos, and malathion, are all found to
be acutely toxic to birds, wildlife, and humans.1,2 They are also
found to cause several diseases in humans.3−6 As a result, most
of them have been banned in several countries or are about to
be banned. Neonicotinoids such as acetamiprid and imidaclo-
prid, which come into play as promising pesticides, also show
potential toxicity. A few of them are known for their connection
to honeybee colony collapse disorder.7 Recently the European
Union put a restriction on the use of neonicotinoids,8 The
American Bird Conservancy called for a ban on the use of
neonicotinoids in seed treatments because of their toxicity to
birds, aquatic invertebrates, and other wildlife.9 As a result,
there is increasing research on developing new classes of
pesticides that are toxic to selected pests and insects but not to
humans and other creatures. In 2007, DuPont introduced
chlorantraniliprole, a new class of insecticide, which belongs to
the anthranilamides. It selectively binds to ryanodine receptors
in insects and controls the release of Ca2+ and essential muscle
function, which finally leads to paralysis followed by insect
Figure 1. 2-Hydroxynaphthalene-1-carbaldehyde-based natural prod-
ucts with potent biological and insecticidal/pest repellent properties.
Received: April 10, 2014
Revised: June 19, 2014
Accepted: June 23, 2014
Published: June 23, 2014
© 2014 American Chemical Society
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antibacterial,14 and antifungal15 properties and so on. The
Table 1. Optimized Reaction Conditions for the Synthesis of
Compounds 4a−4q
compound can be used to treat several ailments.16
Another natural product, stelladerol (Figure 2), is a strong
inhibitor of cyclooxygenase enzyme and phospholipid oxida-
no.
compd
time, min
temp, °C
yield, %
1
4a
4b
4c
4d
4e
4f
40
50
40
45
50
40
45
45
45
45
40
40
50
40
40
40
45
110
120
110
110
110
110
110
110
110
110
110
110
120
110
110
110
110
94
92
93
91
94
95
92
90
91
88
93
92
92
94
94
93
90
2
3
4
5
6
7
4g
4h
4i
8
9
Figure 2. Structure of naphthalene glycoside, stelladerol, which has
potential biological activities.
10
11
12
13
14
15
16
17
4j
4k
4l
tion.17 The compound 2-hydroxynaphthalene-1-carbaldehyde
itself is known to possess moderate antibacterial property.18
Naphthol is a precursor for a variety of insecticides and is a
well-known component with contact insecticidal properties.19
As our group is involved in the synthesis of β-naphthol-based
synthetics,20 we designed and synthesized a series of
naphthalene-based hybrid molecules using a novel green
protocol to screen them for their dual inhibitory activity as
angiotensin converting enzyme inhibitors and calcium channel
blockers in treating resistant hypertension. In a recent study
Venugopala et al. reported that these compounds show good
antimosquito properties.21 The existing literature and recent
studies drove us to screen our compounds for their antifeedant
and toxic properties against major agricultural pests. In the
present paper we describe the synthesis of 2-aminobenzothia-
zolomethylnaphthol derivatives using a green protocol and their
influence on the feeding behavior and toxicity effects against a
major polyphagous pest, Spodoptera litura, and a monophagous
pest, Achaea janata (L).
4m
4n
4o
4p
4q
methanol and help methanol to dissolve the product, resulting in a
decrease in the overall yield. Moreover, the solubility of fluoro and
methoxy derivatives is better in methanol when compared to other
derivatives. A schematic representation of the reaction is given in
Scheme 1.
Scheme 1. Schematic Representation for the Synthesis of
Compounds 4a−4q
MATERIALS AND METHODS
■
Instruments. Commercially available reagent grade chemicals and
solvents were used in all reactions and purification processes. All of the
reactions were monitored by TLC on E. Merck Kieselgel 60 F254, with
detection by UV light, charring with PMA charring solution, or
1
exposure to I2 vapors. The H (300 MHz) and 13C NMR (75 MHz)
were recorded on Avance-300 in DMSO-d6. The spectra were acquired
with sufficiently long relaxation delay to ensure quaternary carbon
relaxation. Also, more scans were used to obtain reasonable sensitivity
of the 13C NMR spectra. Multiplicities arising from 13C−19F couplings
were low in intensity and present over a large area, so they were
counted independently. Chemical shift values are reported in parts per
million relative to DMSO as internal reference. Coupling constant
value J is measured in hertz. s (singlet), d (doublet), t (triplet), brs
(broad singlet), dd (double doublet), m (multiplet). Mass spectra were
recorded on an Agilent LC/MSD trap SL 1100 series spectrometer
with a 70 eV ESI probe, and high-resolution mass spectra were
obtained by using ESI-QTOF mass spectrometry. Infrared spectra
were recorded on a Thermo Nicolet Nexus 670 FT-IR spectrometer.
