Rapid synthesis and biological evaluation of 1,4-dihydropyridine derivatives containing a benzothiazolyl moiety

Article abstract of DOI:10.2478/s11532-009-0114-z

A series of N-(6-methylbenzothiazolyl)-2,3,5,6-tetrasubstituted-4-(aryl)-1,4-dihydropyridines were synthesized by reaction of 2-amino-6-methylbenzothiazole, aromatic aldehyde and active methylene compound in methanol by conventional, as well as, microwave irradiation (solvent free and solid support) methods. The microwave irradiation technique gives better yield and shorter reaction time. Among solid supported microwave irradiation better yields are obtained in acidic alumina as compared to silica, neutral alumina, and basic alumina. All compounds were tested for antibacterial and antifungal activities and results have been compared with standard drugs. Entomological activities were also tested. The results showed that a change in the substitution pattern in 1,4-dihydropyridine derivatives may cause a marked effect on their antimicrobial activity. Versita Warsaw and Springer-Verlag Berlin Heidelberg.

Full text of DOI:10.2478/s11532-009-0114-z

Cent. Eur. J. Chem. • 8(1) • 2010 • 163–173
DOI: 10.2478/s11532-009-0114-z
Central European Journal of Chemistry
Rapid synthesis and biological evaluation
of 1,4-dihydropyridine derivatives
containing a benzothiazolyl moiety
Research Article
Mithlesh1, Pawan K. Pareek1, Ravi Kant2, Sanjeev K. Shukla3, Krishan G. Ojha1*
1 Department of Pure and Applied Chemistry, M.D.S. University, Ajmer, 305009 India
2 Hygia Institute of Pharmaceutical Education and Research, Lucknow, 226020 India
3 SAIF Division, Central Drug Research Institute, Lucknow, 226020 India
Received 12 March 2009; Accepted 11 August 2009
Abstract: A series of N-(6-methylbenzothiazolyl)-2,3,5,6-tetrasubstituted-4-(aryl)-1,4-dihydropyridines were synthesized by reaction of 2-amino-
6-methylbenzothiazole, aromatic aldehyde and active methylene compound in methanol by conventional, as well as, microwave
irradiation (solvent free and solid support) methods. The microwave irradiation technique gives better yield and shorter reaction time.
Among solid supported microwave irradiation better yields are obtained in acidic alumina as compared to silica, neutral alumina, and
basic alumina. All compounds were tested for antibacterial and antifungal activities and results have been compared with standard
drugs. Entomological activities were also tested. The results showed that a change in the substitution pattern in 1,4-dihydropyridine
derivatives may cause a marked effect on their antimicrobial activity.
Keywords: Benzothiazole• 1,4-Dihydropyridine• Antimicrobial activity• Microwave irradiation• Entomological activity
© Versita Warsaw and Springer-Verlag Berlin Heidelberg.
[13], acaricidal, insecticidal, bactericidal, herbicidal [14]
and other pharmacological activities [15]. These are
1. Introduction
used extensively in the treatment of angina pectoris,
hypertensionandarrhythmia[16]andsomecardiovascular
disorder. Several new derivatives of 1,4-DHP have been
produced and pharmacologically evaluated in order to
find drugs with better pharmacological properties [17].
So the pharmacology of 1,4-DHPs derivatives is at the
eve of a novel boom.
Similarly, the benzothiazole ring is present in various
marine and terrestrial natural compounds, which have
useful biological activities [18-21]. As a consequence,
benzothiazloes are bicyclic ring systems with multiple
Dihydropyridine chemistry is of interest from the point
of view of pure research on heterocyclic compounds
and from a biological point of view [1]. Hantzsch
1,4-dihydropyridines (1,4-DHPs), a class of model
compounds of the NADH coenzyme, have been
extensively studied in view of the biological pertinence
of these compounds to the NADH redox process
[2]. Since the early 1980’s the presence of a DHP
ring in the structure of 1,4-DHP derivatives has been
regarded as a prerequisite for calcium (Ca+2) channel
modulating properties [3]. So 1,4-DHPs classes of
compounds are excellent starting synthons for the
development of antitubercular agents [4-6]. As a result,
newly synthesized generations of 1,4-DHPs possess
different pharmacological activities such as anticancer
[7], antidiabetic [8], antianginal [9], bronchodilating [10],
neurotropic [11], antiallergic [12], anti-inflammatory
applications. Benzothiazoles comprise
a class of
therapeutic compounds that exert a wide and broad
spectrum of biological activities such as antimicrobial
[22,23], anticancer [24,25], antifungal [26], antihelmintic
[27], antileishmanial [28] and anticonvulsant [29]
activities. 2-(4-aminophenyl) benzothiazole [30,31]
* E-mail: kgojha@rediffmail.com
163

Rapid synthesis and biological evaluation
of 1,4-dihydropyridine derivatives
containing a benzothiazolyl moiety
comprises a novel mechanistic class of antitumor
agents. Conventional method of synthesis apparently
suffer from disadvantages such as prolonged refluxing,
use of volatile organic solvents, waste effluent and low
to moderate yields, cumbersome workup procedure,
create pollution to the environment and lack selectivity
in the presence of other functional groups.
2.2. General procedure for the synthesis of
N-(6-methylbenzothiazolyl)-2,3,5,6-
tetrasubstituted-4-(aryl)-1,4-dihydropyridines
2.2.1. Conventional Method
A reaction mixture of 2-amino-6-methylbenzothiazole
(0.1 mol), aromatic aldehyde (0.1 mol) and active
methylene compound (0.2 mol) was heated (without
solvent) on a steam bath for 2-3 hours. After elimination
of water, methanol (25 mL) was added directly to the
reaction mixture and refluxed for 10-15 hours. Then, the
reaction mixture was poured into the ice water, the solid
mass separated, and was extracted with diethyl ether
(50 mL) and dried over magnesium sulphate, and finally
recrystallised from methanol (Scheme 1, Table 1)
In light of growing eco-consciousness of energy,
and economic and environmental issues over the recent
decade have compelled the synthetic chemist to add a new
twist to an old theme [32]. So microwave–induced organic
reaction enhancement (MORE) chemistry can be termed
‘eco-chemistry’ because it is easy, effective, economic, eco-
friendlyandisbelievedtobeasteptowardsgreenchemistry.
