Synthesis and antimicrobial activity of new pyridine derivatives-I

Article abstract of DOI:10.1007/s00044-010-9440-0

2-Amino substituted benzothiazoles 2a-l and 2-chloropyridine-3-carboxylic acid 3 were used to prepare 2-[N-(substitutedbenzothiazolyl)amino]pyridine-3- carboxylic acids (4a-l) in 2-ethoxy ethanol. Acid chlorides (5a-l) were condensed with 2-hydroxyethyl piperazine (6) and 2,3-dichloropiperazine (7) to prepare amide derivatives 2-[N-(substituted benzothiazolyl)amino]pyridin-3-yl (4-(2-hydroxyethyl)piperazin-1-yl)methanones (8a-l) and 2-[N-(substituted benzothiazolyl) amino]pyridin-3-yl(2,3- dichloropiperazine-1-yl)methanones (9a-l), respectively. The structures of new compounds have been established on the basis of elemental analysis and spectral (IR, 1H NMR, and Mass spectra) studies. The in vitro antimicrobial activity was screened for all the synthesized compounds. Variable and modest activity were observed against the investigated strains of bacteria and fungi. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s00044-010-9440-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:1033–1041
DOI 10.1007/s00044-010-9440-0
ORIGINAL RESEARCH
Synthesis and antimicrobial activity of new pyridine derivatives-I
•
Navin B. Patel Suresh N. Agravat
•
Faiyazalam M. Shaikh
Received: 14 February 2010 / Accepted: 15 September 2010 / Published online: 30 September 2010
Ó Springer Science+Business Media, LLC 2010
Abstract 2-Amino substituted benzothiazoles 2a–l and
2-chloropyridine-3-carboxylic acid 3 were used to prepare
2-[N-(substitutedbenzothiazolyl)amino]pyridine-3-carbox-
ylic acids (4a–l) in 2-ethoxy ethanol. Acid chlorides (5a–l)
were condensed with 2-hydroxyethyl piperazine (6) and
2,3-dichloropiperazine (7) to prepare amide deriva-
tives 2-[N-(substituted benzothiazolyl)amino]pyridin-3-yl
(4-(2-hydroxyethyl)piperazin-1-yl)methanones (8a–l) and
2-[N-(substituted benzothiazolyl) amino]pyridin-3-yl(2,3-
dichloropiperazine-1-yl)methanones (9a–l), respectively.
The structures of new compounds have been established on
number of heterocyclic compounds containing pyridine ring
are associated with diverse pharmacological properties such
as antimicrobial (Gaonkar et al., 2007; Vijey et al., 2008;
Patel and Patel, 2009a, anticonvulsant (Paronikyan et al.,
2002), antiviral (Bernardino et al., 2007), anti-HIV (Tucker
et al., 2008), antifungal, and antimycobacterial (Mamolo
et al., 2004). Several nitrogen containing heterocyclic
systems find a wide variety of therapeutic activities that’s
why the course of recent work on the synthesis of new
heterocycles of 2-chloropyridine-3-carboxylic acid with
substituted benzothiazoles and piperazines has been
undertaken.
1
the basis of elemental analysis and spectral (IR, H NMR,
and Mass spectra) studies. The in vitro antimicrobial
activity was screened for all the synthesized compounds.
Variable and modest activity were observed against the
investigated strains of bacteria and fungi.
2-Aminosubstituted benzothiazoles have been synthe-
sized and used as an intermediate with parent compound
2-chloropyridine-3-carboxylic acid. Benzothiazoles them-
selves show different activities like antifungal (Lakhan and
Rai, 1986), antiproliferative (Al-Soud et al., 2008), and
antitumor (Mortimer et al., 2006).
Keywords 2-Aminobenzothiazoles ꢀ
2-Chloropyridine-3-carboxylic acid ꢀ Piperazines ꢀ
Antimicrobial activity
Piperazines are most widely used in treatment of intes-
tinal worms in animals and humans. The most important
applications of its derivatives are antibacterial (Letafat
et al., 2007), antimicrobial (Patel and Patel, 2009b; Patel
and Bhagat, 2006), anti-HIV (Al-Soud et al., 2007), and as
cytotoxic agents (Rajabalian et al., 2007).
Introduction
The number of life threatening infections caused by mul-
tidrug-resistant Gram-positive pathogens has reached an
alarming level in hospitals and the community. Infections
caused by these organisms pose a serious challenge to the
scientific community, and the need for an effective therapy
has led to a search for novel antibacterial agents. A large
Prompted by recent literature observations and as a part
of our continuous search for biologically active com-
pounds, we have continued our previous work on 2-chloro
pyridine-3-carboxylic acid (Patel and Bhagat, 2001, 2002)
with substituted benzothiazoles and piperazines. The
search for new, effective, and safe nuclei has led to an
improvement by increasing their potency. Combination of
two active moieties led the significant changes in the bio-
logical activities. With these concepts, we have synthesized
the new pyridine derivatives of 2-chloropyridine-3-car-
boxylic acid with 2-aminosubstituted benzothiazoles and
N. B. Patel (&) ꢀ S. N. Agravat ꢀ F. M. Shaikh
Department of Chemistry, Veer Narmad South Gujarat
University, Surat 395007, Gujarat, India
e-mail: drnavin@satyam.net.in
123

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Med Chem Res (2011) 20:1033–1041
piperazines. This may be achieved by creating new bio-
logically active agents by molecular modifications.
concentrations, were compared with standard drug Peni-
cillin-G, Ampicillin, Amoxicillin, and Amphotericine-B.
