Synthesis and antimicrobial studies of new pyridine derivatives

Article abstract of DOI:10.1007/s10593-010-0432-2

2-(p-Acetylaminobenzenesulfonylamido)-substituted benzothiazoles were prepared from 2-amino-substituted benzothiazoles and p-acetamidobenzenesulfonyl chloride using a mixture of pyridine and Ac₂O, which formed an electrophilic N-acetyl- pyridinium complex facilitating condensation to give the desired products by removal of HCl. 2-[4-(Substituted benzothiazol-2-yl) aminosulfonylanilino]pyridine-3-carboxylic acids (synthesized from 2-chloropyridine-3-carboxylic acid and the corresponding substituted 2-(p-aminobenzenesulfonylamido)benzothiazole in 2-ethoxyethanol using Cu-powder and K₂CO₃) were then converted to acid chlorides, which on further reaction with piperazine and 4-methoxyphenylpiperazine yielded the corresponding 2-[4-(substituted benzothiazol-2-yl)amino-sulfonyl]anilino-3- (piperazinocarbonyl) pyridine and 2-[4-(substituted benzothiazol-2-yl)amino- sulfonyl]anilino-3-[(4-methoxyphenyl)piperazin-1-yl-carbonyl]pyridine. The structures of the new compounds have been established on the basis of their elemental analyses as well as IR, ¹H NMR, and mass-spectral data. All the compounds have been screened for antimicrobial activity and found to possess considerable antibacterial activity.

Full text of DOI:10.1007/s10593-010-0432-2

Chemistry of Heterocyclic Compounds, Vol. 45, No. 11, 2009
SYNTHESIS AND ANTIMICROBIAL
STUDIES OF NEW PYRIDINE DERIVATIVES
N. B. Patel1* and S. N. Agravat1
2-(p-Acetylaminobenzenesulfonylamido)-substituted benzothiazoles were prepared from 2-amino-
substituted benzothiazoles and p-acetamidobenzenesulfonyl chloride using a mixture of pyridine and
Ac2O, which formed an electrophilic N-acetyl- pyridinium complex facilitating condensation to give the
desired products by removal of HCl. 2-[4-(Substituted benzothiazol-2-yl)aminosulfonylanilino]pyridine-
3-carboxylic acids (synthesized from 2-chloropyridine-3-carboxylic acid and the corresponding
substituted 2-(p-aminobenzenesulfonylamido)benzothiazole in 2-ethoxyethanol using Cu-powder and
K2CO3) were then converted to acid chlorides, which on further reaction with piperazine and
4-methoxyphenylpiperazine yielded the corresponding 2-[4-(substituted benzothiazol-2-yl)amino-
sulfonyl]anilino-3-(piperazinocarbonyl) pyridine and 2-[4-(substituted benzothiazol-2-yl)amino-
sulfonyl]anilino-3-[(4-methoxyphenyl)piperazin-1-yl-carbonyl]pyridine. The structures of the new
1
compounds have been established on the basis of their elemental analyses as well as IR, H NMR, and
mass-spectral data. All the compounds have been screened for antimicrobial activity and found to
possess considerable antibacterial activity.
Keywords: N- and ring-substituted 2-aminobenzothiazoles, 2-chloropyridine-3-carboxylic acid,
2-ethoxyethanol, piperazine, antimicrobial activity.
The role played by organic chemistry in the pharmaceutical industry continues to be one of the main
drivers in the drug discovery process. A pyridine nucleus played a central role in the development of different
medical agents such as antimicrobial [1], antiviral [2], anticancer [3], antidepressants, anti-inflammatory, and
analgesic [4]. 2-Aminobenzothiazole and its derivatives possess versatile activities like antibacterial [5],
antifungal [6], and antitubercular [7] activities. Piperazine and its derivatives show a wide range of biological
properties such as antiulcer [8], antidepressant [9], and antibacterial [10, 11].
Searching for new biologically active compounds, we have continued our previous work on
2-chloropyridine-3-carboxylic acid [12-15] with substituted benzothiazole in position 2 and piperazine in position 3
of the pyridine nucleus, encouraged by recent literature observations. The synthetic part of this work is presented in
Scheme 1.
1
Elemental analyses, IR, H NMR, and mass spectral studies characterized the constitution of the
compounds synthesized (Tables 1-3). Thus, the IR spectra of compounds 6a,c,g,h,k possess characteristic bands
around 3435 cm–1 for the N–H stretching, 3130-3070 cm–1 (broad) for the O–H stretching, 1680 cm–1 for
_______
* To whom correspondence should be addressed, e-mail: drnavin@satyam.net.in, snagravat@yahoo.co.in.
1Department of Chemistry, Veer Narmad South Gujarat University, Surat-395 007, Gujarat, India.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1672-1683, November, 2009.
Original article received January 6, 2007; revised version received August 25, 2009.
0009-3122/09/4511-1343©2009 Springer Science+Business Media, Inc.
1343

1
the carbonyl group, and 1450 cm–1 for the C–S stretching of thiazole. Their H NMR spectra indicated a broad
singlet around δ 13.6 ppm for COOH attached in position 3 of the pyridine ring and a sharp singlet around
8.5 ppm for the SO2NH.