General Synthesis. To a 10 mL RB flask were added aldehyde
(1.0 mmol), 2-aminobenzothiazole (1.0 mmol), and β-naphthol (1.0
mmol); these were mixed thoroughly and heated in preheated oil bath
at 110−120 °C for an appropriate time (Table 1). After completion of
reaction as indicated by TLC, the reaction mixture was allowed to
cool. The so-formed solid was powdered, washed with methanol (8
mL × 3 times for compounds except fluoro and methoxy derivatives, 4
mL × 3 times in the case of fluoro and methoxy derivatives), and dried
under vacuum to obtain the corresponding pure 2-aminobenzothia-
zolomethylnaphthol derivative. However, in the case of fluoro- and
methoxy-substituted derivatives, care must be taken during washing or
unreacted material present in the reaction mixture may dissolve in
1. 1-((Benzo[d]thiazol-2-ylamino)(phenyl)methyl)naphthalen-2-
ol (4a): white solid; mp = 200−202 °C; 1H NMR (300 MHz,
DMSO-d6) δ 10.17 (brs, 1H), 8.78 (d, 1H, J = 7.6 Hz), 7.94−7.74 (m,
3H), 7.66 (d, 1H, J = 7.6 Hz), 7.40−7.13 (m, 10H), 7.0 (t, 1H, J = 7.4
Hz); 13C NMR (75 MHz, DMSO-d6) δ 166.3, 153.2, 152.1, 142.5,
132.1, 130.8, 129.6, 128.6, 128.6, 128.1, 126.2, 126.0, 125.4, 123.8,
122.4, 121.0, 120.9, 118.7, 118.4, 118.1, 53.1; IR (KBr) νmax 3376,
3060, 1598, 1547, 1514, 1444, 1331, 1263, 744 cm−1; ESI-MS m/z 383
(M + H). HRMS calcd for C24H19N2OS, 383.1218; found, 383.1206.
2. 1-((Benzo[d]thiazol-2-ylamino)(2,4-dichlorophenyl)methyl)-
naphthalen-2-ol (4b): white solid; mp = 190−192 °C; 1H NMR
(300 MHz, DMSO-d6) δ 10.02−9.91 (brs, 1H), 8.88 (d, 1H, J = 7.0
Hz), 8.02 (d, 1H, J = 8.5 Hz), 7.79 (t, 2H, J = 9.3 Hz), 7.70−7.63 (m,
2H), 7.49 (d, 1H, J = 2.1 Hz), 7.46−7.35 (m, 3H), 7.27 (t, 1H, J = 7.6
Hz), 7.23−7.12 (m, 3H), 7.01 (t, 1H, J = 7.6 Hz); 13C NMR (75
MHz, DMSO-d6) δ 165.2, 153.8, 152.1, 139.0, 133.0, 132.7, 131.8,
131.1, 130.7, 130.0, 128.7, 128.3, 126.6, 126.5, 125.5, 122.6, 122.4,
121.1, 120.9, 118.5, 118.3, 115.9, 52.3; IR (KBr) νmax 3378, 3068,
1592, 1542, 1438, 1371, 1331, 1268, 751 cm−1; ESI-MS m/z 451 (M +
H). HRMS calcd for C24H17N2OSCl2, 451.0438; found, 451.0451.
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3. 1-((Benzo[d]thiazol-2-ylamino)(3-chlorophenyl)methyl)-
naphthalen-2-ol (4c): white solid; mp = 193−194 °C; 1H NMR
(300 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.81 (d, 1H, J = 7.6 Hz),
7.94−7.77 (m, 3H), 7.67 (d, 1H, J = 7.6 Hz), 7.45−7.15 (m, 10H),
7.02 (t, 1H, J = 7.4 Hz); 13C NMR (75 MHz, DMSO-d6) δ 166.1,
153.1, 151.9, 145.3, 132.8, 131.9, 130.8, 130.0, 129.8, 128.6, 128.5,
126.5, 126.1, 125.6, 125.4, 124.8, 123.3, 122.5, 121.1, 120.9, 118.3,
118.2, 118.0, 52.6; IR (KBr) νmax 3360, 3062, 1596, 1573, 1548, 1515,
1444, 1332, 1268, 749 cm−1; ESI-MS m/z 417 (M + H). HRMS calcd
for C24H18N2OSCl, 417.0828; found, 417.0809.