Moderate to modest antimicrobial activity was observed
with most of the tested compounds. However, some com-
pounds demonstrated moderate to fair activity compared to
reference drugs taken in the study. 8b,i (R = 4-NO2,
5-CH3), 9b,d,g,i (R = 4-NO2, 4-NO2, 6-Cl, 5-CH3) against
S. aureus; 8g,h,k (R = 6-Cl, 4-CH3, 4-OCH3), 9b,g,k
(R = 4-NO2, 6-Cl, 4-OCH3) against B. subtilis; 8g,l
(R = 6-Cl, 6-OCH3), 9b,g,h,l (R = 4-NO2, 6-Cl, 4-CH3,
6-OCH3) against E. coli displayed moderate to fair activity
as compared to Penicillin-G and Amoxicillin while with
Ampicillin comparable results were found. 8a (R = H) and
9a (R = H) displayed fair antibacterial activity against
both positive and negative bacteria at both the concentra-
tions. 8b,f (R = 4-NO2, 5-Cl), 9a,e,l (R = H, 4-Cl,
Results and discussion
All the newly synthesized compounds 8a–l and 9a–l
(Scheme 1) were screened for antibacterial and antifungal
activity. Zone of inhibition for synthesized compounds was
determined against two gram-positive bacteria (Staphylo-
coccus aureus ATCC 9144 and Bacillus subtilis ATCC
6633), two gram-negative bacteria (Pseudomonas aeru-
ginosa ATCC 9027 and Escherichia coli ATCC 25922)
and against fungi (Candida albicans ATCC 10231) using
cup-plate method (DMF as a solvent) (Barry, 1976). The
solution of compounds at 100 lg/ml and 200 lg/ml
NH2
Scheme 1 Protocol for the
synthesis of compounds 8a–l
and 9a–l
N
NH4SCN/Br2
R
R
NH2
CH3COOH/NH3
S
2a-l
1a-l
COOH
Cl
N
S
R
NH2
+
N
2a-l
3
140oC
2-Ethoxy ethanol
COOH
N
S
NH
R
N
4a-l
SOCl2
COCl
N
S
NH
R
N
5a-l
0-50C
Stirring
7-8 h
Cl
Cl
HN
N
CH2CH2OH
HN
NH
6
7
Cl
Cl
N
N
CH2CH2OH
CO
N
NH
CO
N
N
NH
R
N
NH
R
N
S
S
8a-l
9a-l
123

Med Chem Res (2011) 20:1033–1041
1035
6-OCH3), 8j,l (R = 6-CH3, 6-OCH3), and 9c,j,k (R =
5-NO2, 6-CH3, 4-OCH3) displayed moderate to fair
antifungal activity against Candida albicans at higher
concentration. It is general observation from above dis-
cussion that almost all the synthesized compounds are
found to have poor to fair activity against corresponding
species.
does not rise beyond 0°C. After all the bromine has been
added (105 min), the solution was stirred for an additional
2 h at 0°C and at room temperature for 10 h. It was then
allowed to stand overnight during which an orange pre-
cipitate settled at the bottom, water (6 ml) was added
quickly, and slurry was heated at 85°C on a steam bath and
filtered while hot. The orange residue was placed in a
reaction flask and treated with 10 ml of glacial acetic acid
heated again to 85°C and filtered while hot. The combined
filtrate was cooled and adjusted to pH-6 with conc.
ammonia solution. The dark yellow precipitate formed was
collected. Recrystallization from benzene (twice) after
treatment with charcoal gave pellets of (2a–l).
Table 3 summarized the in vitro activity of the new
pyridine derivatives 8a–l and 9a–l.
Conclusion
New pyridine derivatives 8a–l and 9a–l were synthesized
starting from building blocks 2-amino benzothiazoles 2 and
2-chloro pyridine-3-carboxylic acid (i.e., 2-chloro nicotinic
acid) 3 and were studied for their antimicrobial activity.
Overall observation from the results of antimicrobial
activity reveals that most of the synthesized compounds are
found to have poor to fair activity against corresponding
species.
General procedure for the preparation of 2-[N-
(substitutedbenzothiazolyl) amino]pyridine-3-
carboxylic acids (4a–l)
Mixture of 2-chloropyridine-3-carboxylic acid 3 (0.015
mol), 2-amino benzothiazoles (2) (0.015 mol), anhydrous
K2CO3 (0.01 mol), and copper powder (0.01 g) was
refluxed in 2-ethoxyethanol (25 ml) under stirring in an oil
bath at 140°C for 5 h. The cooled mixture was diluted with
water, residue formed was filtered, and the resulted solu-
tion was made acidic to pH-5 with dil HCl when pure
product precipitated. The product (4a–l) was recrystallized
from ethanol.
However, the present work provides good outlines on
the antimicrobial study of pyridine derivatives encom-
passing with benzothiazole moiety.
Experimental
The physical constants of 2a–l and 4a–l are given in
Table 1.
Melting points were determined in open capillaries and are
uncorrected. The IR spectra were recorded on Perkin-
Elmer-843 spectrometer using KBr pellets. 1H NMR
spectra were scanned on Bruker DPX-200 FT-NMR
(400 MHz) spectrometer using TMS as an internal standard
and DMSO-d6 as solvent (chemical shift in d ppm) and
mass spectra on a Jeol JMS D-300 spectrometer. Elemental
analyses of the newly synthesized compounds were carried
out on Perkin-Elmer 240C elemental analyzer. The com-
pounds gave satisfactory C, H, and N analysis. Samples
were routinely purified by crystallization from ethanol:
benzene (1:3) and checked by TLC using ethylacetate:
toluene (2.5:7.5) as a mobile phase.
Spectroscopic characterization data of 2a–l and 4a–l are
as similar to previous work (Javier et al., 1986)
General procedure for the preparation of
2-[n-(substitutedbenzothiazolyl)amino]pyridin-3-yl
(4-(2-hydroxy ethyl)piperazin-1-yl)methanones (8a–l)
and 2-[n-(substitutedbenzothiazolyl) amino]pyridin-3-yl
(2,3-dichloropiperazine-1-yl)methanones (9a–l)
2-[N-(substitutedbenzothiazolyl)amino]pyridine-3-carbonyl
chlorides (5a–l) prepared by reported method (Vogel, 1998)
were dissolved in pyridine (10 ml), and the solution was
cooled in an ice bath. To the stirred solution were succes-
sively added in small portion, fresh dried pyridine (5 ml) and
2-hydroxyethylpiperazine (0.01) (6). The mixture was
warmed for 1.5 h at 70°C. After the completion of reaction;
the solvent was removed by vacuum distillation. The crude
product 2-[N-(substitutedbenzothiazolyl)amino]pyridin-3-yl
(4-(2-hydroxyethyl)piperazin-1-yl)methanones (8a–l) were
obtained, collected, and recrystallized from ethanol: benzene
(1:3).