We report a novel environmentally benign approach using a
facile,microwavesynthesisoftitlecompoundscarriedoutby
a solvent free method, and various solid supports like silica
gel, alumina basic, alumina neutral, and alumina acidic. In
view of the biological importance associated with 1,4-DHPs
and benzothiazole and the benefits offered by microwave
heating, it was thought worthwhile to synthetise of N-(6-
methylbenzothiazolyl)-2,3,5,6-tetrasubstituted-4-(Aryl)-1,4-
dihydropyridines followed by antimicrobial susceptibility
testing (AST) against Lactobacillus spp., Pseudomonas
aeruginosa, Staphylococcus aureus, Micrococcus leutius,
Kocuria rosea, Aspergillus niger, Aspergillus candidus
using standard methods and comparison with standard
drugs. All the synthesized derivatives were also screened
for their entomological activities.
2. Experimental procedures
2.1. General Procedures
Scheme 1. Synthesis of N-(6-methylbenzothiazolyl)-2,3,5,6-
tetrasubstituted–4-(aryl)-1,4-dihydropyridines
(R1 = CH3, OC2H5; R2 = C2H5OCO, CH3CO; R3 = H,
N(CH3)2, OCH3, OH, m-NO2)
Reagent grade chemicals were used without further
purification. The substrates and solvents were used
as received. All the melting points are taken in open
capillaries as uncorrected. The purity of the synthesized
compoundswascheckedbyThinLayerChromatographic
studies. IR spectra were scanned on FT IR Perkin Elmer
(Spectrum RX1) spectrophotometer (υ in cm-1) using a
2.2.2. Microwave method
A reaction mixture of 2-amino-6-methylbenzothiazole
(0.01 mol), aromatic aldehyde (0.01 mol) and active
methylene compound (0.02 mol) were combined in a
round bottom flask. The round bottom flask was placed
in a microwave oven, irradiated under a low power
160 Watt, and monitored by TLC using Benzene: DMF
(7:3). To ensure the reproducibility, every reaction is
carried out five times in the microwave. The reaction
mixture was cooled at room temperature and extracted
with diethyl ether (10 mL), dried over magnesium
sulphate, yielded pure product, and was recrystallised
from methanol (Table 1).
1
KBr disc. H NMR sprectra wereere recorded in CDCl3
with tetramethylsilane (TMS) as the internal standard at
300 MHz on a Bruker DRTX-300 spectrophotometer. The
chemical shifts are reported as parts per million (ppm).
Fast atom bombardment mass spectra (FABMS) were
recorded at room temperature on a Jeol SX-102/DA-
6000 mass spectrophotometer/data system usingArgon/
Xenon (6 kV, 10mA) as the FAB gas. The accelerating
potential was 10kV. Microwave synthesis was carried
out in a “Q-pro-M Modified Microwave system”. The
elemental analysis of the compounds was performed on
a Carlo Erba-1108 elemental analyzer.
164

Mithlesh et al.
δ 2.31 (s, 3H, Benzothiazole, CH3), 2.24 (s, 6H,
dihydropyridine (DHP), CH3), 4.90 (s, 1H, DHP),
6.46-8.11 (m, 7H, Ar-H), 1.29 (t, J=7.2 Hz, 6H, DHP,
CH2CH3), 4.17 (q, J=7.2 Hz, 4H, DHP, CH2), 2.82 (s, 6H,
N(CH3)2), 13C-NMR (300MHz, CDCl3) δ 126.3, 135.5,
125.8, 155.8, 133.3, 124.6, 171.7, 22.9, 99.0, 134.9,
127.5, 109.3, 35.9, 18.5, 25.4, 17.3, 59.8, 13.6, 161.0,
61.8, 59.2, 129.3, 115.4, 146.4, 113.1, 129.6, 119.5,
16.5 IR (cm-1): νmax 1063, 1108, 1150, 1586, 1532,
1452, 2996, 1664, 1628,1698; Accurate MS m/z: Calc:
519.66, Found: 519.57, Elemental Anal. Calcd. (CHNS)
for C29H33N3O4S: C, 67.02, H, 6.41, N, 8.09, S, 6.16,
Found: C, 66.98, H, 6.36, N, 8.05, S, 6.12.
2.2.2.1. Solid supported microwave synthesis
A mixture of 2-amino-6-methylbenzothiazole (0.01 mol),
aromatic aldehyde (0.01 mol) and active methylene
compound (0.02 mol) were placed in a round bottom
flask with solid support alumina (acidic /basic /neutral
(1.3 g)) and silica gel. Everything was mixed thoroughly
in a mortar then the reaction mixture was transferred to
a round bottom flask and irradiated under a low power
160 Watt in microwave oven at 30 seconds intervals
of specified times. Upon completion of reaction as
monitored by TLC using Benzene: DMF (7:3). To
ensure the reproducibility every reaction is carried out
five times in the microwave. The reaction mixture was
cooled at room temperature and extracted with diethyl ether
(10 mL), dried over magnesium sulphate, which gave
pure product. The products were then recrystallised
from methanol (Table 2).
N-(6-methylbenzothiazolyl)-3,5-dicarbethoxy-
2,6-diethoxy-4-(p-dimethylaminophenyl)-1,4-
1
dihydropyridine (4b): H-NMR (300 MHz, CDCl3)
δ 2.51 (s, 3H, Benzothiazole, CH3 ), 4.92 (s, 1H,
DHP), 6.45-8.12 (m, 7H, Ar-H), 1.27 (t, J=7.2 Hz,
6H, DHPCOOCH2CH3), 4.15 (q, J=7.1 Hz, 4H,
DHPCOOCH2), 2.80 (s, 6H, N(CH3)2), 1.21 (t, J=7.2 Hz,
2.2.2.2. Spectral and microanalysis data of (4a-4o)
N-(6-methylbenzothiazolyl)-3,5-dicarbethoxy-
2,6-dimethyl-4-(p-dimethylaminophenyl)-1,4- 6H, DHP OCH2CH3), 4.01 (q, J=7.2 Hz, 4H, DHPOCH2)
1
dihydropyridine (4a): H-NMR (300 MHz, CDCl3) 13C-NMR (300MHz, CDCl3) δ 126.5, 134.5, 122.8,
Table 1. Preparation of N-(6-methylbenzothiazolyl)-2,3,5,6-tetrasubstituted-4-(aryl)-1,4- dihydropyridines.