Scheme 1
Hydrolysis
10% H2SO4
NHCOMe
20% NaOH
N
Pyridine
(MeCO)2O
N
SO2NH
S
MeCOHN
+
R
H2N
S
R
3a–1
SO2Cl
EtOCH2CH2OH
Cu-powder
K2CO3
1
2a–1
N
COOH
SO2NH
S
H2N
+
R
N
Cl
4a–1
5
COOH
NH
COCl
NH
SOCl2
N
N
SO2NH
S
SO2NH
7a–1
S
N
N
R
R
6a–1
HN
NR1
CO
NH
N
NR1
8, 9
N
N
SO2NH
10a–l, 11a–1
S
R
2−4, 6, 7, 10, 11 a R = H, b R = 4-NO2, c R = 5-NO2, d R = 6-NO2, e R = 4-Cl, f R = 5-Cl,
g R = 6-Cl, h R = 4-Me, i R = 5-Me, j R = 6-Me, k R = 4-OMe, l R = 6-OMe;
8, 10a-l R1 = H; 9, 11a-l R1 = 4-MeOC6H4
The structures were also proved by the mass spectra, which gave molecular ion peaks at m/z 426, 471,
460, 440, and 456 for 6a,c,g,h,k, respectively.
Acids 6a-l on a treatment (via acid chlorides) with piperazine (8) or 4-(4-methoxyphenyl)piperazine (9)
yielded compounds 10a-l and 11a-l, respectively. Their structures were also confirmed by spectral studies.
The absence of broad absorption bands for O−H stretching in the IR spectrum and the absence of a sharp
1
broad singlet for COOH in the H NMR spectrum confirmed the formation of new amide derivatives 10a-l and
11a-l. Their mass spectra contain peaks at m/z 494, 539, 528, 508, 524 for 10a,d,g,i,k and at m/z 600, 645, 638,
615, 630 for 11a,c,g,h,l, corresponding to their molecular ions, respectively. All the spectra showed a common
peak at m/z 78, corresponding to the pyridinyl cation (see mass spectral fragmentation pattern in
Schemes 2 and 3).
1344

TABLE 1. Characteristics of compounds 2a–l, 4a–l, 6a–l, 10a–l,and 11a–l
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C Yield, %
C
3
H
4
N
5
1
2a
2c
2
6
7
C7H6N2S
55.95
55.97
43.05
43.07
4.00
4.03
2.56
2.58
18.61
18.65
21.48
21.53
12.95
12.93
17.00
17.06
15.50
15.54
13.75
13.77
15.95
15.98
12.34
12.38
13.11
13.16
12.49
12.53
13.13
13.15
14.81
14.86
14.85
14.86
14.84
14.86
12.14
12.15
12.11
12.15
12.10
12.15
12.68
12.72
12.69
12.72
12.70
12.72
12.25
12.28
12.24
12.28
16.97
16.99
18.15
18.17
18.18
18.17
18.16
18.17
15.88
15.89
15.85
15.89
15.90
15.89
16.48
16.52
16.53
16.52
16.49
16.52
147
120
198
119
133
210
215
204
216
206
234
245
256
240
267
228
248
267
198
223
252
272
251
74
72
70
71
72
62
60
61
57
57
66
61
67
59
60
61
63
58
60
64
68
65
61
53
62
59
54
55
63
64
60
62
C7H5N3O2S
2g
2h
2l
C7H5ClN2O2S
C8H8N2S
38.79
38.81
58.50
58.51
53.27
53.31
2.30
2.33
4.89
4.91
4.42
4.47
C8H8N2OS
4a
4d
4g
4i
C13H11N3O2S2
C13H10N4O4S2
C13H10ClN3O2S2
C14H13N3O2S2
C14H13N3O3S2
C19H14N4O4S2
C19H13N5O6S2
C19H13N5O6S2
C19H13N5O6S2
C19H13ClN4O4S2
C19H13ClN4O4S2
C19H13ClN4O4S2
C20H16N4O4S2
C20H16N4O4S2
C20H16N4O4S2
C20H16N4O5S2
C20H16N4O5S2
C23H22N6O3S2
C23H21N7O5S2
C23H21N7O5S2
C23H21N7O5S2
C23H21ClN6O3S2
C23H21ClN6O3S2
51.10
51.13
44.50
44.55
45.94
45.96
52.63
52.65
50.11
50.14
53.49
53.52
48.35
48.40
48.38
48.40
48.36
48.40
49.49
49.52
49.47
49.52
49.50
49.52