General procedure for the preparation of 2-amino
benzothiazoles (2a–l)
To glacial acetic acid (20 ml) precooled to 5°C were added
(0.08 mol) of ammonium thiocynate and (0.01 mol) of
aromatic primary amine. The mixture was placed in
freezing mixture of ice and salt, mechanically stirred while
1.6 ml of bromine in 6 ml of glacial acetic acid was added
from a dropping funnel at such a rate that the temperature
123

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Med Chem Res (2011) 20:1033–1041
Table 1 Physical constant of the synthesized compounds 2a–l and 4a–l
COOH
NH
N
N
R
R
N
S
NH2
S
2a-l
4a-l
Compound
R
Yield (%)
MP (°C)
Molecular formula
Molecular weight
2a
2b
2c
2d
2e
2f
H
74
67
72
68
72
74
70
71
74
64
68
72
61
58
62
64
55
59
61
57
62
59
54
56
147
140
120
180
162
220
198
119
135
129
180
133
216
208
224
241
199
191
219
228
189
195
231
210
C7H6N2S
150.02
195.01
195.01
195.01
215.97
215.97
215.97
164.04
164.04
164.04
180.03
180.03
271.04
316.03
316.03
316.03
305.00
305.00
305.00
285.06
285.06
285.06
301.05
301.05
4-NO2
5-NO2
6-NO2
4-Cl
C7H5O2N3S
C7H5O2N3S
C7H5O2N3S
C7H5O2N2SCl
C7H5O2N2SCl
C7H5O2N2SCl
C8H8N2S
5-Cl
2g
2h
2i
6-Cl
4-CH3
5-CH3
6-CH3
4-OCH3
6-OCH3
H
C8H8N2S
2j
C8H8N2S
2k
2l
C8H8ON2S
C8H8ON2S
4a
4b
4c
4d
4e
4f
C13H9O2N3S
4-NO2
5-NO2
6-NO2
4-Cl
C13H8O4N4S
C13H8O4N4S
C13H8O4N4S
C
C
C
13H8O2N3SCl
13H8O2N3SCl
13H8O2N3SCl
5-Cl
4g
4h
4i
6-Cl
4-CH3
5-CH3
6-CH3
4-OCH3
6-OCH3
C14H11O2N3S
C14H11O2N3S
C14H11O2N3S
C14H11O3N3S
C14H11O3N3S
4j
4k
4l
Similarly, 2-[N-(benzothiazolyl)amino]pyridin-3-yl(2,3-
dichloropiperazine-1-yl)methanones (9a–l) were prepared.
Physical constants and antimicrobial activity of compounds
8a–l and 9a–l are given in Tables 2 and 3, respectively.
C19H21O2N5S: C, 59.51; H, 05.52; N, 18.27. Found: C,
59.48; H, 05.50; N, 18.20.
2-[N-(4-Nitrobenzothiazolyl)amino]pyridin-3-yl
(4-(2-hydroxyethyl)piperazin-1-yl)methanone 8b
2-[N-(benzothiazolyl)amino]pyridin-3-yl(4-(2-
hydroxyethyl)piperazin-1-yl)methanone 8a
IR (KBr) cm-1: 3441 (NH), 3365 (OH), 2921, 2842 (CH2),
1674 (C=O), 1614 (C=N aromatic), 1449 (C–S), 1101 (C–
IR (KBr) cm-1: 3421 (NH), 3375 (OH), 2930, 2855 (CH2),
1675 (C=O), 1612 (C=N aromatic), 1449 (C–S), 1105 (C–
N aliphatic); H NMR (DMSO-d6): d 2.15 (2H, t, [N–
1
CH2–), 2.78 (4H, m, piperazine), 3.15 (4H, m, piperazine),
3.34 (2H, t, –CH2–O–), 4.60 (1H, s, –OH), 8.42–6.85 (6H,
m, pyridine and Ar–H), 10.75 (1H, s, –NH–); MS: m/z: 428
(M?), 384, 357, 343, 329, 302, 274, 195, 180, 154, 149,
136, 122, 77, 55, 45, 41, 31, 27; Anal. Calcd. for
C19H20O4N6S: C, 53.26; H, 04.71; N, 19.62. Found: C,
53.22; H, 04.68; N, 19.56.