Conventional
heating
Microwave
(Neat reaction)
M.P.
0C
Compounds
R1
R2
R3
Time
(h)
Yield
(%)
Time
Yield
(%)
(Sec)
4a
4b
4c
4d
4e
4f
Me
OEt
Me
Me
Oet
Oet
Me
O=COEt
O=COEt
O=COEt
O=COEt
O=COEt
O=COEt
COMe
p-N(Me)2
p-N(Me)2
p-OMe
p-OH
176-177
165-167
178-179
206-208
196-198
209-210
193-194
20.0
20.0
20.0
20.0
20.0
20.0
20.0
50
52
56
48
46
44
45
180
190
210
220
190
190
200
60
69
70
70
65
68
68
p-OH
H
4g
p-OMe
4h
4i
Me
Me
O=COEt
COMe
H
207-208
230-231
20.0
20.0
50
56
200
210
68
70
p-OH
4j
4k
4l
Me
Me
Oet
Me
Oet
Me
COMe
COMe
H
224-225
172-173
182-183
174-175
201-202
220-221
20.0
20.0
20.0
20.0
20.0
20.0
58
60
55
52
50
52
200
190
210
210
180
200
72
72
69
68
64
68
p-N(Me)2
p-OMe
m-NO2
m-NO2
m-NO2
O=COEt
O=COEt
O=COEt
COMe
4m
4n
4o
165
165

Rapid synthesis and biological evaluation
of 1,4-dihydropyridine derivatives
containing a benzothiazolyl moiety
Table 2. Comparitative study of synthesized compounds (4a- 4o) under solid supported microwave irradiation.
Solid supported microwave irradiation
Silica
Gel
Alumina
basic
Alumina
neutral
Alumina
acidic
Compounds
Time
Yield
(%)
Time
Yield
(%)
Time
Yield
(%)
Time
Yield
(%)
(Sec)
(Sec)
(Sec)
(Sec)
4a
4b
4c
4d
4e
4f
210
220
230
260
220
220
230
230
240
230
220
240
220
190
200
55
58
60
55
55
60
60
60
65
62
65
62
61
60
64
260
270
290
300
280
280
290
290
300
280
270
260
290
220
230
52
55
50
55
45
46
45
50
58
60
60
55
54
54
50
140
150
120
120
140
150
140
140
140
120
140
150
90
70
80
80
82
75
80
80
80
82
83
83
85
80
80
76
90
100
80
80
80
100
90
90
90
80
90
90
60
60
70
90
95
85
87
90
92
95
93
95
94
94
98
90
92
88
4g
4h
4i
4j
4k
4l
4m
4n
4o
90
100
1590, 1655, 1680, 1628; Accurate MS m/z: Calc:
522.62, Found: 522.16, Elemental Anal. Calcd. (CHNS)
for C28H30N2O5S: C, 66.38, H, 5.97, N, 5.53, S, 6.33,
Found: C, 66.28, H, 5.90, N, 5.46, S, 6.30.
153.8, 131.3, 122.6, 169.7, 21.9, 99.0, 132.9, 126.5,
108.3, 27.9, 17.9, 24.4, 10.3, 16.6, 58.8, 12.6, 16.0,
161.8, 128.3, 116.4, 145.4, 111.1, 127.6, 117.5, 14.1,
15.5, 57.4, 14.2 IR (cm-1): νmax 1062, 1105, 1151, 1583,
1530, 1450, 2995, 1652, 1622, 1704; Accurate MS m/z:
Calc: 579.71, Found: 579.23., Elemental Anal. Calcd.
(CHNS) for C31H37N3O6S: C, 64.22, H, 6.44, N, 7.25, S,
5.53, Found: C, 64.18, H, 6.37, N, 7.21, S, 5.47.
N-(6-methylbenzothiazolyl)-3,5-dicarbethoxy-2,6-
dimethyl-4-(p-hydroxyphenyl)-1,4-dihydropyridine
1
(4d): H-NMR (300 MHz, CDCl3) δ 2.33 (s, 3H,
Benzothiazole, CH3 ), 2.14 (s, 6H,DHP, CH3), 4.92 (s,
1H, DHP), 6.48-8.14 (m, 7H, Ar-H), 1.30 (t, J=7.0 Hz,
6H, DHP, CH3), 4.21 (q, J=6.9 Hz, 4H, DHP, CH2), 5.02
(s, 1H, Ar-OH), 13C-NMR (300MHz, CDCl3) δ 126.1,
134.2, 125.7, 155.6, 132.3, 124.6, 171.7, 99.0, 134.9,
127.5, 109.3, 35.9, 18.5, 25.4, 11.3, 17.3, 59.8, 13.6,
161.0, 129.3, 115.4, 146.4, 113.1, 129.6, 128.4, 125.5,
20.7 IR (cm-1): νmax 1056, 1227, 1136, 1694, 1536, 1451,
2973, 3650, 1662, 1627, 1694; Accurate MS m/z: Calc:
508.59, Found: 508.16, Elemental Anal. Calcd. (CHNS)
for C27H28N2O5S: C, 65.83, H, 5.73, N, 5.69, S, 6.51,
Found: C, 65.79, H, 5.67, N, 5.62, S, 6.48.
N-(6-methylbenzothiazolyl)-3,5-dicarbethoxy-
2 , 6 - d i m e t h y l - 4 - ( p - m e t h o x y p h e n y l ) - 1 , 4 -
1
dihydropyridine (4c): H-NMR (300 MHz, CDCl3)
δ 2.31 (s, 3H, Benzothiazole, CH3 ), 2.27 (s, 6H,DHP,
CH3), 4.90 (s, 1H, DHP), 6.45-8.12 (m, 7H, Ar-H), 1.27
(t, J=7.2 Hz, 6H, DHP, CH3), 4.19 (q, J=7.2 Hz, 4H, DHP,
CH2), 3.72 (s, 3H, Ar-OCH3), 13C-NMR (300MHz, CDCl3)
δ 126.3, 134.3, 151.8, 130.3, 122.6, 167.7, 20.9, 99.0,
134.9, 127.5, 109.3, 32.9, 18.5, 25.4, 11.3, 17.3, 59.8,
13.6, 161.0, 61.8, 129.3, 115.4, 146.4, 113.1, 129.6,
119.5, 15.1, 46.6 IR (cm-1): νmax 1054, 1225, 1535, 1450,
166

Mithlesh et al.