54.50
54.54
54.48
54.54
54.49
54.54
52.58
52.63
52.60
52.63
55.81
55.85
51.16
51.20
51.18
51.20
51.17
51.20
52.20
52.22
52.17
52.22
3.59
3.63
2.81
2.87
2.94
2.97
4.08
4.11
3.86
3.90
3.30
3.31
2.77
2.78
2.74
2.78
2.75
2.78
2.79
2.84
2.80
2.84
2.78
2.84
3.60
3.65
3.64
3.65
3.59
3.65
3.49
3.53
3.50
3.53
4.44
4.48
3.88
3.92
3.90
3.92
3.87
3.92
3.98
4.00
3.96
4.00
4k
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
10a
10b
10c
10d
10e
10f
195
211
239
261
197
10g
10h
C23H21ClN6O3S2
C24H24N6O3S2
52.19
52.22
56.62
56.67
3.97
4.00
4.75
4.76
234
259
10i
10j
C24H24N6O3S2
C24H24N6O3S2
56.65
56.67
56.66
56.67
4.74
4.76
4.75
4.76
267
270
1345

TABLE 1 (continued)
1
10k
10l
2
3
4
5
6
7
C24H24N6O4S2
54.91
54.95
54.93
54.95
59.96
59.98
55.76
55.80
55.77
55.80
55.75
55.80
56.70
56.73
56.69
56.73
56.71
56.73
60.55
60.57
60.52
60.57
60.53
60.57
59.00
59.03
59.01
59.03
4.60
4.62
4.58
4.62
4.68
4.70
4.20
4.22
4.18
4.22
4.16
4.22
4.25
4.28
4.26
4.28
4.27
4.28
4.89
4.92
4.90
4.92
4.88
4.92
4.78
4.80
4.77
4.80
16.00
16.02
16.01
16.02
13.97
13.99
15.15
15.18
15.14
15.18
15.16
15.18
13.19
13.23
13.21
13.23
13.18
13.23
13.66
13.67
13.60
13.67
13.62
13.67
13.30
13.32
13.27
13.32
218
255
210
232
194
274
225
243
210
185
277
260
180
249
51
60
55
59
61
63
59
53
60
59
66
58
60
61
C24H24N6O4S2
C30H28N6O4S2
C30H27N7O6S2
C30H27N7O6S2
C30H27N7O6S2
C30H27ClN6O4S2
C30H27ClN6O4S2
C30H27ClN6O4S2
C31H30N6O4S2
C31H30N6O4S2
C31H30N6O4S2
C31H30N6O5S2
C31H30N6O5S2
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11k
11l
TABLE 2. IR spectra of compounds 2a,d,e,i,l, 4a,d,g,i,k, and 6a,c,g,h,k
Com-
pound
ν, cm–-1
1
2
2a
3424, 3252 (NH2), 1347 (C–N), 1652 (C=N), 1450 (Bt*)
2d
2e
2i
3455, 3228 (NH2), 1346 (C–N), 1655 (C=N), 1450 (Bt), 1563, 1322 (NO2, asym, sym)
3428, 3212 (NH2), 1648 (C=N), 1451 (Bt), 1337 (C–N), 752 (C–Cl)
3440, 3244 (NH2), 2966 (C–CH3), 1638 (C=N), 1448 (Bt), 1340 (C–N)
3420, 3242 (NH2), 1648 (C=N), 1446 (Bt), 1338 (C–N), 1240 (C–OCH3)
2l
4a
3429, 3218 (NH2), 1632 (C=N), 1444 (Bt), 1362 (S=O, asym), 1340 (C–N),
1150 (S=O, sym)
4d
4g
4i
3439, 3225 (NH2), 1637 (C=N), 1556, (NO2, asym), 1449 (Bt), 1366 (S=O, asym),
1344 (C–N), 1328 (NO2, sym), 1148 (S=O, sym)
3456, 3268 (NH2), 1632 (C=N), 1445 (Bt), 1360 (S=O, asym), 1337 (C–N),
1135 (S=O, sym), 760 (C–Cl)
3381, 3245 (NH2), 2975 (C–CH3), 1650 (C=N), 1454 (Bt), 1362 (S=O, asym),
1338 (C–N), 1144 (S=O, sym)
4k
6a
6c
3450, 3220 (NH2), 1629 (C=N), 1447 (Bt), 1368 (S=O, asym), 1335 (C–N),
1140 (S=O, sym), 1255 (C–OCH3)
3430, 3228 (NH str), 3135–3076 (OH, str, br.), 1690 (C=O), 1488 (C–N, C–C ring str),
1448 (Bt), 1362 (S=O, asym), 1344 (C–N str), 1148 (S=O, sym)
3430, 3235 (NH str), 3142–3030 (OH, str, br.), 1688 (C=O), 1477 (C–N, C–C ring str),
1451 (Bt), 1360 (S=O, asym), 1552, 1325 (NO2, asym, sym), 1345 (C–N str),