4. 1-((Benzo[d]thiazol-2-ylamino)(p-tolyl)methyl)naphthalen-2-
ol (4d). white solid; mp = 180−182 °C; 1H NMR (300 MHz,
DMSO-d6) δ 10.18−10.11 (brs, 1H), 8.78 (d, 1H, J = 7.6 Hz), 7.91−
7.73 (m, 3H), 7.66 (d, 1H, J = 7.4 Hz), 7.39−6.96 (m, 11H), 2.22 (s,
3H); 13C NMR (75 MHz, DMSO-d6) δ 166.2, 153.1, 152.1, 139.4,
135.1, 132.1, 130.7, 129.4, 128.6, 128.5, 126.1, 125.9, 125.4, 123.9,
122.4, 120.9, 120.8, 118.7, 118.3, 118.0, 52.9, 20.5; IR (KBr) νmax
3307, 1535, 1441, 1317, 1261, 744 cm−1; ESI-MS m/z 397 (M + H).
HRMS calcd for C25H21N2OS, 397.1374; found, 397.1373.
5. 1-((Benzo[d]thiazol-2-ylamino)(4-bromophenyl)methyl)-
naphthalen-2-ol (4e): white solid; mp = 202−204 °C; 1H NMR
(300 MHz, DMSO-d6) δ 10.24−10.16 (brs, 1H), 8.82 (d, 1H, J = 7.0
Hz), 7.89−7.75 (m, 3H), 7.67 (d, 1H, J = 7.6 Hz), 7.49−7.36 (m, 4H),
7.30−7.12 (m, 6H), 7.02 (t, 1H, J = 7.6 Hz); 13C NMR (75 MHz,
DMSO-d6) δ 166.1, 153.1, 151.9, 142.1, 131.9, 130.9, 130.8, 129.7,
128.5, 128.2, 126.3, 125.3, 123.5, 122.4, 121.0, 120.8, 119.1, 118.3,
118.1, 52.6; IR (KBr) νmax 3373, 1627, 1541, 1442, 1332, 1267, 1206,
1070, 749, 571 cm−1; ESI-MS m/z 461 (M + H). HRMS calcd for
C24H18N2OSBr, 461.0323; found, 461.0320.
6. 1-((Benzo[d]thiazol-2-ylamino)(4-fluorophenyl)methyl)-
naphthalen-2-ol (4f): white solid; mp = 178−180 °C; 1H NMR
(300 MHz, DMSO-d6) δ 1.22−10.13 (brs, 1H), 8.81 (d, 1H, J = 7.4
Hz), 7.93−7.76 (m, 3H), 7.67 (d, 1H, J = 7.7 Hz), 7.42−7.32 (m, 2H),
7.31−7.15 (m, 6H), 7.93−6.95 (m, 3H); 13C NMR (75 MHz, DMSO-
d6) δ 166.1, 162.2, 159.0, 153.1, 151.9, 138.4, 131.9, 130.7, 129.5,
128.5, 127.9, 127.8, 126.2, 125.3, 123.5, 122.3, 120.9, 120.8, 118.3,
118.0, 114.8, 114.5, 52.6; IR (KBr) νmax 3308, 1537, 1436, 1319, 1286,
1060, 810, 746 cm−1; ESI-MS m/z 401 (M + H). HRMS calcd for
C24H18FN2OS, 401.1123; found, 401.1115.
7. 1-((Benzo[d]thiazol-2-ylamino)(3-phenoxyphenyl)methyl)-
naphthalen-2-ol (4g): white solid; mp = 171−173 °C; 1H NMR
(300 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.78 (d, 1H, J = 7.4 Hz),
7.89−7.73 (m, 3H), 7.66 (d, 1H, J = 7.0 Hz), 7.43−7.16 (m, 9H),
7.06−6.93 (m, 4H), 6.87 (d, 2H, J = 7.6 Hz), 6.79 (dd, 1H, J1 = 7.6
Hz, J2 = 2.1 Hz); 13C NMR (75 MHz, DMSO-d6) δ 166.1, 156.5,
156.0, 153.1, 152.0, 145.0, 132.0, 130.7, 129.7, 128.6, 128.5, 126.2,
125.4, 123.0, 122.4, 121.3, 121.0, 120.8, 118.3, 118.1, 117.9, 116.6,
116.3, 52.7; IR (KBr) νmax 3314, 3052, 1541, 1511, 1451, 1267, 814,
749 cm−1; ESI-MS m/z 475 (M + H). HRMS calcd for C30H23N2O2S,
475.1480; found, 475.1471.
