Synthesis and antibacterial activity of hydrazone derivatives bearing 3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-ylsulfonyl)benzoicacid scaffold

Article abstract of DOI:10.14233/ajchem.2015.18877

The present work describes the synthesis and antibacterial activity of 3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-ylsulfonyl)benzohydrazide derivatives (7a-p) prepared from commercially available 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1). They were charac

Full text of DOI:10.14233/ajchem.2015.18877

Asian Journal of Chemistry; Vol. 27, No. 10 (2015), 3586-3590
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2015.18877
Synthesis and Antibacterial Activity of Hydrazone Derivatives Bearing
3-(6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-ylsulfonyl)benzoicacid Scaffold
1
1
GOWRISANKAR RAO KAKI1,2,*, B. SREENIVASULU , AMINUL ISLAM ,
1
2
2
DUSSA NAGESHWAR , RAGHUBABU KORUPOLU and B. VENKATESHWARA RAO
1Chemical Research and Development Department, APL Research Center, Aurobindo Pharma Ltd, Survey No: 71 and 72, Indrakaran Village,
Sangareddy Mandal, Medak District, Hyderabad-502 329, India
2Department of Engineering Chemistry, A.U. College of Engineering (A), Andhra University, Visakhapatnam-530 003, India
*Corresponding author: Tel/Fax: +91 891 284491; E-mail: gowrisankarkaki2014@gmail.com
Received: 25 November 2014;
Accepted: 2 January 2015;
Published online: 22 June 2015;
AJC-17308
The present work describes the synthesis and antibacterial activity of 3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-ylsulfonyl)benzohydrazide
1
derivatives (7a-p) prepared from commercially available 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1). They were characterized by H
NMR, IR and mass spectral analysis. The synthesized compounds 7a-p, were tested against Gram negative and Gram positive bacterial
strains viz; (i) Escherichia coli (MTCC 443), (ii) Pseudomonas aeruginosa (MTCC 424) (iii) Staphylococcus aureus (MTCC 96) and (iv)
Streptococcus pyogenes (MTCC 442) using agar well diffusion method. Compounds 7g (R = 2-OH, 4-OCHF2), 7h (R = 2-NO2), 7i (R =
3-NO2), 7j (R = 4-NO2) and 7n (4-OH) displayed excellent antibacterial activity (zone of inhibition: 25-32 mm) against both the Gram
positive and Gram negative bacterial strains. Compounds 7f (R = 2-F, 3-Cl), 7k (R = 2-OMe), 7l (R = 4-OMe), 7m (R = 4-OEt), 7o (R =
3-OMe), 7p (R = 3,4-OEt) showed good antibacterial activity (zone of inhibition: 19-26 mm).
Keywords: 4,5,6,7-Tetrahydrothieno[3,2-c]pyridine, 3-(Chlorosulfonyl)benzoicacid, Hydrazones,Antibacterial activity, Norfloxacin.
antimicrobial resistance, combined with the rapid rate of micro-
bial evolution and the slower development of novel antibiotics,
accents the crucial need for novel therapeutics. Development
of new antimicrobial or antipathogenic agents that act upon
new microbial targets is a necessity14.
Hydrazones possess an important class of biologically
active drug molecules15. Hydrazones16,17 having an azometine
-NHN=CH- portion are synthesized by heating the appropriate
substituted hydrazides with aldehydes in solvent. Hydrazone
derivatives possess anti-inflammatory18, anticonvulsant,
analgesic, anti-HIV, antimicrobial19-21, antibacterial22,23 and
antitumor properties24.
Inspired by the various biological activities associated with
hydrazone and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine
derivative, the present work is focused towards the synthesis
and antibacterial activity of 3-(6,7-dihydrothieno[3,2-c]pyridin-
5(4H)-ylsulfonyl)benzohydrazide derivatives (7a-p) prepared
from commercially available 4,5,6,7-tetrahydrothieno[3,2-
c]pyridine.
INTRODUCTION
4,5,6,7-Tetrahydrothieno[3,2-c]pyridine and its derivatives,
e.g. clopidogrel1 and ticlopidine2, are well recognized for their
non-cytotoxic and complement inhibition properties. A series
of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine have been evaluated
for their human phenylethanolamine-N-methyltransferase
inhibitory potency and affinity for the α2-adrenoceptor3. 4,5,6,7-
Tetrahydrothieno[3,2-c]pyridine derivatives are known as bio-
active molecules since very long time and are well known for
anti-inflammatory and analgesic agents4-8. They are used in
medicine as allosteric adenosine receptor modulators for uses
including protection against hypoxia and ischemia induced
injury and treatment of adenosine-sensitive cardiac arrhythmias9-11
.