1138 (S=O, sym)
6g
6h
6k
3424, 3236 (NH str), 3136-3044 (OH, str, br.), 1685 (C=O), 1470 (C–N, C–C ring str),
1448 (Bt), 1358 (S=O, asym), 1344 (C–N str), 1142 (S=O, sym), 756 (C–Cl)
3432, 3224 (NH str), 3128–3078 (OH, str, br.), 2980 (C–CH3), 1680 (C=O),
1472 (C–N, C–C ring str), 1450 (Bt), 1355 (S=O, asym), 1345 (C–N str), 1150 (S=O, sym)
3422, 3228 (NH str), 3140–3026 (OH, str, br.), 1678 (C=O), 1475 (C–N, C–C ring str),
1450 (Bt), 1360 (S=O, asym), 1340 (C–N str), 1258 (C–OCH3), 1148 (S=O, sym)
1346

TABLE 2 (continued)
1
2
10a
10d
10g
10i
3433, 3298 (NH str), 2926, 2842 (C–H str), 1682 (Amide-I), 1490 (C–N, C–C),
1451 (Bt), 1345 (S=O, asym), 1290 (C–N Ar), 1166 (S=O, sym), 1100 (C–N al)
3428, 3308 (NH str), 2940, 2845 (C–H str), 1681 (Amide-I), 1488 (C–N, C–C),
1448 (Bt), 1350 (S=O, asym), 1290 (C–N Ar), 1166 (S=O, sym), 1102 (C–N al)
3422, 3300 (NH str), 2933, 2852 (C–H str), 1680 (Amide-I), 1488 (C–N, C–C), 1451 (Bt),
1348 (S=O, asym), 1288 (C–N Ar), 1165 (S=O, sym), 1098 (C–N al)
3430, 3311 (NH str), 2930, 2844 (C–H str), 1684 (Amide-I), 1492 (C–N, C–C), 1449 (Bt),
1352 (S=O, asym), 1282 (C–N Ar), 1169 (S=O, sym), 1094 (C–N al)
10k
11a
11c
11g
11h
11l
3431, 3318 (NH str), 2942, 2851 (C–H str), 1678 (Amide-I), 1482 (C–N, C–C), 1450 (Bt),
1355 (S=O, asym), 1284 (C–N Ar), 1170 (S=O, sym), 1092 (C–N al)
3418, 3315 (NH str), 2940, 2850 (C–H str), 1675 (Amide-I), 1484 (C–N, C–C), 1448 (Bt),
1350 (S=O, asym), 1279 (C–N Ar), 1161 (S=O, sym), 1099 (C–N al)
3420, 3322 (NH str), 2933, 2845 (C–H str), 1678 (Amide-I), 1487 (C–N, C–C), 1450 (Bt),
1346 (S=O, asym), 1280 (C–N Ar), 1165 (S=O, sym), 1100 (C–N al)
3429, 3295 (NH str), 2928, 2840 (C–H str), 1680 (Amide-I), 1486 (C–N, C–C), 1452 (Bt),
1348 (S=O, asym), 1286 (C–N Ar), 1164 (S=O, sym), 1098 (C–N al)
3436, 3318 (NH str), 2922, 2838 (C–H str), 1681 (Amide-I), 1494 (C–N, C–C), 1448 (Bt),
1353 (S=O, asym), 1283 (C–N Ar), 1165 (S=O, sym), 1096 (C–N al)
3427, 3310 (NH str), 2935, 2835 (C–H str), 1674 (Amide-I), 1480 (C–N, C–C), 1450 (Bt),
1351 (S=O, asym), 1288 (C–N Ar), 1168 (S=O, sym), 1100 (C–N al)
______
* Bt – benzothiazole.
TABLE 3. 1H NMR spectra of compounds 2a,d,e,i,l, 4a,d,g,i,k, and 6a,c,g,h,k
Com-
pound
δ, ppm
1
2
2a
8.05-7.58 (4H, m, H Ar), 5.71 (2H, s, NH2)
8.10-7.52 (3H, m, H Ar), 5.80 (2H, s, NH2)
8.00-7.48 (3H, m, H Ar), 5.76 (2H, s, NH2)
2d
2e
2i
8.08-7.50 (3H, m, H Ar), 5.78 (2H, s, NH2), 2.35 (3H, s, CH3)
8.12-7.60 (3H, m, H Ar), 5.71 (2H, s, NH2), 3.90 (3H, s, OCH3)
8.50 (IH, s, SO2NH), 7.947.10 (8H, m, H Ar), 5.75 (2H, s, NH2)
8.58 (IH, s, SO2NH), 8.00-7.15 (7H, m, H Ar), 5.78 (2H, s, NH2)
8.60 (IH, s, SO2NH), 7.967.12 (7H, m, H Ar), 5.76 (2H, s, NH2)
8.54 (IH, s, SO2NH), 8.007.16 (7H, m, H Ar), 5.80 (2H, s, NH2), 2.38 (3H, s, CH3)
21
4a
4d
4g
4i
4k