8. 1-((Benzo[d]thiazol-2-ylamino)(naphthalen-2-yl)methyl)-
naphthalen-2-ol (4h): white solid; mp = 190−192 °C; 1H NMR
(300 MHz, DMSO-d6) δ 10.21−10.16 (brs, 1H), 8.91 (d, 1H, J = 7.4
Hz), 7.95 (d, 1H, J = 7.9 Hz), 7.89−7.74 (m, 6H), 7.68 (d, 1H, J = 7.9
Hz), 7.53−7.40 (m, 3H), 7.38−7.15 (m, 6H), 7.02 (m, 1H); 13C NMR
(75 MHz, DMSO-d6) δ 166.2, 153.1, 152.0, 140.1, 132.6, 132.1, 131.7,
130.7, 129.6, 128.5, 128.4, 127.5, 127.3, 126.1, 126.0, 125.4, 125.3,
124.9, 123.8, 123.6, 122.3, 120.9, 120.8, 118.5, 118.3, 118.0, 53.3; IR
(KBr) νmax 3313, 3052, 1541, 1442, 1264, 814, 749 cm−1; ESI-MS m/z
433 (M + H). HRMS calcd for C28H21N2OS, 433.1374; found,
433.1387.
m/z 413 (M + H). HRMS calcd for C25H21N2O2S, 413.1323; found,
413.1319.
10. 6.1.1.20. 1-((Benzo[d]thiazol-2-ylamino)(3,4,5-
trimethoxyphenyl)methyl)naphthalen-2-ol (4j): white solid; mp =
1
170−172 °C; H NMR (300 MHz, DMSO-d6) δ 10.42−10.30 (brs,
1H), 8.63−8.37 (brs, 1H), 7.98−7.87 (brs, 1H), 7.75−7.63 (m, 2H),
7.52−7.31 (m, 3H), 7.28−7.15 (m, 3H), 7.11−6.94 (m, 2H), 6.58 (s,
2H), 3.70 (s, 3H), 3.66 (s, 6H); 13C NMR (75 MHz, DMSO-d6) δ
166.3, 153.3, 152.4, 137.0, 136.1, 132.0, 129.9, 129.1, 128.6, 128.1,
125.8, 125.1, 123.0, 122.2, 120.8, 120.1, 119.1, 118.8, 117.9, 103.6,
95.6, 59.8, 55.4, 54.3; IR (KBr) νmax 3317, 2923, 2833, 1590, 1538,
1441, 1315, 1248, 1171, 1030, 813, 745 cm−1; ESI-MS m/z 473 (M +
H). HRMS calcd for C27H25N2O4S, 473.1535; found, 473.1527.
11. 1-((Benzo[d]thiazol-2-ylamino)(4-(dimethylamino)phenyl)-
naphthalen-2-ol (4k): white solid; mp = 156−158 °C; 1H NMR
(300 MHz, DMSO-d6) δ 10.22−10.04 (brs, 1H), 8.71 (d, 1H, J = 7.4
Hz), 7.93 (d, 1H, J = 7.5 Hz), 7.77 (t, 2H, J = 9.1 Hz), 7.64 (d, 1H, J =
7.4 Hz), 7.39−7.29 (m, 2H), 7.28−7.11 (m, 4H), 7.07 (d, 2H, J = 8.5
Hz), 6.99 (t, 1H, J = 7.9 Hz), 6.63 (d, 2H, J = 8.9 Hz), 2.80 (s, 6H);
13C NMR (75 MHz, DMSO-d6) δ 166.2, 153.0, 152.1, 149.0, 132.1,
130.5, 129.5, 129.1, 128.6, 128.4, 126.8, 125.9, 125.3, 122.2, 120.7,
118.9, 118.4, 117.9, 112.2, 53.1, 40.1; IR (KBr) νmax 3315, 2849, 1602,
1538, 1446, 1318, 1264, 1165, 810, 745 cm−1; ESI-MS m/z 426 (M +
H). HRMS calcd for C26H24N3OS, 426.1640; found, 426.1639.
12. 4-((Benzo[d]thiazol-2-ylamino)(2-hydroxynaphthalen-1-yl)-
1
methyl)benzonitrile (4l): white solid; mp = 213−215 °C; H NMR
(300 MHz, DMSO-d6) δ 10.31−10.20 (brs, 1H), 8.85 (d, 1H, J = 7.0
Hz), 7.89−7.78 (m, 3H), 7.76−7.65 (m, 3H), 7.46−7.33 (m, 5H),
7.31−7.17 (m, 3H), 7.03 (t, 1H, J = 7.4 Hz); 13C NMR (75 MHz,
DMSO-d6) δ 166.1, 153.2, 151.9, 148.8, 132.0, 130.8, 130.0, 128.6,
128.5, 127.0, 126.5, 125.4, 123.2, 122.5, 121.2, 120.9, 118.8, 118.3,
117.8, 108.9, 53.0; IR (KBr) νmax 3379, 3056, 2226, 1573, 1541, 1437,
1329, 1270, 1026, 751 cm−1; ESI-MS m/z 408 (M + H). HRMS calcd
for C25H18N3OS, 408.1170; found, 408.1163.