Even though there has been a steadfast increase in resis-
tance to antimicrobial agents between important bacterial
pathogens throughout the world. It is well known that the number
of new antimicrobial agents being brought to the market had a
steady turn down in the past decades. The lack of interest by
pharmaceutical industry in antibacterial agents is related to
number of factors, including many generic antimicrobial agents
currently on the market that still have varying degrees of
usefulness and that are considered first lines of therapy by
many public health authorities12,13. The worldwide rise of
EXPERIMENTAL
Solvents and reagents were obtained from commercial
source and used without purification. The IR spectra (νmax
,
cm-1) were recorded in solid state KBr dispersion using Perkin

Vol. 27, No. 10 (2015)
Synthesis and Antibacterial Activity of Hydrazone Derivatives 3587
Elmer FT-IR spectrometer. The 1H NMR spectra was recorded
on Bruker-Avance 500 MHz spectrometer. The chemical shifts
were reported in δ/ppm relative to TMS. The mass spectra were
recorded on using a Perkin Elmer PE-SCIEX-API 2000 mass
spectrometer. The reactions were monitored by Thin-layer
chromatography (TLC). Melting points were determined on
Polman melting point apparatus (Model No MP96) by open
capillary method and are uncorrected. All the reactions were
carried out under nitrogen atmosphere.
cold ethanol followed by n-hexane to obtain the pure com-
pounds. Yields of the product varied between 80 and 90 %.
3-(6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-ylsulfonyl)-
N'-[(E)-phenylmethylidene]benzohydrazide (7a): Offwhite
solid; m.p.: 220-221 °C; IR (KBr, νmax, cm-1): 3436, 3223, 3067,
2908, 2841, 1643, 1603, 1557, 1490, 1476, 1466, 1449, 1426,
1399, 1366, 1348, 1322, 1311, 1296, 1272, 1240, 1203, 1172,
1146, 1086, 1061, 1035, 1023, 991, 968, 942, 891, 871, 851,
1
831, 807, 756, 743, 715, 691, 657; H NMR (500 MHz,
Synthesis of 3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-
ylsulfonyl)benzoic acid (3): To a solution of compound 1 (12.5
g, 71.42 mmol) in methanol (90 mL) was added triethylamine
(10.5 g, 103.78 mmol) followed by 3-(chlorosulfonyl)benzoic
acid (15 g, 68.181 mmol) at 20-25 °C and stirred for 4 h. After
completion of the reaction, the precipitated solid was filtered
at the pump and dried. The crude compound was recrystallized
from ethanol to obtain the pure compound 3. White solid,Yield:
18 g, 81 %; m.p.: 220-223 °C; 1H NMR (500 MHz, DMSO-
d6): δ 11.54 (s, 1H), 8.26 (t, J = 1.5 Hz, 1H), 8.22 (d, J = 1.5
Hz, 1H), 8.02 (d, J = 6.5 Hz, 1H), 7.76 (t, J = 8.5 Hz, 1H),
7.32 (d, J = 4.5 Hz, 1H), 6.86 (d, J = 5.5 Hz, 1H), 4.20 (brs,
2H), 3.42 (brs, 2H), 2.42 (brs, 2H).
Synthesis of methyl 3-(6,7-dihydrothieno[3,2-c]pyridin-
5(4H)-ylsulfonyl)benzoate (4): To a solution of compound 3
(15 g, 46.38 mmol) in methanol (100 mL) was added sulphuric
acid (1.66 mL) and refluxed for 5 h. After completion of the
reaction, methanol was evaporated under reduced pressure and
the obtained residue was taken in ethyl acetate (100 mL) and
washed with 10 % aquous NaHCO3 solution (2 × 35 mL)
followed by water and brine solution. The organic layer was
separated, dried over Na2SO4, filtered and evaporated to afford
compound 4. Off white solid, Yield: 14 g, 92 %; m.p.: 140-
143 °C.
Synthesis of 3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-
ylsulfonyl)benzohydrazide (5): To a solution of compound
4 (12 g, 35.56 mmol) in methanol (90 mL) was added hydrazine
hydrate (6.24 g, 124.86 mmol) and heated to 50 °C for 15 h.