6a
6c
6g
6h
8.52 (1H, s, SO2NH), 7.927.00 (7H, m, H Ar), 5.74 (2H, s, NH2), 3.80 (3H, s, OCH,)
13.65 (IH, s, COOH), 10.68 (IH, s, NH), 8.50 (IH, s, SO2NH), 8.11-7.20 (11H, m, H Py*, Ar)
13.70 (IH, s, COOH), 10.74 (IH, s, NH), 8.58 (IH, s, SO2NH), 8.15-7.14 (10H, m, H Py, Ar)
13.65 (IH, s, COOH), 10.75 (IH, s, NH), 8.60 (IH, s, SO2NH), 8.20-7.24 (10H, m, H Py, Ar)
13.70 (IH, s, COOH), 10.70 (IH, s, NH), 8.58 (IH, s, SO2NH),
8.22-7.15 (10H, m, H Py, Ar), 2.40 (3H, s, CH3)
6k
13.77 (IH, s, COOH), 10.77 (IH, s, NH), 8.54 (IH, s, SO2NH),
8.21-7.18 (10H, m, H Py, Ar), 3.87 (3H, s, OCH3)
10a
l0d
10g
10i
10k
11a
10.60 (IH, s, NH), 9.25 (IH, s, NH), 8.58 (IH, s, SO2NH), 8.20-7.38 (11H, m, H Py, Ar),
3.20-2.94 (8H, m, P)
10.58 (IH, s, NH), 9.32 (IH, s, NH), 8.60 (IH, s, SO2NH), 8.22-7.35 (10H, m, H Py, Ar),
3.18-2.95 (8H, m, P)
10.62 (IH, s, NH), 9.34 (IH, s, NH), 8.64 (IH, s, SO2NH), 8.20-7.40 (10H, m, H Py, Ar),
3.15-2.90 (8H, m, P)
10.62 (IH, s, NH), 9.35 (IH, s, NH), 8.65 (IH, s, S02NH), 8.18-7.30 (10H, m, H Py, Ar),
3.22-2.92 (8H, m, P), 2.44 (3H, s, CH3)
10.60 (IH, s, NH), 9.33 (IH, s, NH), 8.58 (IH, s, SO2NH), 8.22-7.33 (10H, m, H Py, Ar),
3.90 (3H, s, OCH3), 3.20−2.92 (8H, m, P)
10.55 (IH, s, NH), 8.50 (IH, s, SOjNH), 8.16-7.40 (15H, m, Py, H Ar),
3.80 (3H, s, OCH3), 3.12−2.88 (8H, m, P)
1347

TABLE 3 (continued)
1
2
11c
11g
11h
11l
10.62 (IH, s, NH), 8.54 (IH, s, SOjNH), 8.187.38 (14H, m, Py, H Ar),
3.86 (3H, s, OCH3), 3.15-2.86 (8H, m, P)
10.58 (IH, s, NH), 8.58 (IH, s, S02NH), 8.157.30 (14H, m, Py, H Ar),
3.90 (3H, s, OCH3), 3.12-2.85 (8H, m, P)
10.54 (IH, s, NH), 8.52 (IH, s, S02NH), 8.187.38 (14H, m, Py, H Ar), 3.92 (3H, s, OCH3),
3.15-2.90 (8H, m, P), 2.48 (3H, s, CH3)
10.52 (IH, s, NH), 8.58 (IH, s, SO2NH), 8.207.32 (14H, m, Py, H Ar),
3.94 (3H, s, OCH3), 3.78 (3H, s, OCH3), 3.142.88 (8H, m, P)
______
* Py − pyridine, P − piperazine.
Scheme 2
+
.
COOH
NH
.
_
–H2O
[18]
N
Cl
[35.5]
Cl
S
C
SO2NH
N
m/z 460 (M+)
+
+
.
.
O
COOH
NH
N
N
.
S
SO2NH
N
S
SO2NH
N
N
m/z 442
m/z 424
_
.
CO
[28]
+
N
.
COOH
S
Cl
SO2NH
N
N
m/z 414
+
N
m/z 122
+
.
H
N
_
CO2
[44]
SO2
N
NH
S
Cl
N
H
m/z 416
_
SO2
[64]
+
.
N
_
H
+
.
.
_
Cl
[35.5]
HN
Cl
S
+
NH
N
N
m/z 184
m/z 78
m/z 170
_
_
.
N
HCN
[27]
NH
[15]
+
.
HN
S
NH
[15]
_
C2H2
[26]
m/z 149
+
+
C4H3
m/z 51
C6H5
m/z 77
.
_
CS [44]
C6H3NCl
m/z 125
N
.
_
CNS [58]
C6H3Cl
+
m/z 111
Cl
S
.
_
CN [26]
C6H3SCl
m/z 169
m/z 143
1348

Scheme 3
+
.
CO
N
NH
Me
_
+
.
N
N
NH
N
S
N
H
SO2NH
m/z 84
N
m/z 41
_
m/z 508 [M+]
N
CH
m/z 27
_
N
m/z 55
+
+
.
.
Me
Me
CO
N
CO
N
N
N
S
S
N
N
SO2NH
N
H
SO2NH
N
H
m/z 467
m/z 481
+
Me .
CO
N
CH2
N
N
_
N
SO2NH
S
_
N
H
N
m/z 55
m/z 453
m/z 41
_
N
CH
m/z 27
+
O
C
Me .
N
N
N
SO2NH
S
H
m/z 426
_
.
CO
[28]
+
.
Me
+
_
SO2
[64]
.
N
N
N
N
N
SO2NH
m/z 398
S
H
H
m/z 170
+
.
–
[15]
NH
N
m/z 78
+
+
.