1
N aliphatic); H NMR (DMSO-d6): d 2.12 (2H, t, [N–
CH2–), 2.84 (4H, m, piperazine), 3.16 (4H, m, piperazine),
3.34 (2H, t, –CH2–O–), 4.58 (1H, s, –OH), 8.43–6.87 (7H,
m, pyridine and Ar–H), 10.64 (1H, s, –NH–); MS: m/z: 383
(M?), 353, 339, 312, 298, 284, 257, 229, 150, 137,128,
122, 96, 78, 77, 64, 55, 45, 41, 31, 27; Anal. Calcd. for
123

Med Chem Res (2011) 20:1033–1041
1037
Table 2 Physical constant of the synthesized compounds 8a–l and 9a–l
Cl
Cl
CON
NCH2CH2OH
CON
NH
N
N
R
N
NH
N
R
S
NH
S
8a-l
9a-l
Compound
R
Yield (%)
MP (°C)
Molecular formula
Molecular weight
8a
8b
8c
8d
8e
8f
H
70
64
65
69
59
64
58
56
63
63
58
63
71
65
68
67
55
67
61
58
63
62
56
57
212
199
232
207
234
210
189
242
239
194
224
228
222
199
191
210
226
214
235
219
239
229
207
195
C19H21O2N5S
C19H20O4N6S
C19H20O4N6S
C19H20O4N6S
383.14
428.13
428.13
428.13
417.10
417.10
417.10
397.16
397.16
397.16
413.15
413.15
407.04
452.02
452.02
452.02
441.00
441.00
441.00
421.05
421.05
421.05
437.05
437.05
4-NO2
5-NO2
6-NO2
4-Cl
C
C
C
19H20O2N5SCl
19H20O2N5SCl
19H20O2N5SCl
5-Cl
8g
8h
8i
6-Cl
4-CH3
5-CH3
6-CH3
4-OCH3
6-OCH3
H
C20H23O2N5S
C20H23O2N5S
C20H23O2N5S
C20H23O3N5S
C20H23O3N5S
8j
8k
8l
9a
9b
9c
9d
9e
9f
C17H15ON5SCl2
4-NO2
5-NO2
6-NO2
4-Cl
C17H14O3N6SCl2
C17H14O3N6SCl2
C17H14O3N6SCl2
C
C
C
17H14ON5SCl3
17H14ON5SCl3
17H14ON5SCl3
5-Cl
9g
9h
9i
6-Cl
4-CH3
5-CH3
6-CH3
4-OCH3
6-OCH3
C18H17ON5SCl2
C18H17ON5SCl2
C18H17ON5SCl2
C18H17O2N5SCl2
C18H17O2N5SCl2
9j
9k
9l
2-[N-(5-Nitrobenzothiazolyl)amino]pyridin-3-yl
(4-(2-hydroxyethyl)piperazin-1-yl)methanone 8c
2-[N-(6-Nitrobenzothiazolyl)amino]pyridin-3-yl
(4-(2-hydroxyethyl)piperazin-1-yl)methanone 8d
IR (KBr) cm-1: 3445 (NH), 3369 (OH), 2928, 2843 (CH2),
1678 (C=O), 1613 (C=N aromatic), 1448 (C–S), 1104 (C–
IR (KBr) cm-1: 3443 (NH), 3368 (OH), 2925, 2844 (CH2),
1680 (C=O), 1615 (C=N aromatic), 1447 (C–S), 1102 (C–
1
1
N aliphatic); H NMR (DMSO-d6): d 2.17 (2H, t, [N–
N aliphatic); H NMR (DMSO-d6): d 2.16 (2H, t, [N–
CH2–), 2.82 (4H, m, piperazine), 3.19 (4H, m, piperazine),
3.32 (2H, t, –CH2–O–), 4.62 (1H, s, –OH), 8.41–6.84 (6H,
m, pyridine and Ar–H), 10.71 (1H, s, –NH–); MS: m/z: 428
(M?), 384, 357, 343, 329, 302, 274, 195, 180, 154, 149,
136, 122, 77, 55, 45, 41, 31, 27; Anal. Calcd. for
C19H20O4N6S: C, 53.26; H, 04.71; N, 19.62. Found: C,
53.20; H, 04.65; N, 19.55.
CH2–), 2.80 (4H, m, piperazine), 3.18 (4H, m, piperazine),
3.35 (2H, t, –CH2–O–), 4.61 (1H, s, –OH), 8.43–6.87 (6H,
m, pyridine and Ar–H), 10.74 (1H, s, –NH–) MS: m/z: 428
(M?), 384, 357, 343, 329, 302, 274, 195, 180, 154, 149,
136, 122, 77, 55, 45, 41, 31, 27; Anal. Calcd. for
C19H20O4N6S: C, 53.26; H, 04.71; N, 19.62. Found: C,
53.19; H, 04.67; N, 19.58.
123

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Med Chem Res (2011) 20:1033–1041
2-[N-(5-Chlorobenzothiazolyl)amino]pyridin-3-yl
(4-(2-hydroxyethyl)piperazin-1-yl)methanone 8f
Table 3 Antimicrobial and antifungal activity data of 8a–l and 9a–l
Zone of inhibition in mm at 100 and 200 lg/ml, respectively
IR (KBr) cm-1: 3429 (NH), 3364 (OH), 2938, 2846 (CH2),
1665 (C=O), 1618 (C=N aromatic), 1451 (C–S), 1097 (C–
Compound
Gram-negative
Gram-positive
Fungi
P.
aeruginosa
E. coli S.
B.
C.
aureus Subtilis albicans
1
N aliphatic); H NMR (DMSO-d6): d 2.16 (2H, t, [N–
CH2–), 2.82 (4H, m, piperazine), 3.14 (4H, m, piperazine),
3.32 (2H, t, –CH2–O–), 4.56 (1H, s, –OH), 8.42–6.86 (6H,
m, pyridine and Ar–H), 10.66 (1H, s, –NH–); MS: m/z: 417
(M?), 387, 373, 346, 332, 318, 291, 263, 184, 169, 149,
143, 125, 111, 77, 55, 45, 41, 31, 27; Anal. Calcd. for
C19H20O2N5SCl: C, 54.66; H, 04.83; N, 16.79. Found: C,
54.58; H, 04.78; N, 16.68.