N-(6-methylbenzothiazolyl)-3,5-dicarbethoxy- 4.12 (q, 4H, DHP, CH2), 13C-NMR (300MHz, CDCl3) δ
2 , 6 - d i e t h o x y - 4 - ( p - h y d r o x y p h e n y l ) - 1 , 4 126.3, 135.5, 155.8, 133.3, 124.6, 171.7, 22.9, 99.0,
1
dihydropyridine (4e): H-NMR (300 MHz, CDCl3) δ 134.9, 127.5, 109.3, 35.9, 18.5, 25.4, 11.3, 17.3, 59.8,
2.30 (s, 3H, Benzothiazole, CH3 ), 4.90 (s, 1H, DHP), 13.6, 161.0, 61.8, 129.3, 115.4, 146.4, 129.6, 128.4,
6.45-8.12 (m, 7H, Ar-H), 1.27 (t, J=7.2 Hz, 6H, DHP, 125.5, 20.9 IR (cm-1): νmax 1058, 1209, 1378, 1595,
COOCH2CH3), 4.17 (q, J=7.2 Hz, 4H, DHP, COOCH2), 1545, 1450, 2973, 1628, 1678; Accurate MS m/z:
5.05 (s, 1H, Ar-OH), 1.21 (t, 6H, DHP, OCH2CH3), 4.00 Calc: 492.17, Found: 492.59, Elemental Anal. Calcd.
(q, 4H, DHP, OCH2) 13C-NMR (300MHz, CDCl3) δ (CHNS) for C27H28N2O4S: C, 68.04, H, 5.93, N, 5.88, S,
126.3, 135.5, 122.8, 151.8, 130.3, 122.7, 168.7, 20.9, 6.71, Found: C, 68.01, H, 5.87, N, 5.82, S, 6.65.
16.6, 99.0, 134.9, 127.5, 109.3, 25.4, 11.3, 17.6, 59.8,
N-(6-methylbenzothiazolyl)-3,5-diacetyl-2,6-
13.6, 161.0, 61.8, 129.3, 115.4, 146.4, 113.1, 129.6, dimethyl-4-(p-hydroxyphenyl)-1,4-dihydropyridine
1
119.5, 16.5, 58.4, 20.9 IR (cm-1): νmax 1055, 1228, (4i):
H-NMR (300 MHz, CDCl3) δ 2.30 (s, 3H,
1137, 1594, 1538, 1452,1593, 2975, 3575, 1650, 1624, Benzothiazole, CH3 ), 2.20 (s, 6H, DHP, CH3), 4.93 (s,
1689; Accurate MS m/z: Calc: 568.64, Found: 568.18, 1H, DHP), 6.44-8.12 (m, 7H, Ar-H), 2.30 (s, 6H, DHP,
Elemental Anal. Calcd. (CHNS) for C29H32N2O7S: C, COCH3), 5.01 (s, 1H, Ar-OH), 13C-NMR (300MHz,
63.02, H, 5.84, N, 5.07, S, 5.79, Found: C, 62.98, H, CDCl3) δ 126.5, 134.3, 122.8, 151.8, 130.3, 168.7,
5.83, N, 5.02, S, 5.71.
N-(6-methylbenzothiazolyl)-3,5-dicarbethoxy- 11.3, 27.0, 199.5, 27.6, 129.3, 115.1, 146.7, 118.5,
2,6-diethoxy-4-(phenyl)-1,4-dihydropyridine
(4f): 15.9 56.0 IR (cm-1): νmax 1054, 1207, 1137, 1535, 1590,
20.9, 16.6, 99.0, 127.5, 109.3, 32.9, 18.9, 125.4, 17.6,
1
H-NMR (300 MHz, CDCl3) δ 2.34 (s, 3H, Benzothiazole, 1450, 2975, 3573, 1660, 1628, 1691; Accurate MS m/z:
CH3 ), 4.93 (s, 1H, DHP), 6.42-8.12 (m, 8H, Ar-H), 1.26 Calc: 448.14, Found: 448.54, Elemental Anal. Calcd.
(t, J=7.1 Hz, 6H, DHP, COOCH2CH3), 4.15 (q, J=7.1 (CHNS) for C25H24N2O3S: C, 69.42, H, 5.59, N, 6.48, S,
Hz, 4H, DHP, COOCH2), 1.21 (t, J=7.2 Hz, 6H, DHP, 7.41, Found: C, 69.37, H, 5.52, N, 6.42, S, 7.38.
OCH2CH3), 4.03 (q, J=7.2 Hz, 4H, DHP, OCH2).13C-NMR
N-(6-methylbenzothiazolyl)-3,5-diacetyl-
(300MHz, CDCl3) δ 126.3, 135.1, 124.8, 155.4, 131.3, 2,6-dimethyl-4-(phenyl)-1,4-dihydropyridine
1
171.7, 22.8, 99.0, 134.7, 127.4, 109.2, 28.9, 18.9, (4j): H-NMR (300 MHz, CDCl3) δ 4.22 (s, 3H,
25.4, 11.3, 17.6, 59.8, 13.6, 161.0, 61.8, 129.3, 115.4, Benzothiazole, CH3), 2.14 (s, 6H, DHP, CH3), 4.95 (s,
146.4, 113.1, 129.6, 119.5, 15.1, 16.5, 14.8 IR (cm-1): 1H, DHP), 6.47-8.12 (m, 8H, Ar-H), 2.29 (s, 6H, DHP,
νmax 1058, 1210, 1380, 1597, 1546, 1458, 2975, 1628, COCH3),). 13C-NMR (300MHz, CDCl3) δ 126.5, 134.2,
1684;Accurate MS m/z: Calc: 522.64, Found: 522.19, 121.8, 151.7, 130.2, 168.6, 20.8, 16.5, 99.0, 1334.8,
Elemental Anal. Calcd. (CHNS) for C29H32N2O6S: C, 127.6, 110.3, 32.8, 124.4, 17.6, 11.3, 122.4, 27.6,
64.90, H, 6.01, N, 5.22, S, 5.96, Found: C, 64.87, H, 128.3, 115.2, 146.7, 129.3, 118.5, 16.0, 46.4 IR (cm-