Me
_
N
C6H5+
m/z 77
–CH3
[15]
HCN
[27]
N
HN
S
+
HN
S
C4H3
m/z 51
m/z 149
m/z 164
C7H6N
m/z 105
.
–
CS [44]
Me
_
N
.
CNS [58]
C7H6
m/z 91
+
_
.
S
CN [26]
m/z 149
C7H3S
m/z 123
The structure-activity relationship study of different pyridine derivatives revealed that the substitution of
pyridine in position 3 has a marked influence on antimicrobial activity. This concept inspired us to synthesize
compounds 10a-l and 11a-l, which were screened for antibacterial and antifungal activity against Gram-positive
bacteria Pseudomonas sp. and B. subtilis and Gram-negative Ceretium and E. coli and against fungi C. albicans
using a cup-plate method with DMF as a solvent [16]. The activity of compounds at 100 and 200 µg/ml
concentrations was compared with penicillin G, ampicillin, amoxicillin, and amphotericin B as standard drugs.
Table 5 summarizes the in vitro activity of new pyridine derivatives.
1349

TABLE 4. MS data of compounds 6a,c,g,h,k, 10a-l, and 11a-l
Com-
m/z
pound
6a
426 [M+], 408, 382, 380, 170, 150, 135, 122, 109, 91, 78, 77, 51
6c
471 [M+], 453, 427, 426, 425, 195, 180, 170, 154, 149, 136, 122, 78, 77, 51
460 [M+], 442, 424, 416, 414, 184, 170, 169, 149, 143, 125, 122, 111, 78, 77, 51
440 [M+], 426, 422, 396, 394, 170, 164, 149, 123, 122, 105, 91, 78, 77, 51
456 [M+], 438, 426, 412, 410, 180, 170, 165, 149, 139, 122, 121, 107, 78, 77, 51
494 [M+], 467, 453, 439, 412, 384, 170, 150, 135, 109, 91, 84, 78, 77, 55, 51, 41, 27
6g
6h
6k
10a
10d
539 [M+], 512, 498, 484, 457, 429, 195, 180, 170, 154, 149, 136, 122, 84, 78, 77, 55, 51,
41, 27
10g
528 [M+], 501, 487, 473, 446, 418, 184, 170, 169, 150, 143, 125, 111, 84, 78, 77, 55, 51,
41, 27
10i
508 [M+], 481, 467, 453, 426, 398, 170, 164, 149, 123, 105, 91, 84, 78, 77, 55, 51, 41, 27
10k
524 [M+], 497, 483, 469, 442, 414, 180, 170, 165, 149, 139, 121, 107, 84, 78, 77, 55, 51,
41, 27
11a
11c
11g
11h
11l
600 [M+], 494, 467, 453, 439, 412, 384, 192, 170, 150, 135, 109, 108, 91, 78, 77, 55, 51,
41, 27
645 [M+], 539, 512, 498, 484, 457, 429, 195, 192, 180, 170, 154, 149, 136, 122, 108, 78,
77, 55, 51, 41, 27
638 [M+], 528, 501, 487, 473, 446, 418, 192, 184, 170, 169, 150, 143, 125, 111, 108, 78,
77, 55, 51, 41, 27
615 [M+], 508, 481, 467, 453, 426, 398, 192, 170, 164, 149, 123, 108, 105, 91, 78, 77, 55,
51, 41, 27
630 [M+], 524, 497, 483, 469, 442, 414, 192, 180, 170, 165, 149, 139, 121, 108, 107, 78,
77, 55, 51, 41, 27
Compounds 10f,i,j,k, 11c,e,k displayed good activity against Pseudomonas sp; 10b,c,f,h,j,l, 11d,f,h −
against B. subtilis; 10a,h,i,j, 11e,f,l − against E. coli; 10e,g,k, 11c,h,l − against Ceretium when compared to
penicillin G and amoxicillin. Compounds 10f,j,l, 11e,h,k showed good activity against Pseudomonas sp;
10c,f,h,i,l, 11f,h − against B. subtilis; 10a,g,h,j,l, 11c,e,f − against E. coli, and 10e,k, 11d,h,k,l − against
Ceretium at a higher concentration. Compounds 10f,j, 11e,h,k were active against Pseudomonas sp; 10c,l, 11f,h −
against B. subtilis; 10e,k, 11h,l − against Ceretium; and 10h,j, 11f − against E. coli in both the dilutions. All the
compounds synthesized were sensitive against Gram-positive and Gram-negative bacteria.
Compounds 10g,j and 11g,l displayed good antifungal activity against C. albicans. Compounds 10g,j,l
and 11a,d,g,l showed a satisfactory antifungal activity at a higher concentration, while others were moderate to
less active.
Comparing these results with those of standard antibacterial and antifungal drugs, we concluded that
most of the compound show moderate activity in the above tests. Compounds 10c,f,j,l and 11c,f,h,l against
Gram-positive bacteria 10b,g,h,l and 11c,f,j,l against Gram-negative bacteria exhibited a higher value of
antibacterial activity as compared with other substituted derivatives. The compounds with unsubstituted or
chloro-substituted benzothiazole nucleus caused a good inhibition of C. albicans in both dilutions.