8a
8
8
9
11
7
7
5
4
0
6
5
8
9
8
5
9
5
6
8
6
8
7
0
8
4
8
0
6
8
5
8
6
8
3
0
7
4
8
3
6
5
7
12
11
9
6
8
8
0
7
5
7
7
8
0
6
0
6
5
8
7
3
5
5
4
7
0
8
-
10
9
3
4
2
0
3
3
0
0
1
2
4
0
3
2
1
0
3
1
0
0
2
2
3
4
–
–
–
8
5
7
4
2
6
4
1
0
2
5
4
5
5
4
4
3
6
2
1
0
3
5
4
6
–
–
–
18
8b
8c
7
8
8d
6
8
6
8e
7
9
7
8
8f
0
3
0
5
8g
7
10
7
6 10
9
9
8h
6
3
7
5
10
8
2-[N-(6-Chlorobenzothiazolyl)amino]pyridin-3-yl
(4-(2-hydroxyethyl)piperazin-1-yl)methanone 8g
8i
5
6
6 10
10
3
8j
0
0
0
3
8
7
6
3
8
8
0
8k
7
9
8
10
4
IR (KBr) cm-1: 3428 (NH), 3366 (OH), 2940, 2847 (CH2),
1666 (C=O), 1617 (C=N aromatic), 1450 (C–S), 1099 (C–
8l
4
5
9
9a
4
5
7
7
1
N aliphatic); H NMR (DMSO-d6): d 2.14 (2H, t, [N–
9b
8
9
9 10
10
9
10
7
CH2–), 2.80 (4H, m, piperazine), 3.13 (4H, m, piperazine),
3.30 (2H, t, –CH2–O–), 4.55 (1H, s, –OH), 8.43–6.87 (6H,
m, pyridine and Ar–H), 10.65 (1H, s, –NH–); MS: m/z: 417
(M?), 387, 373, 346, 332, 318, 291, 263, 184, 169, 149,
143, 125, 111, 77, 55, 45, 41, 31, 27; Anal. Calcd. for
C19H20O2N5SCl: C, 54.66; H, 04.83; N, 16.79. Found: C,
54.56; H, 04.81; N, 16.72.
9c
5
6
4
6
4
2
7
5
6
5
3
9
9d
6
8
8
7
9e
3
3
4
6
9f
0
2
0
5
9g
8
8
10
6
6
9h
6
7
8 10
4
9i
6
8
5
3
0
8
7
3
4
9
10
4
7
9j
0
0
0
2-[N-(4-Methylbenzothiazolyl)amino]pyridin-3-yl
(4-(2-hydroxyethyl)piperazin-1-yl) methanone 8h
9k
7
8
6
9
9l
4
7
6
2
IR (KBr) cm-1: 3446 (NH), 3358 (OH), 2927, 2855 (CH2),
1684 (C=O), 1614 (C=N aromatic), 1448 (C–S), 1096 (C–
Penicillin-G
Ampicillin
Amoxicillin
Amphotericin-B
13
18
15
–
22
31
27
–
14 25 12 21 14 25
18 30 15 28 17 30
16 28 13 24 16 29
1
N aliphatic); H NMR (DMSO-d6): d 2.10 (2H, t, [N–
–
–
–
–
–
–
CH2–), 2.85 (4H, m, piperazine), 3.16 (4H, m, piperazine),
3.36 (2H, t, –CH2–O–), 4.58 (1H, s, –OH), 8.43–6.87 (6H,
m, pyridine and Ar–H), 10.64 (1H, s, –NH–); MS: m/z: 397
(M?), 367, 353, 326, 312, 298, 271, 243, 164, 149, 123,
105, 91, 77, 55, 45, 41, 31, 27; Anal. Calcd. for
C20H23O2N5S: C, 60.43; H, 05.84; N, 17.63. Found: C,
60.35; H, 05.82; N, 17.58.
2-[N-(4-Chlorobenzothiazolyl)amino]pyridin-3-yl
(4-(2-hydroxyethyl)piperazin-1-yl) methanone 8e
IR (KBr) cm-1: 3425 (NH), 3365 (OH), 2939, 2845 (CH2),
1667 (C=O), 1616 (C=N aromatic), 1448 (C–S), 1096 (C–
1
N aliphatic); H NMR (DMSO-d6): d 2.15 (2H, t, [N–
2-[N-(5-Methylbenzothiazolyl)amino]pyridin-3-yl
(4-(2-hydroxyethyl)piperazin-1-yl)methanone 8i
CH2–), 2.81 (4H, m, piperazine), 3.15 (4H, m, piperazine),
3.31 (2H, t, –CH2–O–), 4.57 (1H, s, –OH), 8.41–6.85 (6H,
m, pyridine and Ar–H), 10.68 (1H, s, –NH–); MS: m/z: 417
(M?), 387, 373, 346, 332, 318, 291, 263, 184, 169, 149,
143, 125, 111, 77, 55, 45, 41, 31, 27; Anal. Calcd. for
C19H20O2N5SCl: C, 54.66; H, 04.83; N, 16.79. Found: C,
54.55; H, 04.80; N, 16.70.
IR (KBr) cm-1: 3445 (NH), 3355 (OH), 2925, 2854 (CH2),
1685 (C=O), 1619 (C=N aromatic), 1446 (C–S), 1097 (C–
1
N aliphatic); H NMR (DMSO-d6): d 2.12 (2H, t, [N–
CH2–), 2.88 (4H, m, piperazine), 3.15 (4H, m, piperazine),
3.37 (2H, t, –CH2–O–), 4.56 (1H, s, –OH), 8.41–6.89 (6H,
123

Med Chem Res (2011) 20:1033–1041
1039
2-[N-(benzothiazolyl)amino]pyridin-3-yl
(2,3-dichloropiperazine-1-yl)methanone 9a
m, pyridine and Ar–H), 10.65 (1H, s, –NH–); MS: m/z: 397
(M?), 367, 353, 326, 312, 298, 271, 243, 164, 149, 123,
105, 91, 77, 55, 45, 41, 31, 27; Anal. Calcd. for
C20H23O2N5S: C, 60.43; H, 05.84; N, 17.63. Found: C,
60.38; H, 05.81; N, 17.56.
IR (KBr) cm-1: 3464 (NH), 2931 (CH2), 1675 (C=O),
1612 (C=N aromatic), 1450 (C–S), 1103 (C–N aliphatic);
1H NMR (DMSO-d6): d 2.14 (2H, t, –CH2N–, piperazine),
2.42 (2H, t, –CH2N–, piperazine), 2.70 (1H, d, –CHClN–),
2.96 (1H, d, –CHClN–), 8.43–6.87 (7H, m, pyridine and
Ar–H), 10.64 (2H, s,–NH–); MS: m/z: 407 (M?), 346, 332,
284, 257, 229, 152, 150, 135, 125, 109, 91, 89, 77, 75, 63,
27; Anal. Calcd. for C17H15ON5SCl2: C, 50.12; H, 03.71;
N, 17.20. Found: C, 50.05; H, 03.67; N, 17.15.