After completion of the reaction, methanol was evaporated
under reduced pressure to obtain crude compound. The crude
compound was recrystallized from ethanol to obtain the pure
compound 5. Offwhite solid,Yield: 10 g, 83 %; m.p.: 175-178
°C; IR (KBr, νmax, cm-1): 3478, 3389, 3346, 3331, 3245, 3216,
3155, 3093, 3077, 3062, 2974, 2858, 1725, 1712, 1679, 1636,
1624, 1603, 1596, 1582, 1572, 1556, 1505, 1482, 1470, 1467,
1461, 1438, 1430, 1425, 1421, 1407, 1399, 1385, 1365, 1362,
1336, 1326, 1320, 1312, 1300, 1282, 1277, 1250, 1237, 1224,
1191, 1181, 1157, 1135, 1127, 1104, 1086, 1046, 1022, 1014,
991, 982, 968, 959, 943, 921, 917, 907, 856, 804, 754, 732,
659, cm-1; 1H NMR (500 MHz, DMSO-d6): δ 10.07 (s, 1H),
8.22 (t, J = 2.0 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.93 (t, J =
6.5 Hz, 1H), 7.70 (t, J = 8.5 Hz, 1H), 7.32 (d, J = 4.5 Hz, 1H),
6.84 (d, J = 5.5 Hz, 1H), 4.58 (brs, 2H), 4.20 (brs, 2H), 3.40
(brs, 2H), 2.84 (brs, 2H).
DMSO-d6): δ 12.05 (s, 1H), 8.48 (s, 1H), 8.32 (s, 1H), 8.20
(d, J = 9.0 Hz, 1H), 8.0 (d, J = 9.0 Hz, 1H), 7.79-7.73 (m, 3H),
7.47-7.43 (m, 3H), 7.30 (d, J = 7.0 Hz, 1H), 6.84 (d, J = 6.5
Hz, 1H), 4.21 (brs, 2H), 3.43 (brt, J = 7.5 Hz, 2H), 2.82 (brt,
J = 7.0 Hz, 2H); ESI-MS: m/z, 426.4 (M + H)+.
N'-[(E)-(2-Chlorophenyl)methylidene]-3-(6,7-dihydro-
thieno[3,2-c]pyridin-5(4H)-ylsulfonyl)benzohydrazide
(7b): Pale yellow solid; m.p.: 229-231 °C; IR (KBr, νmax, cm-1):
3449, 3186, 3068, 2919, 2845, 1658, 1594, 1551, 1463, 1442,
1431, 1413, 1400, 1367, 1348, 1312, 1298, 1281, 1239, 1218,
1200, 1175, 1166, 1145, 1125, 1086, 1068, 1046, 1030, 992,
975, 944, 896, 864, 851, 824, 775, 754, 738, 718, 701, 688,
664, 1H NMR (500 MHz, DMSO-d6): δ 12.28 (s, 1H), 8.88 (s,
1H), 8.34 (s, 1H), 8.22 (d, J = 9.5 Hz, 1H), 8.08-8.00 (m, 2H),
7.78 (t, J = 9.5 Hz, 1H), 7.54 (t, J = 9.5 Hz, 1H), 7.50-7.46 (m,
2H), 7.29 (d, J = 6.5 Hz, 1H), 6.84 (d, J = 6.5 Hz, 1H), 4.22
(brs, 2H), 3.43 (t, J = 7.5 Hz, 2H), 2.82 (brt, J = 7.0 Hz, 2H);
ESI-MS: m/z, 460.4 (M + H)+.
N'-[(E)-(3-Chlorophenyl)methylidene]-3-(6,7-dihydro-
thieno[3,2-c]pyridin-5(4H)-ylsulfonyl)benzohydrazide (7c):
Pale yellow solid; m.p.: 238-240 °C; IR (KBr, νmax, cm-1): 3443,
3216, 3059, 2908, 2856, 2323, 1656, 1614, 1601, 1558, 1475,
1458, 1431, 1415, 1402, 1363, 1352, 1324, 1312, 1299, 1278,
1240, 1223, 1202, 1299, 1278, 1240, 1223, 1202, 1176, 1151,
1131, 1099, 1083, 1024, 990, 975, 948, 920, 896, 880, 866,
1
828, 812, 791, 779, 754, 739, 728, 715, 688, 662; H NMR
(500 MHz, DMSO-d6): δ 12.19 (s, 1H), 8.46 (s, 1H), 8.32 (s,
1H), 8.20 (d, J = 9.5 Hz, 1H), 8.0 (d, J = 10.0 Hz, 1H), 7.80-
7.75 (m, 3H), 7.70 (brt, J = 3.5 Hz, 1H), 7.50 (brt, J = 5.5 Hz,
1H), 7.30 (d, J = 6.5 Hz, 1H), 6.84 (d, J = 6.5 Hz, 1H), 4.20
(brs, 2H), 3.43 (t, J = 7.5 Hz, 2H), 2.82 (brs, 2H); ESI-MS:
m/z, 460.4 (M + H)+.