EXPERIMENTAL
Melting points were taken in open capillaries and are uncorrected. IR spectra were recorded on a Perkin-
1
Elmer-843 spectrometer using KBr pellets. H NMR spectra were scanned on a Bruker DPX-200 FT-NMR
spectrometer using TMS as an internal standard and DMSO-d6 as a solvent. The FAB mass spectra were
recorded on a JEOL SX 102/DA-6000 mass spectrometer using argon/xenon as the FAB gas. The samples were
routinely purified by crystallization from ethanol–benzene, 1:3.
1350

TABLE 5. Antimicrobial data of compounds 10 and 11
Activity (inhibition zone, mm), 100 and 200 µg/ml
Com-
pound
Antibacterial
Antifungal
Gram-positive
Pseudomonas sp. B. subtilis
Gram-negative
Ceretium E. coli
C. albicans
10a
10b
10c
10d
10e
10f
10g
10h
10i
4
3
6
5
7
8
2
5
8
8
7
12
11
4
2
2
8
2
8
9
7
1
2
8
10
3
16
5
2
3
1
1
7
11
5
2
4
2
5
—
5
1
—
8
2
6
10
7
15
10
11
7
2
11
3
9
13
12
3
8
12
5
—
7
—
6
—
11
9
4
—
8
8
13
15
10
17
4
—
9
15
13
11
7
3
9
2
10
15
9
7
3
6
8
1
8
10j
10k
10l
10
8
9
—
9
—
17
11
5
10
—
7
6
10
9
3
5
5
12
5
9
17
6
7
12
11
4
4
11
10
9
11a
11b
11c
11d
11e
11f
11g
11h
11i
2
3
3
8
5
3
3
3
5
1
6
3
1
8
11
5
7
8
8
10
12
4
7
13
4
—
5
1
2
8
11
—
15
10
13
3
7
—
8
10
2
8
12
7
—
8
3
12
16
7
1
3
2
4
10
3
—
6
1
—
7
1
7
—
10
3
3
11
9
13
4
10
2
15
4
3
5
5
2
—
7
3
1
1
11j
11k
7
10
12
8
3
3
2
4
8
5
8
8
—
7
1
7
12
13
22
1
3
2
8
11l
Penicil-
lin G
7
11
25
8
8
10
25
6
10
12
21
14
13
14
Ampi-
cillin
Amoxi-
cillin
15
13
28
24
17
16
30
29
18
15
31
27
18
16
30
28
Ampho-
tericin B
8
18
2-Amino-6-chlorobenzothiazole (2g) [5]. To glacial AcOH (20 ml) precooled to 5°C, ammonium
thiocyanate (0.08 mol) and p-chloroaniline (0.01 mol) were added. The mixture was placed into a freezing mixture of
ice and salt, mechanically stirred, while 1.6 ml of bromine in 6 ml of glacial AcOH was added from a dropping
funnel at such a rate that the temperature did not rise beyond 0°C. After all the bromine was added (105 min), the
solution was stirred at 0°C for an additional 2 h and at room temperature for 10 h. Then it was allowed to stand
overnight during which period an orange precipitate settled at the bottom, water (6 ml) was added quickly and the
slurry was heated at 85°C on a steam bath and filtered off while hot. The orange residue was placed into the reaction
flask and treated with 10 ml of glacial AcOH, heated again to 85°C and filtered off while hot. The combined filtrate
was cooled and adjusted to pH 6 with concentrated ammonia solution. The dark-yellow precipitate formed was
collected. Recrystallization from benzene (twice) after treatment with charcoal gave colorless plates of
chlorobenzothiazole 2g. Other compounds were prepared using the same method.
2-(p-Acetylaminobenzenesulfonylamino)-6-chlorobenzothiazole (3g) [6, 17]. Compound 2g was taken in
a mixture of pyridine (4 ml) and Ac2O (20 ml). To the solution formed, p-acetylaminobenzenesulfonyl chloride
(1) [18] (2.5 g, 0.01 mol) was added and the reaction mixture was kept on a water bath for 5 h, then filtered off
and poured onto acidic crushed ice. The solid product 3g obtained was recrystallized from ethanol.
1351

2-[4-(6-Chlorobenzothiazol-2-yl)aminosulfonylanilino]pyridine-3-carboxylic Acid (6g) [19]. A mixture
of 2-chloropyridine-3-carboxylic acid (5) (0.015 mol), 4-(p-aminobenzenesulfonylamino)-6-chloro-benzothiazole
(4g) [20] (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,
the precipitate formed was filtered off, and the resulting solution was acidified to pH 5 with diluted HCl, while
product 6g was precipitated. The latter was recrystallized from absolute alcohol. Similarly, other compounds can
be prepared by using the same method.