2-[N-(6-Methylbenzothiazolyl)amino]pyridin-3-yl
(4-(2-hydroxyethyl)piperazin-1-yl)methanone 8j
IR (KBr) cm-1: 3444 (NH), 3358 (OH), 2926, 2854 (CH2),
1681 (C=O), 1615 (C=N aromatic), 1445 (C–S), 1099 (C–
1
N aliphatic); H NMR (DMSO-d6): d 2.09 (2H, t, [N–
2-[N-(4-Nitrobenzothiazolyl)amino]pyridin-3-yl
(2,3-dichloropiperazine-1-yl)methanone 9b
CH2–), 2.86 (4H, m, piperazine), 3.14 (4H, m, piperazine),
3.35 (2H, t, –CH2–O–), 4.57 (1H, s, –OH), 8.40–6.88 (6H,
m, pyridine and Ar–H), 10.69 (1H, s, –NH–); MS: m/z: 397
(M?), 367, 353, 326, 312, 298, 271, 243, 164, 149, 123,
105, 91, 77, 55, 45, 41, 31, 27; Anal. Calcd. for
C20H23O2N5S: C, 60.43; H, 05.84; N, 17.63. Found: C,
60.34; H, 05.80; N, 17.57.
IR (KBr) cm-1: 3435 (NH), 2915, 2854 (CH2), 1669
(C=O), 1614 (C=N aromatic), 1448 (C–S), 1096 (C–N
1
aliphatic); H NMR (DMSO-d6): d 2.13 (2H, t, –CH2N–,
piperazine), 2.36 (2H, t, –CH2N–, piperazine), 2.70 (1H, d,
–CHClN–), 2.94 (1H, d, –CHClN–), 8.39–6.86 (6H, m,
pyridine and Ar–H), 10.71 (2H, s, –NH–); MS: m/z: 452
(M?), 389, 375, 327, 300, 272, 195, 180, 153, 152, 149,
135, 125, 121, 89, 77, 75, 63, 27; Anal. Calcd. for
C17H14O3N6SCl2: C, 45.13; H, 03.12; N, 18.59. Found: C,
45.09; H, 03.10; N, 18.50.
2-[N-(4-Methoxybenzothiazolyl)amino]pyridin-3-yl
(4-(2-hydroxyethyl)piperazin-1-yl) methanone 8k
IR (KBr) cm-1: 3460 (NH), 3370 (OH), 2915, 2850 (CH2),
1665 (C=O), 1616 (C=N aromatic), 1446 (C–S), 1106 (C–
1
2-[N-(5-Nitrobenzothiazolyl)amino]pyridin-3-yl
(2,3-dichloropiperazine-1-yl)methanone 9c
N aliphatic); H NMR (DMSO-d6): d 2.14 (2H, t, [N–
CH2–), 2.86 (4H, m, piperazine), 3.11 (4H, m, piperazine),
3.32 (2H, t, –CH2–O–), 4.56 (1H, s, –OH), 8.45–6.86 (6H,
m, pyridine and Ar–H), 10.75 (1H, s, –NH–); MS: m/z: 413
(M?), 383, 369, 342, 328, 314, 287, 259, 180, 165, 149,
138, 128, 120, 106, 77, 55, 45, 41, 31, 27; Anal. Calcd. for
C20H23O3N5S: C, 58.09; H, 05.61; N, 16.95. Found: C,
58.01; H, 05.60; N, 16.88.
IR (KBr) cm-1: 3436 (NH), 2918, 2855 (CH2), 1668
(C=O), 1613 (C=N aromatic), 1449 (C–S), 1095 (C–N
1
aliphatic); H NMR (DMSO-d6): d 2.12 (2H, t, –CH2N–,
piperazine), 2.35 (2H, t, –CH2N–, piperazine), 2.71 (1H, d,
–CHClN–), 2.92 (1H, d, –CHClN–), 8.43–6.87 (6H, m,
pyridine and Ar–H), 10.69 (2H, s, –NH–); MS: m/z: 452
(M?), 389, 375, 327, 300, 272, 195, 180, 153, 152, 149,
135, 125, 121, 89, 77, 75, 63, 27; Anal. Calcd. for
C17H14O3N6SCl2: C, 45.13; H, 03.12; N, 18.59. Found: C,
45.08; H, 03.08; N, 18.52.
2-[N-(6-Methoxybenzothiazolyl)amino]pyridin-3-yl
(4-(2-hydroxyethyl)piperazin-1-yl) methanone 8l
IR (KBr) cm-1: 3459 (NH), 3371 (OH), 2914, 2851 (CH2),
1664 (C=O), 1611 (C=N aromatic), 1449 (C–S), 1105 (C–
2-[N-(6-Nitrobenzothiazolyl)amino]pyridin-3-yl
(2,3-dichloropiperazine-1-yl)methanone 9d
1
N aliphatic); H NMR (DMSO-d6): d 2.10 (2H, t, [N–
CH2–), 2.85 (4H, m, piperazine), 3.10 (4H, m, piperazine),
3.31 (2H, t, –CH2–O–), 4.57 (1H, s, –OH), 8.43–6.87 (6H,
m, pyridine and Ar–H), 10.78 (1H, s, –NH–); MS: m/z: 413
(M?), 383, 369, 342, 328, 314, 287, 259, 180, 165, 149,
138, 128, 120, 106, 77, 55, 45, 41, 31, 27; Anal. Calcd. for
C20H23O3N5S: C, 58.09; H, 05.61; N, 16.95. Found: C,
58.03; H, 05.58; N, 16.90.