6.00 N, 5.19, S, 5.91.
1): νmax 1056, 1209, 1375, 1594, 1543, 1455, 2974,
N-(6-methylbenzothiazolyl)-3,5-diacetyl-2,6- 1628, 1694, 1667; Accurate MS m/z: Calc: 432.15,
dimethyl-4-(p-methoxyphenyl)-1,4-dihydropyridine Found: 432.54, Elemental Anal. Calcd. (CHNS) for
1
(4g):
H-NMR (300 MHz, CDCl3) δ 2.50 (s, 3H, C25H24N2O2S: C, 72.09, H, 5.81, N, 6.73, S, 7.68,
Benzothiazole, CH3 ), 2.17 (s, 6H, DHP, CH3), 4.95 (s, Found: C, 72.02, H, 5.78, N, 6.70, S, 7.62.
1H, DHP), 6.47-8.12 (m, 7H, Ar-H), 2.29 (s, 6H, DHP,
N-(6-methylbenzothiazolyl)-3,5-diacetyl-
COCH3), 3.72 (s, 3H, Ar-OCH3), 13C-NMR (300MHz, 2,6-dimethyl-4-(p-dimethylaminophenyl)-1,4-
1
CDCl3) δ 126.5, 134.3, 122.8, 151.8, 130.3, 168.7, 20.9, dihydropyridine (4k): H-NMR (300 MHz, CDCl3) δ
16.6, 99.0, 127.5, 109.3, 32.9, 18.9, 125.4, 17.6, 11.3, 2.31 (s, 3H, Benzothiazole, CH3 ), 2.27 (s, 6H, DHP,
27.0, 199.5, 27.6, 129.3, 115.1, 146.7, 115.1, 118.5, CH3), 4.92 (s, 1H, DHP), 6.47-8.12 (m, 7H, Ar-H), 2.31
15.9, 46.6 IR (cm-1): νmax 1053, 1226, 1535, 1450, 1596, (s, 6H, DHP, COCH3), 2.84 (s, 6H, N(CH3)2), 13C-NMR
1622, 1682; Accurate MS m/z: Calc: 462.56, Found: (300MHz, CDCl3) δ 126.5, 134.3, 122.7, 151.89, 130.3,
462.16, ElementalAnal. Calcd. (CHNS) for C26H26N2O3S: 122.6, 168.7, 20.9, 16.6, 99.0, 134.9, 127.5, 109.3,
C, 69.93, H, 5.87, N, 6.27 S, 7.17, Found: C, 69.88, H, 32.9, 18.9, 125.4, 17.6, 11.3, 199.5, 27.6, 129.3, 115.1,
5.85, N, 6.21, S, 7.14.
N-(6-methylbenzothiazolyl)-3,5-dicarbethoxy- 1103, 1150, 1582,1528, 1451, 2994, 1622, 1656,
2,6-dimethyl-4-(phenyl)-1,4-dihydropyridine (4h): 1687; Accurate MS m/z: Calc: 475.19, Found: 475.61,
146.7, 129.2, 119.5, 15.8, 16.2 IR (cm-1): νmax 1063,
1
H-NMR (300 MHz, CDCl3) δ 2.50 (s, 3H, Benzothiazole, Elemental Anal. Calcd. (CHNS) for C27H29N3O2S: C,
CH3 ), 2.30 (s, 6H, DHP, CH3), 4.93 (s, 1H, DHP), 6.46- 70.56, H, 6.36, N, 9.15, S, 6.96, Found: C, 70.52, H,
8.10 (m, 8H, Ar-H), 1.25 (t, J=7.2 Hz, 6H, DHP, CH3), 6.32, N, 9.10, S, 6.92.
167
167

Rapid synthesis and biological evaluation
of 1,4-dihydropyridine derivatives
containing a benzothiazolyl moiety
N-(6-methylbenzothiazolyl)-3,5-dicarbethoxy- 8.12 (m, 3H, Ar-H), 7.80-8.01 (m, 4H, Ar-H), 2.30 (s,
2 , 6 - d i e t h o x y - 4 - ( p - m e t h o x y p h e n y l ) - 1 , 4 - 6H, DHP, COCH3), 13C-NMR (300MHz, CDCl3) δ 126.5,
1
dihydropyridine (4l):
H-NMR (300 MHz, CDCl3) δ 134.3, 122.8, 151.8, 130.3, 122.6, 168.7, 20.9, 16.6,
2.32 (s, 3H, Benzothiazole, CH3 ), 4.98 (s, 1H, DHP), 99.0, 134.9, 127.5, 109.3, 32.9, 18.9, 25.4, 17.6, 11.3,
6.47-8.12 (m, 7H, Ar-H), 1.29 (t, J=7.2 Hz, 6H, DHP, 27.0, 129.2, 131.7, 128.4, 128.2, 126.4, 20.9, IR (cm-1):
COOCH2CH3), 4.17 (q, 4H, DHP, COOCH2), 3.72 (s, νmax 1054, 1207, 1137, 1535, 1590, 1450, 2975, 1505,
3H, Ar-OCH3), 1.21 (t, 6H, DHP, OCH2CH3), 4.02 (q, 4H, 1390, 3573, 1660, 1628, 1691; Accurate MS m/z: Calc:
DHP, OCH2). 13C-NMR (300MHz, CDCl3) δ 126.3, 135.4, 461.14, Found: 461.54, Elemental Anal. Calcd. (CHNS)
124.8, 155.9, 133.3, 124.5, 171.7, 22.9, 99.0, 134.9, for C25H23N3O4S: C, 65.06, H, 5.03, N, 9.11, S, 6.93,
127.5, 109.3, 29.9, 18.9, 25.4, 11.3, 17.6, 59.8, 13.6, Found: C, 65.02, H, 5.502, N, 9.09, S, 6.87.