N'-[(E)-(4-Chlorophenyl)methylidene]-3-(6,7-dihydro-
thieno[3,2-c]pyridin-5(4H)-ylsulfonyl)benzohydrazide
(7d): Pale yellow solid; m.p.: 210-212 °C; IR (KBr, νmax, cm-1):
3212, 3182, 3076, 3050, 2918, 2856, 1654, 1605, 1596, 1571,
1543, 1490, 1469, 1459, 1429, 1403, 1363, 1351, 1322, 1290,
1278, 1238, 1219, 1201, 1176, 1166, 1140, 1112, 1086, 1065,
1024, 1012, 990, 974, 955, 942, 894, 866, 851, 819, 774, 748,
738, 716, 695, 684, 663; 1H NMR (500 MHz, DMSO-d6): δ
12.13 (s, 1H), 8.40 (s, 1H), 8.32 (s, 1H), 8.20 (d, J = 10.0 Hz,
1H), 8.0 (d, J = 10.0 Hz, 1H), 7.79-7.76 (m, 3H), 7.52 (d, J =
11.0 Hz, 2H), 7.30 (d, J = 6.5 Hz, 1H), 6.84 (d, J = 6.5 Hz,
1H), 4.20 (brs, 2H), 3.43 (t, J = 7.5 Hz, 2H), 2.82 (brs, 2H);
ESI-MS: m/z, 460.4 (M + H)+.
General experimental procedure for the synthesis of
hydrazones derivatives (7a-p): To a stirred solution of com-
pound 5 (500 mg, 148.18 mmol) in ethanol (15 mL) was added
corresponding aromatic aldehydes 6a-p (1.03 mmol) and
heated to reflux for 12 h. After completion of the reaction, the
reaction mixture was cooled to 10 °C, filtered and washed with
N'-[(E)-(3-Bromophenyl)methylidene]-3-(6,7-dihydro-
thieno[3,2-c]pyridin-5(4H)-ylsulfonyl)benzohydrazide (7e):
Yellow solid; m.p.: 235-236 °C; IR (KBr, νmax, cm-1): 3108,
3092, 3086, 3055, 2975, 2968, 2947, 2908, 2879, 2855, 2409,
2346, 2003, 1656, 1604, 1600, 1587, 1556, 1496, 1475, 1464,

3588 Kaki et al.
Asian J. Chem.
1458, 1442, 1431, 1425, 1416, 1391, 1319, 1311, 1305, 1299,
1286, 1277, 1249, 1240, 1233, 1225, 1209, 1203, 1195, 1175,
1166, 1150, 1134, 1131, 1117, 1103, 1096, 1083, 1068, 1036,
1276, 1246, 1238, 1212, 1199, 1194, 1165, 1153, 1145, 1114,
1087, 1073, 1069, 1037, 1027, 1015, 991, 980, 976, 971, 960,
954, 943, 920, 914, 905, 897, 873, 867, 859, 827, 817, 810,
1
1
962, 954, 940, 873, 775, 660; H NMR (500 MHz, DMSO-
720, 650; H NMR (500 MHz, DMSO-d6): δ 12.32 (s, 1H),
d6): δ 12.19 (s, 1H), 8.44 (s, 1H), 8.32 (s, 1H), 8.21 (d, J = 9.0
Hz, 1H), 8.02 (d, J = 10.0 Hz, 1H), 7.94 (s, 1H), 7.79-7.54 (m,
2H), 7.62 (d, J = 10.0 Hz, 1H), 7.41 (t, J = 10.0 Hz, 1H), 7.30
(d, J = 6.5 Hz, 1H), 6.84 (d, J = 6.5 Hz, 1H), 4.20 (brs, 2H),
3.43 (t, J = 7.5 Hz, 2H), 2.82 (brs, 2H); ESI-MS: m/z, 504.2
(M + H)+.
8.60 (s, 1H), 8.33 (s, 1H), 8.28 (d, J = 8.5 Hz, 1H), 8.24 (d, J
= 9.0 Hz, 2H), 8.20 (d, J = 9.5 Hz, 1H), 8.01 (d, J = 10.0 Hz,
1H), 7.80-7.74 (m, 2H), 7.30 (d, J = 6.0 Hz, 1H), 6.84 (d, J =
6.5 Hz, 1H), 4.22 (brs, 2H), 3.44 (brt, J = 7.0 Hz, 2H), 2.82
(brs, 2H); ESI-MS: m/z, 469.5 (M-H)+.