IR (KBr) cm-1: 3434 (NH), 2921, 2857 (CH2), 1665
(C=O), 1614 (C=N aromatic), 1452 (C–S), 1092 (C–N
1
aliphatic); H NMR (DMSO-d6): d 2.15 (2H, t, –CH2N–,
piperazine), 2.38 (2H, t, –CH2N–, piperazine), 2.74 (1H, d,
–CHClN–), 2.91 (1H, d, –CHClN–), 8.43–6.86 (6H, m,
pyridine and Ar–H), 10.66 (2H, s, –NH–); MS: m/z: 452
123

1040
Med Chem Res (2011) 20:1033–1041
1
(M?), 389, 375, 327, 300, 272, 195, 180, 153, 152, 149,
135, 125, 121, 89, 77, 75, 63, 27; Anal. Calcd. for
C17H14O3N6SCl2: C, 45.13; H, 03.12; N, 18.59. Found: C,
45.05; H, 03.09; N, 18.51.
aliphatic); H NMR (DMSO-d6): d 2.19 (2H, t, –CH2N–,
piperazine), 2.33 (2H, t, –CH2N–, piperazine), 2.70 (1H, d,
–CHClN–), 2.81 (1H, d, –CHClN–), 8.43–6.87 (6H, m,
pyridine and Ar–H), 10.76 (2H, s, –NH–); MS: m/z: 421
(M?), 360, 346, 298, 271, 243, 164, 152, 149, 125, 123,
105, 91, 89, 77, 75, 63, 27; Anal. Calcd. for
C18H17ON5SCl2: C, 51.30; H, 04.07; N, 16.63. Found: C,
51.21; H, 04.04; N, 16.59.
2-[N-(4-Chlorobenzothiazolyl)amino]pyridin-3-yl
(2,3-dichloropiperazine-1-yl)methanone 9e
IR (KBr) cm-1: 3465 (NH), 2926, 2852 (CH2), 1685
(C=O), 1612 (C=N aromatic), 1449 (C–S), 1102 (C–N
2-[N-(5-Methylbenzothiazolyl)amino]pyridin-3-yl
(2,3-dichloropiperazine-1-yl)methanone 9i
1
aliphatic); H NMR (DMSO-d6): d 2.19 (2H, t, –CH2N–,
piperazine), 2.46 (2H, t, –CH2N–, piperazine), 2.61 (1H, d,
–CHClN–), 2.85 (1H, d, –CHClN–), 8.42–6.86 (6H, m,
pyridine and Ar–H), 10.75 (2H, s, –NH–); MS: m/z: 441
(M?), 380, 366, 318, 291, 263, 184, 169, 152, 149, 143,
125, 111, 89, 77, 75, 63, 27; Anal. Calcd. for
C17H14ON5SCl3: C, 46.26; H, 03.20; N, 15.88. Found: C,
46.19; H, 03.17; N, 15.82.
IR (KBr) cm-1: 3440 (NH), 2935, 2855 (CH2), 1678
(C=O), 1612 (C=N aromatic), 1448 (C–S), 1091 (C–N
1
aliphatic); H NMR (DMSO-d6): d 2.18 (2H, t, –CH2N–,
piperazine), 2.31 (2H, t, –CH2N–, piperazine), 2.68 (1H, d,
–CHClN–), 2.88 (1H, d, –CHClN–), 8.45–6.89 (6H, m,
pyridine and Ar–H), 10.75 (2H, s, –NH–); MS: m/z: 421
(M?), 360, 346, 298, 271, 243, 164, 152, 149, 125, 123,
105, 91, 89, 77, 75, 63, 27; Anal. Calcd. for
C18H17ON5SCl2: C, 51.30; H, 04.07; N, 16.63. Found: C,
51.23 H, 04.05; N, 16.57.
2-[N-(5-Chlorobenzothiazolyl)amino]pyridin-3-yl
(2,3-dichloropiperazine-1-yl)methanone 9f
IR (KBr) cm-1: 3466 (NH), 2924, 2848 (CH2), 1684
(C=O), 1615 (C=N aromatic), 1446 (C–S), 1099 (C–N
1
aliphatic); H NMR (DMSO-d6): d 2.22 (2H, t, –CH2N–,
2-[N-(6-Methylbenzothiazolyl)amino]pyridin-3-yl
(2,3-dichloropiperazine-1-yl)methanone 9j
piperazine), 2.44 (2H, t, –CH2N–, piperazine), 2.65 (1H, d,
–CHClN–), 2.85 (1H, d, –CHClN–), 8.38–6.86 (6H, m,
pyridine and Ar–H), 10.77 (2H, s, –NH–); MS: m/z: 441
(M?), 380, 366, 318, 291, 263, 184, 169, 152, 149, 143,
125, 111, 89, 77, 75, 63, 27; Anal. Calcd. for
C17H14ON5SCl3: C, 46.26; H, 03.20; N, 15.88. Found: C,
46.15; H, 03.15; N, 15.79.
IR (KBr) cm-1: 3442 (NH), 2937, 2854 (CH2), 1680
(C=O), 1611 (C=N aromatic), 1447 (C–S), 1092 (C–N
1
aliphatic); H NMR (DMSO-d6): d 2.21 (2H, t, –CH2N–,
piperazine), 2.36 (2H, t, –CH2N–, piperazine), 2.67 (1H, d,
–CHClN–), 2.86 (1H, d, –CHClN–), 8.44–6.89 (6H, m,
pyridine and Ar–H), 10.69 (2H, s, –NH–); MS: m/z: 421
(M?), 360, 346, 298, 271, 243, 164, 152, 149, 125, 123,
105, 91, 89, 77, 75, 63, 27; Anal. Calcd. for
C18H17ON5SCl2: C, 51.30; H, 04.07; N, 16.63. Found: C,
51.25; H, 04.03; N, 16.56.