161.0, 61.8, 129.3, 115.4, 146.7, 113.2, 119.6, 15.2, 16.7,
58.4, 46.7 IR (cm-1): νmax 1053, 1224, 1136, 1534, 1590,
2.3. Antimicrobial Assay
1450, 2973, 1701, 1622, 1653, 1701; Accurate MS m/z:
Calc: 582.20, Found: 582.67, Elemental Anal. Calcd.
(CHNS) for C30H34N2O7S: C, 63.58, H, 6.05, N, 4.95, S,
5.65, Found: C, 63.52, H, 6.01, N, 4.91, S, 5.62.
All the synthesized compounds were tested for
their antibacterial activity against various bacteria,
Lactobacillus
sp.,
Pseudomonas
aeruginosa,
Staphylococcus aureus, Micrococcus leutius, Kocuria
rosea and antifungal activity against fungi Aspergillus
niger and Aspergillus candidus using paper disc
method. Muller Hinton Agar (Hi-Media Pvt. Ltd. Mumbai,
India) was used to culture the test bacteria and Potato
Dextrose Agar was used to culture fungi. The microbial
culture were grown at 370C for 8 hours and then
appropriately diluted with sterile 0.8% saline solution.
The concentration of test drugs was kept 200 µg mL-1
in DMF. Standard drugs Novobiocine, Gentamycin,
Kanamycin, Amikacin (for antibacterial) and Ampicilline
(for antifungal) were used for comparison. The
antimicrobial activity was evaluated by measuring the
zone of growth inhibition around disc of test organism
(Table 3).
N-(6-methylbenzothiazolyl)-3,5-dicarbethoxy-
2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine
1
(4m): H-NMR (300 MHz, CDCl3) δ 2.31 (s, 3H,
Benzothiazole, CH3 ), 2.12 (s, 6H,DHP, CH3), 4.90 (s,
1H, DHP), 6.48-8.14 (m, 3H, Ar-H), 7.70-8.01 (m, 4H,
Ar-H), 1.28 (t, J=7.0 Hz, 6H, DHP, CH3), 4.20 (q, J=6.9
Hz, 4H, DHP, CH2) ).13C-NMR (300MHz, CDCl3) δ 126.5,
134.3, 122.8, 151.8, 130.3, 168.7, 70.2, 154.3, 127.5,
109.3, 29.5, 18.9, 17.6, 11.3, 58.3, 14.8, 171.0, 59.2,
13.6, 161.0, 61.7, 137.7, 129.2, 128.4, 20.9, 16.2, 15.9,
IR (cm-1): νmax 1056, 1227, 1136, 1694, 1536, 1451, 2973,
1514, 1390, 3650, 1662, 1627, 1694; Accurate MS m/z:
Calc: 507.15, Found: 507.58, Elemental Anal. Calcd.
(CHNS) for C27H27N3O6S: C, 62.17, H, 5.22, N, 8.06, S,
6.15, Found: C, 62.15, H, 5.20, N, 8.02, S, 6.12.
N-(6-methylbenzothiazolyl)-3,5-dicarbethoxy-
2,6-diethoxy-4-(m-nitrophenyl)-1,4 dihydropyridine
(4n): H-NMR (300 MHz, CDCl3) δ 2.29 (s, 3H,
2.4. Antifeedant activity
The antifeedant activity of these compounds was also
carriedoutbyleafdipmethod[41,42], usingfourthinstars
larvae of Spodoptera litura. The leaf discs of about 25
cm2 were prepared and dipped for thirty seconds in
various concentrations of the test compounds. Now air-
dried the leaf discs to evaporate the excess acetone
and the leaf discs offered for feeding. The insects were
allowed to feed for 24 h. After 24 h leaf area uneaten
was measured by using leaf area meter. The difference
between leaf area provided and the leaf area uneaten
is taken as amount of leaf area consumed. The feeding
inhibition was calculated and used for calculation of
effective concentration (EC50/LD50) using Maximum
likelihood programmer (MLP) 3.01. The results of
antifeedant activity are summarized in Table 4.
1
Benzothiazole, CH3 ), 4.90 (s, 1H, DHP), 6.45-8.12
(m, 3H, Ar-H), 7.90-8.10 (m, 4H, Ar-H), 1.26 (t, J=7.2
Hz, 6H, DHP, COOCH2CH3), 4.16 (q, J=7.2 Hz, 4H,
DHP, COOCH2), 1.21 (t, 6H, DHP, OCH2CH3), 4.00 (q,
4H, DHP, OCH2) 13C-NMR (300MHz, CDCl3) δ 126.3,
134.2, 123.8, 153.8, 132.3, 124.6, 167.7, 70.1, 153.3,
127.4, 109.4, 30.5, 18.9, 17.6, 11.3, 17.3, 58.3, 14.8,
171.0, 59.2, 13.6, 161.0, 61.7, 137.7, 129.2, 128.4,
20.9, 16.2, 15.9, IR (cm-1): νmax 1055, 1228, 1137, 1594,
1538, 1452,1593, 2975,1520, 1380, 3575, 1650, 1624,
1689; Accurate MS m/z: Calc: 582.19, Found: 582.65,
Elemental Anal. Calcd. (CHNS) for C29H31N3O8S: C,
59.77, H, 5.54, N, 7.22, S, 5.49, Found: C, 59.74, H,
5.47, N, 7.19, S, 5.47.
2.5. Acaricidal activity
The acaricidal activity of these compounds was carried
out by leaf dip method [41,42]. Leaf discs of Mulberry
(5 cm2 diameter) were dipped in different concentration
N-(6-methylbenzothiazolyl)-3,5-diacetyl-2,6-
dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine (4o):
H-NMR (300 MHz, CDCl3) δ 2.30 (s, 3H, Benzothiazole,
1
CH3 ), 2.20 (s, 6H, DHP, CH3), 4.93 (s, 1H, DHP), 6.44-
168

Mithlesh et al.
Table 3. Antimicrobial activities of compounds 4a-4o.