3-(6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-ylsulfonyl)-
N'-[(E)-(4-nitrophenyl)methylidene]benzohydrazide (7j):
Pale yellow solid; m.p.: 239-240 °C; IR (KBr, νmax, cm-1): 3113,
3086, 3068, 3055, 2985, 2898, 2844, 2443, 1694, 1598, 1589,
1539, 1511, 1471, 1458, 1448, 1422, 1402, 1393, 1345, 1323,
1305, 1288, 1263, 1205, 1160, 1139, 1094, 1076, 1032, 1010,
989, 967, 945, 937, 896, 860, 833, 806, 771, 752, 741, 716,
707, 694, 680, 661; 1H NMR (500 MHz, DMSO-d6): δ 12.35
(s, 1H), 8.58 (s, 1H), 8.34-8.29 (m, 3H), 8.20 (d, J = 9.5 Hz,
1H), 8.03-8.0 (m, 3H), 7.78 (t, J = 10.0 Hz, 1H), 7.30 (d, J =
6.0 Hz, 1H), 6.84 (d, J = 6.0 Hz, 1H), 4.20 (brs, 2H), 3.43 (brt,
J = 7.0 Hz, 2H), 2.82 (brs, 2H); ESI-MS: m/z, 469.5 (M-H)+.
3-(6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-ylsulfonyl)-
N'-[(E)-(2-methoxyphenyl)methylidene]benzohydrazide
N'-[(E)-(3-Chloro-2-fluorophenyl)methylidene]-3-(6,7-
dihydrothieno[3,2-c]pyridin-5(4H)-ylsulfonyl)benzo-
hydrazide (7f): Pale yellow solid; m.p.: 235-236 °C; IR (KBr,
ν
max, cm-1): 3075, 3054, 2920, 2859, 2345, 1656, 1601, 1544,
1450, 1428, 1408, 1367, 1351, 1321, 1310, 1297, 1231, 120,
1173, 1148, 1137, 1110, 1085, 1065, 1024, 990, 974, 950,
941, 895, 882, 868, 822, 775, 747, 738, 731, 717, 704, 684,
663; 1H NMR (500 MHz, DMSO-d6): δ 12.28 (s, 1H), 8.71 (s,
1H), 8.34 (s, 1H), 8.22 (d, J = 9.5 Hz, 1H), 8.0 (d, J = 9.5 Hz,
1H), 7.91 (t, J = 8.5 Hz, 1H), 7.78 (t, J = 10.0 Hz, 1H), 7.70 (t,
J = 9.5 Hz, 1H), 7.35-7.31 (m, 2H), 6.84 (d, J = 6.0 Hz, 1H),
4.22 (brs, 2H), 3.42 (brs, 2H), 2.82 (brs, 2H); ESI-MS: m/z,
478.2 (M-H)+.
1
3-(6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-ylsulfonyl)-
N'-[(E)-(4-difluoromethoxy-2-hydroxyphenyl)methyli-
dene]benzohydrazide (7g): Pale yellow solid; m.p.: 170-172
°C; IR (KBr, νmax, cm-1): 3125, 3067, 2943, 2917, 28880, 2851,
2408, 2325, 1663, 1622, 1601, 1591, 1585, 1580, 1560, 1535,
1522, 1516, 1509, 1485, 1475, 1470, 1458, 1454, 1434, 1408,
1376, 1369, 1349 1331, 1312, 1293, 1284, 1260, 1240, 1220,
1168, 1155, 1130, 1068, 1052, 1004, 990, 968, 945, 903, 895,
886, 881, 855, 844, 839, 830, 825, 804, 787, 781, 740, 707,
662; 1H NMR (500 MHz, DMSO-d6): δ 12.02 (s, 1H), 10.20
(s, 1H), 8.34 (s, 1H), 8.32 (s, 1H), 8.20 (d, J = 10.0 Hz, 1H),
8.0 (d, J = 10.0 Hz, 1H), 7.76 (t, J = 9.0 Hz, 1H), 7.44 (d, J =
2.0 Hz, 1H), 7.23 (d, J = 6.5 Hz, 1H), 7.19-7.14 (m, 2H), 6.84
(d, J = 6.5 Hz, 1H), 4.20 (brs, 2H), 3.42 (t, J = 7.0 Hz, 2H),
2.48 (t, J = 7.0 Hz, 2H); ESI-MS: m/z, 508.0 (M + H)+.