2-[N-(6-Chlorobenzothiazolyl)amino]pyridin-3-yl
(2,3-dichloropiperazine-1-yl)methanone 9g
IR (KBr) cm-1: 3467 (NH), 2925, 2849 (CH2), 1683
(C=O), 1613 (C=N aromatic), 1448 (C–S), 1100 (C–N
1
aliphatic); H NMR (DMSO-d6): d 2.20 (2H, t, –CH2N–,
2-[N-(4-Methoxybenzothiazolyl)amino]pyridin-3-yl
(2,3-dichloropiperazine-1-yl)methanone 9k
piperazine), 2.45 (2H, t, –CH2N–, piperazine), 2.62 (1H, d,
–CHClN–), 2.86 (1H, d, –CHClN–), 8.43–6.87 (6H, m,
pyridine and Ar–H), 10.74 (2H, s, –NH–); MS: m/z: 441
(M?), 380, 366, 318, 291, 263, 184, 169, 152, 149, 143,
125, 111, 89, 77, 75, 63, 27; Anal. Calcd. for
C17H14ON5SCl3: C, 46.26; H, 03.20; N, 15.88. Found: C,
46.17; H, 03.16; N, 15.83.
IR (KBr) cm-1: 3465 (NH), 2919, 2856 (CH2), 1678
(C=O), 1619 (C=N aromatic), 1450 (C–S), 1090 (C–N
1
aliphatic); H NMR (DMSO-d6): d 2.10 (2H, t, –CH2N–,
piperazine), 2.48 (2H, t, –CH2N–, piperazine), 2.66 (1H, d,
–CHClN–), 2.90 (1H, d, –CHClN–), 8.43–6.87 (6H, m,
pyridine and Ar–H), 10.76 (2H, s, –NH–); MS: m/z: 437
(M?), 376, 362, 314, 287, 259, 180, 165, 152, 149, 139,
125, 121, 107, 89, 77, 75, 63, 27; Anal. Calcd. for
C18H17O2N5SCl2: C, 49.42; H, 03.92; N, 16.02. Found: C,
49.35; H, 03.90; N, 15.96.
2-[N-(4-Methylbenzothiazolyl)amino]pyridin-3-yl
(2,3-dichloropiperazine-1-yl)methanone 9h
IR (KBr) cm-1: 3441 (NH), 2936, 2856 (CH2), 1680
(C=O), 1618 (C=N aromatic), 1449 (C–S), 1090 (C–N
123

Med Chem Res (2011) 20:1033–1041
1041
Letafat B, Emami S, Negar M, Faramarzi M, Samadi N, Shafiee A,
Foroumadi A (2007) Synthesis and antibacterial activity of new
N-[2-(thiophen-3-yl)ethyl] piperazinyl quinolones. Chem Pharm
Bull 55:894–898
2-[N-(6-Methoxybenzothiazolyl)amino]pyridin-3-yl
(2,3-dichloropiperazine-1-yl)methanone 9l
IR (KBr) cm-1: 3465 (NH), 2916, 2855 (CH2), 1675
(C=O), 1617 (C=N aromatic), 1451 (C–S), 1092 (C–N
Mamolo MG, Zampieri D, Falagiani V, Vio L, Fermeglia M, Ferrone
M, Pricl S, Banfi E, Scialino
G (2004) Antifungal and
1
antimycobacterial activity of new N1-[1-aryl-2-(1H-imidazol-1-yl
and 1H–1,2,4-triazol-1-yl)-ethylidene]-pyridine-2-carboxamidra-
zone derivatives: a combined experimental and computational
approach. ARKIVOC v:231–250
aliphatic); H NMR (DMSO-d6): d 2.13 (2H, t, –CH2N–,
piperazine), 2.47 (2H, t, –CH2N–, piperazine), 2.65 (1H, d,
–CHClN–), 2.89 (1H, d, –CHClN–), 8.39–6.84 (6H, m,
pyridine and Ar–H), 10.75 (2H, s, –NH–); MS: m/z: 437
(M?), 376, 362, 314, 287, 259, 180, 165, 152, 149, 139,
125, 121, 107, 89, 77, 75, 63, 27; Anal. Calcd. for
C18H17O2N5SCl2: C, 49.42; H, 03.92; N, 16.02. Found: C,
49.38; H, 03.88; N, 15.95.
Mortimer CG, Wells G, Crochard J, Stone EL, Bradshaw TD, Stevens
MFG, Westwell AD (2006) Antitumor benzothiazoles. 26.1
2-(3,4-dimethoxyphenyl)-5-fluorobenzothiazole (GW 610, NSC
721648), a simple fluorinated 2-arylbenzothiazole, shows potent
and selective inhibitory activity against lung, colon, and breast
cancer cell lines. J Med Chem 49:179–185
Paronikyan EG, Noravyan AS, Dzhagatspanyan IA, Nazaryan IM,
Paronikyan RG (2002) Synthesis and anticonvulsant activity of
isothiazolo[5,4-B]pyrano (thiopyrano)[4,3-d]pyridine and iso-
thiazolo [4,5-b]-2,7-naphthyridine derivatives. Pharma Chem J
36:465–467
Patel NB, Bhagat PR (2001) Synthesis and antibacterial activity of 2-
(aryl thioureido)-3-[40-(40-p-nitrophenyl carbonyl)piperazin-10-yl
carbonyl]pyridine. Indian J Heterocycl Chem 11:77–78
Patel NB, Bhagat PR (2002) 2-[40-(p-acetamido phenyl carbonyl)
piperazin-10-yl]-3-(N-aryl thioureido carbonyl)pyridine as anti-
bacterial agents. Indian J Heterocycl Chem 12:83–84
Patel NB, Bhagat P (2006) Synthesis and antimicrobial studies on
fluoroquinolone with sulfonamides at C-3 and 4-(p-nitro-
benzoyl)piperazine at C-7 position. Indian J Heterocyl Chem
16:205–211
Acknowledgments The authors thank to the Head, Department of
Chemistry, VNSGU, Surat for providing necessary research facilities;
SAIF, Chandigarh for 1H NMR and mass spectra; and CDRI, Luc-
know for elementary analysis. Authors are also thankful to the Head
of Bioscience Department of VNSGU, Surat for biological screening.
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