Antibacterial activitya
Antifungal activitya
Compounds
4a
B1
B2
B3
B4
B5
F1
F2
+
++
++
++
++
+
+
4b
++
++
++
+
++
++
+++
++
++
++
++
++
+
++
++
+
+
++
++
++
+
4c
4d
++
++
++
++
4e
++
++
++
++
4f
+
++
++
++
++
+
4g
++
+
++
++
++
++
++
+
++
++
++
+
4h
+
++
++
++
4i
+
++
++
++
++
++
+
4j
+
+
++
++
++
4k
4l
++
+
++
++
++
+++
++
+
+
++
++
+++
+++++
++++
++++
+
++
++++
++
+++
+
++
++++
+++
+++
+
4m
++
++
+++
+
++++
+++
++++
+
++++
+++
++++
-
++++
+++
++++
+
4n
4o
Benzothiazole
Blank
-
-
-
-
-
-
-
Novobiocine
Gentamycin
Kanamycin
+
+++
++++
++
+++
++++
+++
+++++
+++++
++++
++++
++++
++++
-
-
+++
+
-
-
-
-
Amikacin
+++
++++
-
+++
-
+++++
-
++++
-
-
-
Ampicilline
+++++
+++++
-
a Data represent zones of inhibition (mm) as follows:
- no measurable activity; + 5-7 mm; ++ 7-14 mm; +++ 15-21 mm; ++++ 22-28 mm; +++++ >29 mm
B1 Lactobacillus spp.; B2 Pseudomonas aeruginosa; B3 Staphylococcus aureus; B4 Micrococcus leutius; B5 Kocuria rosea; F1
Aspergillus candidus; F2 = Aspergillus niger
for 30 seconds. Now air dried the leaf discs to remove acetone and tween 20 emulsifier served as control.
the excess of acetone and placed over wet cotton in The mortality data was used for calculation of LC50/
Petri plate. The adult female mites were released on LD50 using Maximum Likelihood Programmer (MLP)
treated leaf discs and mortality data were recorded 3.01.The results of acaricidal activity are summarized
after 48 hours. Mites released on leaf treated only with in Table 5.
169
169

Rapid synthesis and biological evaluation
of 1,4-dihydropyridine derivatives
containing a benzothiazolyl moiety
Table 4. Antifeedant activity of compounds 4a-4o.
Compounds
Fiducial
Limits
Chi. Sq.
LC50/LD50
at 24 h
1.35
Slop
+
4
(3)
4a
4b
4c
4d
4e
4f
0.78–3.42
0.64–1.74
0.41–0.83
0.60–1.42
0.84–2.33
0.68–2.42
0.31–0.47
0.33–0.64
0.42–1.05
0.46–0.77
0.28–0.50
0.24–0.55
0.47-0.78
0.34-0.56
0.25-0.57
0.80±0.12
1.01±0.11
1.02±0.13
1.05±0.13
1.06±0.14
0.96±0.14
1.26±0.13
1.00±0.10
0.83±0.13
1.50±0.15
1.01±0.12
0.95±0.12
1.50±0.14
1.02±0.12
0.96±0.16
0.41 (3)
0.65 (3)
0.34 (3)
1.03 (3)
0.77 (3)
0.21 (3)
3.39 (3)
0.67 (3)
1.68 (3)
2.56 (3)
5.34 (3)
0.25 (3)
2.58 (3)
5.37 (3)
0.27 (3)
0.97
0.37
0.85
1.23
1.13
4g
4h
4i
0.37
0.42
0.62
4j
0.57
4k
4l
0.56
0.36
4m
4n
4o
0.60
1.01
0.38
all the condensed products were in close agreement
with the calculated values, the infrared (IR) spectrum
of compounds 4 display two characteristic bands at
1622 and 1698 cm-1 due to C=C, and CO2 stretching,
respectively. The 1H nuclear magnetic resonance
(NMR) spectrum of compounds 4 and its derivatives
exhibit characteristic signals at δ 4.90-4.98 and δ 4.21
due to DHP proton and DHPCOOCH2, respectively.
Formation of compounds 4 was further confirmed on
the basis of 13C-NMR spectroscopy. Similarly the mass
spectra of the 1,4-dihydropyridine derivatives revealed
a molecular ion peak at m/z values corresponding to the
molecular weight of the target compound. Thus on the
basis of spectral data all the products 4a-4o have been
identified.
3. Results and discussions
Synthesis of title compounds by conventional methods
suffer from long reaction time, moderate yields, tedious
workup (Table 1), and requirement of large quantity
of solvent associated with conventional method
is another problem. A relatively more versatile yet
simplified procedure was created, in which 2-amino-6-
methylbenzothiazole, aromatic aldehydes and active
methylene compounds could react without using
any solvent (without, as well as, with solid support).
Microwave synthesis has received attention as new
strategy for organic synthesis due to the fact that many
reactions seem to proceed with much alacrity under
such conditions as opposed to the corresponding
thermal-assisted reaction [33]. The strategy worked well,
affording the desired product in improved yields and in
significantly lower reaction time (Tables 1 and 2). In
microwave promoted reactions, solid supports like silica
gel, alumina basic, alumina neutral and alumina acidic
has been used, and it is found that the acidic alumina is
the best solid support in the present investigation. The
structures of all the synthesized compounds 4a-4o were
established on the basis of spectroscopic and analytical
data. The elemental analysis (C, N and H) found for
3.1. Antibacterial Activity
The antibacterial activity of all the synthesized
compounds were tested in-vitro against pathogenic
microbial strains, Lactobacillus spp., Pseudomonas
aeruginosa, Staphylococcus aureus, Micrococcus lutius
and Kocuria rosea and the results were compared with
some standard drugs like novobiocine, gentamycin,
kanamycin and amkacin. In case of Lactobacillus
spp. Compounds 4a, 4m, 4n and 4o exhibit higher
170

Mithlesh et al.
Table 5. Acaricidal activity of compounds 4a-4o.
Slop
+
Compounds
Fiducial
Limits
Chi. Sq.