3-(6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-ylsulfonyl)-
N'-[(E)-(2-nitrophenyl)methylidene]benzohydrazide (7h):
Yellow solid; m.p.: 233-234 °C; IR (KBr, νmax, cm-1): 3125,
3068, 2945, 2920, 2879, 2846, 2458, 2332, 2097, 2003, 1660,
1615, 1600, 1591, 1552, 1538, 1526, 1485, 1463, 1447, 1440,
1423, 1414, 1406, 1400, 1395, 1367, 1360, 1346, 1340, 1334,
1327, 1315, 1307, 1300, 1282, 1272, 1247, 1238, 1228, 1217,
1206, 1199, 1192, 1174, 1168, 1164, 1155, 1150, 1142, 1138,
1114, 1087, 1072, 1068, 1037, 1029, 1011, 993, 971, 946,
(7k): White solid; m.p.: 194-195 °C; H NMR (500 MHz,
DMSO-d6): δ 12.05 (s, 1H), 8.84 (s, 1H), 8.35 (s, 1H), 8.24
(d, J = 9.0 Hz, 1H), 7.98-7.94 (m, 1H), 7.88 (dd, J = 8.0, 10.0
Hz, 1H), 7.56 (t, J = 10.0 Hz, 1H), 7.40 (t, J = 10.0 Hz, 1H),
7.30 (d, J = 6.5 Hz, 1H), 7.10 (t, J = 10.5 Hz, 1H), 7.02 (t, J =
6.5 Hz, 1H), 6.84 (d, J = 6.5 Hz, 1H), 4.20 (brs, 2H), 3.86 (s,
3H), 3.42 (t, J = 7.5 Hz, 2H), 2.82 (brs, 2H); IR (KBr, νmax
,
cm-1): 3323, 3209, 3196, 3185, 3116, 3108, 3101, 3070, 3061,
3053, 2938, 2925, 2890, 2882, 2858, 2843, 2627, 2601, 2097,
1646, 1621, 1600, 1585, 1574, 1565, 1551, 1528, 1509, 1482,
1467, 1461, 1459, 1437, 1419, 1403, 1388, 1381, 1363, 1359,
1350, 1340, 1335, 1328, 1311, 1304, 1301, 1289, 1267, 1248,
1239, 1224, 12116, 1207, 1201, 1191, 1167, 1151, 1142, 11145,
ESI-MS: m/z, 456.0 (M + H)+.
3-(6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-ylsulfonyl)-
N'-[(E)-(4-methoxyphenyl)methylidene]benzohydrazide
(7l): White solid; m.p.: 225-227 °C; IR (KBr, νmax, cm-1): 3324,
3222, 3127, 3066, 3016, 3007, 2980, 2930, 2920, 2908, 2877,
2834, 2576, 2555, 2182, 2024, 1643, 1622, 1605, 1583, 1557,
1528, 1512, 1484, 1466, 1445, 1442, 1434, 1420, 1407, 1401,
1391, 1347, 1331, 1322, 1317, 1298, 1282, 1259, 1195, 1171,
1154, 1146, 1118, 1087, 1078, 1068, 1045, 1027, 1005, 990,
977, 969, 959, 942, 903, 891, 878, 863, 852, 829, 820, 807,
792.1H NMR (500 MHz, DMSO-d6): δ 11.92 (s, 1H), 8.42 (s,
1H), 8.31 (s, 1H), 8.20 (d, J = 9.5 Hz, 1H), 8.04-7.94 (m, 1H),
7.76 (d, J = 10.0 Hz, 1H), 7.68 (d, J = 10.5 Hz, 2H), 7.30 (t,
J = 6.5 Hz, 1H), 7.03 (d, J = 11.0 Hz, 2H), 6.84 (d, J = 6.5 Hz,
1H), 4.20 (brs, 2H), 3.80 (s, 3H), 3.42 (t, J = 7.5 Hz, 2H), 2.82
(t, J = 6.5 Hz, 2H); ESI-MS: m/z, 456.0 (M + H)+.
1
908, 897, 874, 862, 850, 770, 752, 711, 655; H NMR (500
MHz, DMSO-d6): δ 12.40 (s, 1H), 8.90 (s, 1H), 8.33 (s, 1H),
8.22 (d, J = 9.5 Hz, 1H), 8.14-8.08 (m, 2H), 8.01 (d, J = 10.0
Hz, 1H), 7.85-7.76 (m, 2H), 7.72-7.60 (m, 1H), 7.30 (d, J =
6.0 Hz, 1H), 6.84 (d, J = 6.5 Hz, 1H), 4.22 (brs, 2H), 3.44 (brt,
J = 7.0 Hz, 2H), 2.82 (brs, 2H); ESI-MS: m/z, 469.5 (M-H)+.