2-[4-(6-Chlorobenzothiazol-2-yl)aminosulfonyl]anilino-3-(piperazinocarbonyl)pyridine
(10g)
(Tables 2, 4) [21]. 2-[4-(6-Chlorobenzothiazol-2-yl)aminosulfonyl]anilinopyridine-3-carbonyl chloride (7g)
prepared from acid 6g by the method reported [22] was dissolved in pyridine (10 ml) and the solution was cooled in
an ice bath. To the stirred solution, fresh dried pyridine (5 ml) and piperazine (8) (0.01 mol) were successively
added in small portions. The mixture was warmed at 70°C for 1.5 h. After the reaction was completed the
solvent was removed by vacuum distillation. Crude product 10g was recrystallized from EtOH−benzene, 1:3.
Similarly, compounds 10a-f, h-l were prepared. 2-[(4-Substituted benzothiazol-2-yl)-2-aminosulfonyl]anilino-
3-[4-(4-methoxyphenyl)piperazin-1-ylcarbonyl]pyridines 11a–l were prepared by the same procedure using
4-(4-methoxyphenyl)piperazine (9).
The authors are grateful to the head of the Department of Chemistry for providing research facilities, SAIF,
Chandigarh for providing spectral data and CDRI, Lucknow for elemental analysis. The authors are also thankful to
the head of the Bioscience Department of VNSGU, Surat, for determining the antimicrobial activity.
REFERENCES
1.
2.
P. D. Bouzard, P. D. Cesare, C. Dussy, J. P. Jacquet, and A. Jaegly, J. Heterocycl. Chem., 29, 985 (1992).
O. Tabarrini, G. Manfroni, A. Fravolini, V. Cecchetti, S. Stefano, E. D. Clereq, J. Rozenski, B. Canard,
H. Dutarte, J. Paeshuyse, and J. Neyts, J. Med. Chem., 49, 2621 (2006).
3.
S. X. Cai, N. S. Jia, J. Herich, J. Guastella, S. Reddy, B. Tseng, J. Drewe, and S. Kasibhatla, J. Med.
Chem., 46, 2474 (2003).
4.
5.
J. A. Lowe, Austrian Pat. 388378; Chem. Abstr., 112, 21008 (1990).
B. M. Gurupadaiah, E. Jayachandran, B. ShivaKumar, A. N. Nagappa, and L. V. G. Nargund, Indian
J. Heterocycl. Chem., 7, 213 (1998).
6.
P. Gopkumar, B. Shivakumar, E. Jayachandran, A. N. Nagappa, L. V. G. Nargund, and
B. M. Gurupadaiah, Indian J. Heterocycl. Chem., 11, 39 (2001).
7.
8.
B. G. Khadse and S. R. Sengupta, Indian J. Chem., 32B, 407 (1993).
S. I. Ratzne, D. Bazsing, I. Jakozi, L. G. Kovanyine, G. Blasko, G. Siming, I. Gacsalyi, and E. Schmidt, PCT
Int. Appl. WO 97 44334 (1997); Chem. Abstr., 128, 34786 (1998).
9.
10.
R. C. Trpathi, P. R. Dua, R. C. Srimal, and A. K. Saxena, Indian J. Chem., 34B, 116 (1995).
K. Araki, T. Kuroda, S. Uemori, A. Morigucsi, Y. Ikeda, F. Hirayama, Y. Yokoyama, E. Iwao, and
T. Yakushiji, J. Med. Chem., 36, 1356 (1993).
11.
S. Seshadri, N. M. Sanghavi, K. V. Naik, S. K. Tawate, M. N. Trivedi, and M. A. Fruitwala, Indian
J. Chem., 32B, 688 (1993).
12.
13.
14.
15.
N. B. Patel and S. N. Agravat, Indian J. Heterocycl. Chem., 15, 395 (2006).
N. B. Patel and S. N. Agravat, Oriental J. Chem., 22, 333 (2006).
N. B. Patel and S. N. Agravat, J. Saudi Chem. Soc., 10, 373 (2006).
N. B. Patel and P. R. Bhagat, J. Indian Coun. Chem., 18, 56 (2001).
1352

16.
A. L. Barry, The Antimicrobial Susceptibility Test; Principles and Practices, Lea and Febiger,
Philadelphia, Pa, USA, 1976.
17.
18.
19.
S. R. Bhusare, R. P. Pawar, and Y. B. Vibhute, Indian J. Heterocycl. Chem., 11, 79 (2001).
A. I. Vogel, Small Scale Preparations, CBS Publ., Distributors, Delhi, 2nd ed., 1998, Pt I, p. 366.
J. A. Lowe III, R. L. Archer, D. S. Chapin, J. B. Cheng, D. Helweg, J. L. Johnson, B. K. Koe,
L. A. Lebel, P. F. Moore, J. A. Nielsen, L. L. Russo, and J. T. Shirley, J. Med. Chem., 34, 624 (1991).
A. I. Vogel, Small Scale Preparations, CBS Publ., Distributors, Delhi, 2nd ed., 1998, Pt II, p. 209.
M. Vlassa, J. Barbe, and P. Brounat, Indian J. Heterocycl. Chem., 7, 149 (1997).
20.
21.
22.
A. I. Vogel, Small Scale Preparations, CBS Publ., Distributors, Delhi, 2nd ed., 1998, Pt I, p. 345.
1353