(3)
LC50/LD50
at 24 h
0.17
4
4a
4b
4c
4d
4e
4f
0.09–0.31
0.11–0.23
0.15–0.35
0.13–0.30
0.05–0.09
0.09–0.23
0.14–0.30
0.36–1.87
0.06–0.19
0.11–0.29
0.07–0.16
0.03–0.05
0.13-0.32
0.07-0.20
0.06-0.09
0.77±0.87
0.88±0.09
0.09±0.08
0.95±0.08
1.23±0.09
0.64±0.05
0.80±0.07
0.63±0.07
0.63±0.05
0.77±0.07
0.80±0.5
1.71 (3)
2.13 (3)
8.26 (3)
7.51 (3)
14.26 (3)
6.11(3)
0.14
0.24
0.10
0.07
0.12
4g
4h
4i
6.90 (3)
3.56 (3)
8.42 (3)
1.68 (3)
9.09 (3)
15. 87 (3)
1.73 (3)
9.15 (3)
15.80 (3)
0.17
0.68
0.10
4j
0.17
4k
4l
0.26
0.76±0.06
0.80±0.09
0.89±0.05
0.76±0.09
0.38
4m
4n
4o
0.20
0.15
0.45
activity (Inhibition zone = 22-28 mm) while rest of the low concentrations may cause bacteriostatic conditions
compounds, except 4e (Inhibition zone = 5 mm) shows which slow down the growth of bacteria (Table 3).
moderate activity. In case of Pseudomonas aeruginosa
3.2. Antifungal Activity
compounds 4m, 4n, 4o show higher activity than the
Theantifungalactivityofallthesecompoundswerecarried
out against two pathogenic fungal strains Aspergillus
niger and Aspergillus candidus using Ampicilin as a
standard. It was found that compounds 4m, 4n and
4o show potent activity. Compound 4m exhibit higher
efficacy against both fungal strains. The higher efficacy
of this compound may be due to the presence of nitrogen
and sulphur content (containing a lone pair of electrons),
presence of two methyl groups along with a nitro group
on the phenyl ring. These compounds generally damage
the fungal strains by puncturing the cell wall similar to
the mechanism proposedfor bacteria. The water and lipid
solubility also increases the activity due to presence of
polar groups in the molecules [35] (Table 3).
rest of the compounds. The inhibition of compounds 4a,
4f, 4m and 4o was higher in case of Staphylococcus
aureus while rest of the were moderately active. In case
of Micrococcus lutius and Kocuria rosea compounds
4m, 4n, 4o and 4j show higher efficacy than the rest
of the compounds. The activity results clearly indicate
that the compounds 4, 4n and 4o along with 4a, 4f and
4j show higher activity against the bacterial strains in
comparison to the rest of the compounds. The presence
of methyl and m-nitro groups, in 4m and 4o, play an
important role in activity, while in compound 4n presence
of an ethoxy group, along with nitro group, justify the
activity. It may be found that the nitro group present
on the phenyl ring generally form complexes with
metaloenzymes,particularlythosewhichareresponsible
in basic physiology such as cytochrome oxidase. These 3.3. Entomological Activity
compounds may react with the peptidoglycan layer of The newly synthesized compounds were also screened
the bacterial cell wall and damage it by penetrating in out for their entomological activity (antifeedant and
such a manner that the phenyl ring gets entered inside acraricidal) against Spodoptera litura (an insect which
the cell by puncturing it, followed by bacterial cell death damages the Indian agriculture crops) and Tetranychus
[34]. Sometimes these compounds when present in urticae of mites (damage house goods) respectively.
171
171

Rapid synthesis and biological evaluation
of 1,4-dihydropyridine derivatives
containing a benzothiazolyl moiety
3.4. Antifeedant activity
4. Conclusion
The Antifeedant activity of the newly synthesized
compounds was tested by a leaf dip method against
larvae of Spodoptera litura. The results clearly indicate
that the compounds show higher, moderate and less
antifeedant activity against the larvae of the insect.
Compounds 4c, 4l, 4g and 4o show higher activity,
compounds 4m, 4k, 4j, 4h and 4a show moderate
activity while the rest of the compounds exhibit lower
activity as seen by their LC50/LD50 results. The results
clearly show that the presence of methyl and methoxy
groups onthe aromatic ring enhance the activity. The
presence of N(Me)2 group as R3 in the side ring also plays
an important role in activity. It may be found that these
compounds may cause a spasm condition in insects by
interacting with the active site of the enzyme responsible
for nervous breakdown in insects [36] (Table 4).
We have developed an economical, solvent free, very
efficient microwave assisted protocol for the synthesis
of N-(6-methylbenzothiazolyl)-2,3,5,6-tetrasubstituted-
4-(aryl)-1,4-dihydropyridines which can be a viable
alternative to their conventional synthesis. The synthetic
protocol has the inherent potential for future drug
synthesis. The 1,4-dihydropyridine derivatives (4a-4o)
showed potent antimicrobial activity against various
bacterial and fungal strains. The maximum antibacterial
and antifungal activity was exhibited by 4m, 4n and 4o.
The presence of R3 = m-NO2 substituent on the phenyl
ring along with a variation in solubility plays a significant
role in determining the antimicrobial activity of the
compounds in comparison to other substituents [38].
The ortho and meta electron withdrawing groups on the
aromatic ring enhances the activity while anything at the
para position reduces activity [39,40]. The compounds
also show potent antifeedant and acaricidal activity
against Spodoptera litura and Tetranychus urticae,
respectively, where solubility of the compounds plays a
significant role [37]. From the results, it is clear that these
compounds would be better used in drug development
to combat bacterial and fungal infections, and would be
better used as pesticides in the future as well.
3.5. Acaricidal Activity
The Acaricidal activity of these compounds was
performed by the same method, as in the case of
Antifeedant activity, against Tetranychus urticae, a
species of mite using acetone as a standard. The
results obtained clearly show that compound 4e shows
the highest acaricidal activity with respect to the other
compounds. The higher activity of this compound is due
to the presence of three polar groups in the molecules
which enhances the water and lipid solubility of this
compound. It is reported that the compounds which are
easily soluble in polar solvent have higher activity against
microbes and insect pests or mites [37]. Compounds 4b,
4d, 4f and 4i shows moderate activity and the rest of
the compounds show lower to moderate activity against
the mites. Besides solubility, the presence of a lone pair
of electrons on the nitrogen and sulphur along with the
phenyl ring, having varying side groups, may also be
responsible for variation in activity (Table 5).
Acknowledgement
We are thankful to CDRI, Lucknow, for spectral studies.
We are also thankful to Dr. Ashish Bhatnagar Head,
Department of Microbiology, MDS University, Ajmer for
providing antimicrobial screening facility.
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