3-(6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-ylsulfonyl)-
N'-[(E)-(3-nitrophenyl)methylidene]benzohydrazide (7i):
Yellow solid; m.p.: 190-192 °C; IR (KBr, νmax, cm-1): 3124,
3070, 3062, 3041, 2971, 2961, 2939, 2923, 2881, 2856, 2039,
1661, 1622, 1607, 1588, 1537, 1487, 1463, 1445, 1438, 1421,
1414, 1406, 1400, 1394, 1349, 1329, 1313, 1306, 1300, 1285,
3-(6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-ylsulfonyl)-
N'-[(E)-(4-ethoxyphenyl)methylidene]benzohydrazide
(7m): Off white solid; m.p.: 240-243 °C; IR (KBr, νmax, cm-1):
3221, 3066, 2980, 2908, 1641, 1603, 1557, 1510, 1475, 1424,
1392, 1349, 1323, 1298, 1272, 1252, 1171, 1146, 1113, 1089,
1068, 1044, 991, 968, 942, 892, 862, 834, 808, 768, 743, 716,
1
686, 665; H NMR (500 MHz, DMSO-d6): δ 11.92 (s, 1H),

Vol. 27, No. 10 (2015)
Synthesis and Antibacterial Activity of Hydrazone Derivatives 3589
8.42 (s, 1H), 8.32 (s, 1H), 8.20 (d, J = 9.5 Hz, 1H), 8.04 (d, J
= 9.5 Hz, 1H), 7.76 (t, J = 9.5 Hz, 1H), 7.66 (d, J = 11.0 Hz,
2H), 7.30 (d, J = 6.5 Hz, 1H), 7.00 (d, J = 10.5 Hz, 2H), 6.84
(d, J = 6.5 Hz, 1H), 4.20 (brs, 2H), 4.08 (q, J = 8.0 Hz, 2H),
3.44 (t, J = 7.0 Hz, 2H), 2.82 (brt, J = 6.5 Hz, 2H), 1.34 (t, J =
8.0 Hz, 3H); ESI-MS: m/z, 470.4 (M + H)+.
3-(6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-ylsulfonyl)-
N'-[(E)-(4-hydroxyphenyl)methylidene]benzohydrazide
(7n): White solid; m.p.: 197-198 °C; IR (KBr, νmax, cm-1): 3228,
3066, 2931, 2906, 2845, 2693, 1642, 1604, 1584, 1562, 1514,
1452, 1426, 1400, 1367, 1347, 1322, 1298, 1240, 1172, 1146,
1087, 1064, 1031, 991, 973, 941, 894, 864, 833, 807, 768,
738, 713, 685, 666; 1H NMR (500 MHz, DMSO-d6): δ 11.85
(s, 1H), 9.94 (brs, 1H), 8.37 (s, 1H), 8.30 (s, 1H), 8.20 (d, J =
10 Hz, 1H), 7.98 (d, J = 10.0 Hz, 1H), 7.75 (t, J = 10.0 Hz,
1H), 7.56 (d, J = 10.0 Hz, 2H), 7.30 (d, J = 6.5 Hz, 1H), 6.84
(t, J = 6.0 Hz, 1H), 4.20 (brs, 2H), 3.42 (t, J = 7.0 Hz, 2H),
2.82 (t, J = 7.0 Hz, 2H); ESI-MS: m/z, 442.5 (M + H)+.
3-(6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-ylsulfonyl)-
N'-[(E)-(4-ethoxy-3-methoxyphenyl)methylidene]benzo-
N'-[(E)-(3,4-diethoxyphenyl)methylidene]-3-(6,7-dihy-
drothieno[3,2-c]pyridin-5(4H)-ylsulfonyl)benzohydrazide
(7p): Off white solid; m.p.: 178-179 °C; 1H NMR (500 MHz,
DMSO-d6): δ 11.92 (s, 1H), 8.38 (s, 1H), 8.30 (s, 1H), 8.18
(d, J = 10.0 Hz, 1H), 7.98 (dd, J = 9.5 Hz, 1H), 7.76 (t, J =
10.0 Hz, 1H), 7.31 (dd, J = 2.0, 11.5 Hz, 1H), 7.20 (dd, J =
2.5, 10.0 Hz, 1H), 7.03 (d, J = 10.5 Hz, 1H), 6.84 (d, J = 6.0
Hz, 1H), 4.20 (brs, 2H), 4.08 (q, J = 9.0 Hz, 4H), 3.42 (brt,
J = 7.0 Hz, 2H), 2.82 (t, J = 7.0 Hz, 2H), 1.35 (t, J = 9.0 Hz,
6H); ESI-MS: m/z, 513.63 (M + H)+.
Biological assay: The synthesized compounds 7a-p, were
tested against Gram negative and Gram positive bacterial
strains viz; (i) Escherichia coli (MTCC 443), (ii) Pseudomonas
aeruginosa (MTCC 424) (iii) Staphylococcus aureus (MTCC
96) and (iv) Streptococcus pyogenes (MTCC 442). The antibac-
terial activity of the compounds was carried out using agar
well diffusion method according to the literature protocol25,26
.