13. 1-((Benzo[d]thiazol-2-ylamino)(2-bromo-5-fluorophenyl)-
1
methyl)naphthalen-2-ol (4m): white solid; mp = 198−200 °C; H
NMR (300 MHz, DMSO-d6) δ 9.92 (brs, 1H), 8.90 (d, 1H, J = 7.4
Hz), 8.05 (d, 1H, J = 8.7 Hz), 7.80 (t, 2H, J = 9.3 Hz), 7.66 (d, 1H, J =
7.7 Hz), 7.61−7.54 (m, 1H), 7.39−7.34 (m, 3H), 7.28 (t, 1H, J = 7.4
Hz), 7.20 (t, 1H, J = 7.6 Hz), 7.14−6.97 (m, 4H); 13C NMR (75
MHz, DMSO-d6) δ 165.0, 162.6, 159.4, 153.7, 152.0, 144.2, 144.1,
134.1, 134.0, 132.8, 130.6, 129.9, 128.5, 128.1, 126.5, 125.3, 122.4,
122.3, 121.0, 120.8, 118.5, 118.2, 116.9, 116.7, 116.6, 115.6, 115.3,
54.7; IR (KBr) νmax 3383, 1598, 1543, 1512, 1453, 1431, 1265, 812,
752 cm−1; ESI-MS m/z 479 (M + H). HRMS calcd for
C24H17BrFN2OS, 479.0204; found, 479.0190.
14. 1-((Benzo[d]thiazol-2-ylamino)(3-bromophenyl)naphthalen-
2-ol (4n): white solid; mp = 201−203 °C; 1H NMR (300 MHz,
DMSO-d6) δ 10.27−10.20 (brs, 1H), 8.84 (d, 1H, J = 7.4 Hz), 7.92−
7.77 (m, 3H), 7.68 (d, 1H, J = 7.6 Hz), 7.45−7.15 (m, 11H), 7.02 (t,
1H, J = 7.6 Hz); 13C NMR (75 MHz, DMSO-d6) δ 166.0, 153.1,
151.9, 145.5, 131.9, 130.7, 130.2, 129.8, 129.0, 128.5, 126.4, 125.4,
125.1, 123.3, 122.4, 121.4, 121.0, 120.8, 118.3, 118.1, 118.0, 52.6; IR
(KBr) νmax 3377, 3058, 1543, 1511, 1435, 1327, 1268, 747 cm−1; MS-
ESI m/z 461 (M + H). HRMS calcd for C24H18BrN2OS, 461.0323;
found, 461.0312.
15. 1-((Benzo[d]thiazol-2-ylamino)(3,4-dichlorophenyl)-
naphthalen-2-ol (4o): white solid; mp = 212−214 °C; 1H NMR
(300 MHz, DMSO-d6) δ 10.28−10.24 (brs, 1H), 8.87 (d, 1H, J = 7.2
Hz), 7.93−7.79 (m, 3H), 7.69 (d, 1H, J = 7.6 Hz), 7.53 (d, 1H, J = 8.3
Hz), 7.47−7.37 (m, 3H), 7.32−7.15 (m, 5H), 7.03 (t, 1H J = 7.7 Hz);
13C NMR (75 MHz, DMSO-d6) δ 166.0, 153.2, 151.8, 144.0, 131.9,
130.8, 130.6, 130.2, 130.0, 128.6, 128.4, 127.7, 126.6, 126.5, 125.4,
123.1, 122.5, 121.1, 120.9, 118.3, 118.2, 117.6, 52.3; IR (KBr) νmax
3379, 1577, 1540, 11461, 1328, 1268, 1205, 1028, 816, 747 cm−1; ESI-
MS m/z 451 (M + H). HRMS calcd for C24H17Cl2N2OS, 451.0438;
found, 451.0439.
16. 1-((Benzo[d]thiazol-2-ylamino)(3-fluorophenyl)naphthalen-
2-ol (4p): white solid; mp = 179−181 °C; 1H NMR (300 MHz,
DMSO-d6) δ 10.26−10.19 (brs, 1H), 8.84 (d, 1H, J = 7.4 Hz), 7.90−
9. 1-((Benzo[d]thiazol-2-ylamino)(4-methoxyphenyl)methyl)-
naphthalen-2-ol (4i): white solid; mp = 190−192 °C; 1H NMR
(300 MHz, DMSO-d6) δ 10.19−10.11 (brs, 1H), 8.79 (d, 1H, J = 7.4
Hz), 7.94−7.84 (brs, 1H), 7.79 (t, 2H, J = 8.7 Hz), 7.66 (d, 1H, J = 7.6
Hz), 7.42−7.12 (m, 9H), 7.0 (t, 1H, J = 7.9 Hz), 6.83 (d, 1H, J = 8.7
Hz), 3.68 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 166.2, 157.7,
153.0, 152.1, 134.1, 132.1, 130.6, 129.4, 128.6, 128.5, 127.2, 126.1,
125.3, 123.8, 122.3, 120.9, 120.8, 118.7, 118.4, 118.0, 113.5, 54.9, 52.8;
IR (KBr)
3313, 3052, 1541, 1442, 1264, 814, 749 cm−1; ESI-MS
νmax
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7.78 (m, 3H), 7.68 (d, 1H, J = 7.7 Hz), 7.43−7.17 (m, 7H), 7.07−6.96
(m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 166.1, 163.7, 160.5, 153.1,
151.9, 145.8, 145.8, 131.9, 130.7, 130.0, 129.9, 129.7, 128.5, 126.3,
125.4, 123.4, 122.4, 122.1, 121.0, 120.8, 118.3, 118.1, 113.0, 112.8,
112.5, 52.7; IR (KBr) νmax 3387, 1587, 1536, 1482, 1439, 1329, 1244,
1053, 749 cm−1; ESI-MS m/z 401 (M + H). HRMS calcd for
C24H18FN2OS, 401.1123; found, 401.1118.
17. 1-((Benzo[d]thiazol-2-ylamino)(4-isopropylphenyl)-
naphthalen-2-ol (4q): white solid; mp = 191−193 °C; 1H NMR
(300 MHz, DMSO-d6) δ 10.17−10.09 (brs, 1H), 8.78 (d, 1h, J = 7.6
Hz), 7.98−7.87 (brs, 1H), 7.79 (t, 2H, J = 7.8 Hz), 7.66 (d, 1H, J = 7.6
Hz), 7.4−7.32 (m, 2H), 7.30−7.10 (m, 8H), 7.00 (t, 1H, J = 8.1 Hz),
2.89−2.74 (m, 1H), 1.14 (dd, 6H, J1 = 7.0 Hz, J2 = 1.5 Hz); 13C NMR
(75 MHz, DMSO-d6) δ 166.2, 153.0, 152.1, 146.1, 139.6, 132.1, 130.6,
129.3, 128.5, 128.4, 126.1, 126.0, 125.9, 125.3, 123.7, 122.3, 120.8,
120.8, 118.7, 118.4, 118.0, 53.0, 32.9, 23.8, 23.7; IR (KBr) νmax 3314,
3055, 2957, 1540, 1450, 1268, 1060, 746 cm−1; ESI-MS m/z 425 (M +
H). HRMS calcd for C27H25N2OS, 425.1687; found, 425.1704.
Test Insects. S. litura and A. janata larvae used in this study were
obtained from a laboratory colony maintained in the Biology and
Biotechnology Division, IICT, Hyderabad, India. The culture has been
continuously maintained on castor leaves (Ricinus communis) at room
temperature (26 2 °C), 65 5% relative humidity, and 16:8 L:D
photoperiod in the laboratory.
Antifeedant Bioassay. The antifeedant activity of the compounds
was tested against tobacco caterpillar, S. litura (F.), and castor
semilooper, A. janata (L.). The experiments were conducted according
to the classical no-choice leaf disk method described earlier by Akhtar
et al.22 To study the antifeedant activity of the test compounds, a small
circular disk of 4 cm diameter was cut from fresh castor leaves. The
leaf disks were treated on their upper surface with individual
concentrations of the test compounds; after that, the leaf disks were
air-dried at room temperature, and each leaf disk was transferred to a
separate Petri plate of 15 cm diameter containing wet filter paper.
Control leaf disks were treated with the same volume of the DMSO
only. The third-instar larvae of S. litura and A. janata (starved for 4−5
h prior to the experiment) were allowed to feed to assess antifeedant
activity. Progress of the consumption of the leaf area was measured at
6, 12, and 24 h period intervals in both treated and control leaf disks.
Areas of control and treated leaf disks consumed were measured after
24 h using a leaf area meter (AM-300, ADC Bioscientific Limited,
Hoddesdon, UK). The antifeedant index was then calculated as (C −
T)/(C + T) × 100, where C is the consumption of control leaf disks
and T is consumption of treated leaf disks.23 For each concentration,
10 experimental sets were assayed. All tests were replicated three
times. The mean of the 30 sets was taken for each compound. Means
were subjected to probit analysis.24
Topical Bioassay. Toxicity of the test compounds was determined
by topical application to the third instar larvae of test insects.25 Two
micrograms of compounds was applied directly to the dorsum of the
larva in a 1 μL drop of DMSO using a micro applicator. Insects treated
with solvent alone were considered as controls. The treated and
control larvae were treated on fresh castor leaves. Mortality was
measured daily until 2 days after treatment. Larvae that lost elasticity
and heavy water loss from their body and showed no responses when
their tails were pinched with forceps were regarded as dead. On the
basis of three independent trials, each experiment was conducted in
five replicates, leading to 15 replicates with each concentration of
compounds. The mean of 15 replicates was taken for each compound,
and the percentage of mortality with standard deviation was calculated.
Data Analysis. Antifeedant index was calculated using five different
concentrations of each test compound, and data were subjected to
probit analysis24 to determine the ED50 value representing the
concentrations that caused 50% feeding deterrence along with the 95%
fiducial limits. The data were analyzed by completely randomized, one-
way analysis of variance (ANOVA), and the means were separated
using the Tukey HSD test (Biostat 2008).
RESULTS AND DISCUSSION
■
Scheme 1 illustrates the general procedure for the synthesis of
2-aminobenzothiazolomethylnaphthol derivatives. The syn-
thesis procedure is completely green, economic, and high-
yielding. A total of 17 derivatives were synthesized and
screened for their antifeedant effect (Table 2) and toxicity
(Table 3) against S. litura and A. janata.
Table 2. Antifeedant Effect of 2-
Aminobenzothiazolomethylnaphthol Derivatives 4a−q
against S. litura and A. janata by No-Choice Leaf Disk
Bioassay Method
a
antifeedant ED50, μg/cm2 (95% FL )
compd
S. litura
A. janata
4a
4b
4c
4d
4e
4f
>300
185.2 (175.0−192.3)
204.7 (204.5−204.9)
31.7 (21.0−37.6)
13.9 (12.7−14.8)
>300
109.9 (96.7−123.1)
59.2 (53.9−63.0)
16.4 (16.1−16.7)
>300
19.3 (19.1−19.6)
>300
17.2 (13.8−19.6)
219.0 (216.9−220.8)
265.2 (257.6−271.6)
10.2 (8.6−10.8)
7.7 (4.0−11.9)
111.2 (58.4−138.4)
21.9 (20.9−22.5)
43.4 (43.1−43.6)
33.4 (29.8−37.3)
81.7 (79.23−83.88)
76.7 (73.6−79.2)
230.9 (228.8−232.9)
4.7 (3.5−6.0)
4g
4h
4i
201.7 (197.0−205.2)
7.0 (6.3−7.8)
5.2 (4.3−5.8)
103.9 (100.0−107.0)
31.7 (19.0−38.9)
28.0 (27.8−28.2)
46.7 (39.7−53.7)
73.6 (62.4−80.2)
89.2 (80.9−94.4)
>300
4j
4k
4l
4m
4n
4o
4p
4q
azadirachtin
3.1 (2.0−4.0)
a
Fiducial limits.
The antifeedant activity of the 2-aminobenzothiazolomethyl-
naphthol derivatives was studied using the no-choice leaf disk
method. The results are summarized in Table 2. It is interesting
to note that most of the derivatives synthesized have good
antifeedancy against S. litura and A. janata. A few of them, 4d,
4f, 4i, and 4j, show a high level of antifeedancy even at lower
concentrations (5−100 μg/cm2) against both insects. Deriva-
tives 4d, 4f, 4i, and 4j showed significant antifeedant activity
(ED50) at lower doses of 16.4, 19.3, 7.0, and 5.2 μg/cm2 against
S. litura and lower doses of 13.9, 17.2, 10.2, and 7.7 μg/cm2
against A. janata, respectively.
Compounds 4a−q were primarily screened for their toxicity
using topical bioassay method at a dosage of 0.5 μg/insect
(Table 3). Compounds 4d, 4f, 4i, and 4j showed 100%
mortality against both species. Interestingly, two compounds, 4l
and 4m, showed 100% mortality against A. janata but were least
toxic to S. litura. To estimate the mortality rate at a lower dose,
we again screened the compounds at a dosage of 0.2 μg/insect
(Table 3). Derivative 4j produced high mortality >95% against
the larvae of both S. litura and A. janata, whereas derivative 4i
showed high mortality, that is, >95%, against S. litura but only
moderate mortality, that is, >85% and <95% against A. janata.
On the contrary, derivatives 4d and 4m showed moderate
mortality against A. janata, leaving them least toxic to S. litura.
Larval death took place soon after exposure to the treatment.
Derivatives 4i and 4j are very potent in penetrating the larval
body through cuticle and cause lethal effects because in these
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Table 3. Toxicity Effects of 2-Aminobenzothiazolomethylnaphthol Derivatives 4a−q against S. litura and A. janata by Topical
Bioassay Method
a
b
mortality, %, SE
mortality, %, SE
compd
S. litura
A. janata
S. litura
A. janata
4a
4b
4c
4d
4e
4f
13.6 0.3
16.0 0.8
67.7 0.8
100 0.0
3.7 0.3
16.6 0.5
14.1 0.4
70.5 1.0
100 0.0
5.5 0.4
6.4 0.5
4.4 0.7
42.2 2.3
84.7 1.1
0.0 0.0
70.5 0.8
0.0 0.0
13.2 0.8
98.6 0.5
96.3 1.6
43.0 2.7
59.4 1.3
45.5 1.4
60.2 0.9
42.5 0.8
0.0 0.0
0.0 0.0
100 0.0
7.8 0.6
0.0 0.0
56.4 2.7
88.1 0.9
0.0 0.0
100 0.0
10.5 0.8
27.4 0.5
100 0.0
100 0.0
64.6 2.0
77.7 2.3
80.0 0.9
78.8 0.6
64.2 1.7
24.33 1.3
13.3 0.4
100 0.0
6.5 0.4
63.5 1.6
0.0 0.0
4g
4h
4i
67.6 0.5
100 0.0
100 0.0
32.3 1.2
100 0.0
100 0.0
69 0.7
47.1 2.0
89.1 1.0
99.3 0.5
20.6 1.8
61.6 1.0
89.1 1.2
50.1 1.3
64.5 1.3
19.4 1.4
4.3 0.4
4j
4k
4l
4m
4n
4o
99.7 0.4
31.7 1.3
17.4 0.3
100 0.0
4p
4q
azadirachtin
100 0.0
100 0.0
a
b
Mortality at a dosage of 0.5 μg/insect. Mortality at a dosage of 0.2 μg/insect.
treatments the feeding was absolutely prevented. It appears,
from the results, that derivative 4j is a strong feeding deterrent
and strongly toxic, where as 4i is a strong feeding deterrent but
strongly toxic against S. litura and moderately toxic against A.
janata. On the other hand, compound 4f is a strong feeding
deterrent but least toxic against both S. litura and A. janata. The
treatments could cause desirable impact on larval feeding and
survival and could totally achieve the management of these two
major crop pests under laboratory conditions. Therefore, these
compounds can be used as both antifeedants and pesticides.
It is clear from their structures that the compounds were
differently substituted on the phenyl ring, leaving naphthyl and
benzothiazole rings unsubstituted. Even though it may not be
appropriate to draw a precise structure−activity relationship
with the present data, we can observe from the results that the
4-bromophenyl (4e) and 4-phenoxyphenyl (4g) derivatives are
completely nontoxic at a dosage of 0.2 μg/insect, whereas the
3,4,5-trimethoxyphenyl (4j) derivative is strongly toxic, leaving
the others in between. Fused and bulky substituted phenyl
derivatives 4b, 4e, 4g, 4h, 4k, and 4q are inactive or least active
along with unsubstituted phenyl derivative 4a, whereas 3,4,5-
trimethoxy-substituted (4j) phenyl has strong antifeedancy and
toxicity. However, in the case of the 4-methoxy (4i) phenyl
derivative toxicity increases for S. litura and decreases for A.
janata. The derivatives substituted with chloro, cyano,
dimethylamino, dichloro, and fluoro substituents have com-
paratively low antifeedancy and are least toxic. From the above
results we may conclude that the 3,4,5-trimethoxy derivative is
strongly antifeedant and toxic, but 4-methoxy derivatives are
strong antifeedants with selective toxicity against S. litura.
Overall, we identified a novel class of synthetic molecules
that do not belong to organochlorides, organophosphates,
carbamates, neonicotinoids, and anthranilamides as potent
antifeedants and insecticides. These results may enlighten a way
to search for natural product inspired synthetic antifeedants and
insecticides. Compounds 4i and 4j may be useful in protecting
crops from the above insects. Derivatives 4d and 4m are worth
considering as feeding deterrents along with moderate
insecticidal properties, and derivative 4f can be considered as
a strong feeding deterrent with least toxicity. Their potential
field applicability is yet to be explored.
ASSOCIATED CONTENT
* Supporting Information
■
S
Additional experimental details. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*(Ravirala Narender) E-mail: ravindra@iict.res.in,
raviralanarender@gmail.com. Phone: +91-40-27191538. Fax:
+91-40-27193382.
Funding
P.K.K. is thankful to CSIR and R.P. is thankful to ICMR for the
award of senior research fellowships.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The support of A. V. Subrahmanya Sarma and T. Prabhakar
Rao, Centre for NMR and Structural Chemistry, CSIR-IICT, is
greatly acknowledged. Without their support, obtaining a good-
quality 13C NMR spectrum might have been difficult. We are
also thankful to V. J. Rao, Head, CPC Division, CSIR-IICT, for
his constant support and encouragement throughout the work.
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