The compounds were dissolved in dimethylsulphoxide at 100
µg/mL concentrations and the standard antibacterial drug,
Norfloxacin was used as the reference antibiotic. The anti-
bacterial activity was determined by zones showing complete
inhibition (mm). Growth inhibition was calculated with
reference to positive control. All the samples were taken in
triplicates.
hydrazide (7o): White solid; m.p.: 220-221 °C; IR (KBr, νmax
,
cm-1): 3304, 3198, 3105, 3065, 3035, 3018, 3009, 2959, 2945,
2870, 2837, 2030, 1644, 1619, 1603, 1583, 1571, 1562, 1542,
1520, 1512, 1505, 1488, 1477, 1460, 1442, 1434, 1418, 1412,
1405, 1400, 1392, 1347, 1329, 1321, 1317, 1368, 1303, 1296,
1282, 1276, 1265, 1249, 1212, 1202, 1192, 1164, 1150, 1141,
1119, 1113, 1106, 1088, 1072, 1063, 1054, 1049, 1036, 1024,
1006, 990, 968. 1H NMR (500 MHz, DMSO-d6): δ 11.95 (s,
1H), 8.40 (s, 1H), 8.31 (s, 1H), 8.20 (d, J = 10.0 Hz, 1H),
7.98-7.94 (m, 1H), 7.76 (t, J = 10.0 Hz, 1H), 7.34 (d, J = 1.5
Hz, 1H), 7.30 (t, J = 6.0 Hz, 1H), 7.18 (dd, J = 2.5, 10.5 Hz,
1H), 7.02 (d, J = 10.5 Hz, 1H), 6.84 (d, J = 6.0 Hz, 1H), 4.20
(brs, 2H), 4.06 (q, J = 9.0 Hz, 2H), 3.82 (s, 3H), 3.40 (brt, J =
7.0 Hz, 2H), 2.82 (brs, 2H), 1.34 (t, J = 9.0 Hz, 3H); ESI-MS:
m/z, 500.1 (M + H)+.
RESULTS AND DISCUSSION
The synthetic sequence for the preparation of hydrazide-
hydrazone derivatives (7a-p) is shown in Scheme-I. The
starting material 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1)
is utilized as one of the key intermediate for the synthesis of
clopidogrel an antiplatelet drug27. Condensation of 4,5,6,7-
tetrahydrothieno[3,2-c]pyridine (1) with 3-(chlorosulfonyl)-
benzoic acid (2) in presence of triethylamine in methanol
resulted in the formation of 3-(6,7-dihydrothieno[3,2-
c]pyridin-5(4H)-ylsulfonyl)benzoic acid (3). The benzoic acid
CONHNH2
COOMe
COOH
COOH
HN
O
O
S
O
a
b
c
S
O
S
+
N
O
O
N
N
S
O
S
O
Cl
S
S
2
S
1
4
5
3
R
CHO
N
NH
O
7a: R = H; 7b: R = 2-Cl; 7c: R = 3-Cl; 7d: R = 4-Cl; 7e: R =3-Br
7f: R = 2-F, 3-Cl; 7g: R = 2-OH-4-OCHF2; 7h: R =2-NO2; 7i: 3-NO2
7j: R = 4-NO2; 7k: R = 2-OMe; 7l: R = 4-OMe; 7m: R = 4-OEt;
7n: R = 4-OH; 7o: R = 3-OMe, 4-OEt; 7p: R = 3, 4-OEt;
R
6a-6p
d
O
S
O
N
S
7a - 7p
Scheme-I: Synthesis of novel hydrazone derivatives (7a-p)

3590 Kaki et al.
Asian J. Chem.
(3) was converted to corresponding methyl ester derivative
3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-ylsulfonyl)benzoate
(4), which upon reaction with hydrazine hydrate in ethanol at
reflux led to the formation of the key intermediate 3-(6,7-dihydro-
thieno[3,2-c]pyridin-5(4H)-ylsulfonyl)benzohydrazide (5).
Coupling of benzohydrazide (5) with aromatic aldehydes (6a-
p) yielded hydrazo-hydrazide derivatives (7a-p). They were
characterized by 1H NMR, IR and mass spectral analysis. The
mass spectra of compounds showed (M + H) peaks, in agree-
ment with their molecular formula.
that, by further varying R substituent's in the main scaffold
may lead to promising antibacterial agents.
Conclusion
The present paper describes the synthesis and antibacterial
activity of 3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-ylsul-
fonyl)benzohydrazide derivatives (7a-p). The antibacterial
activity data revealed that the hydrazone derivatives with R =
2-OH, 4-CHF2, 2-NO2, 3-NO2, 4-NO2 and 4-OH, exhibited
excellent antibacterial activity while the compounds with R =
2-F, 3-Cl, 2-OMe, 4-OMe, 4-OEt, 3-OMe, 3,4-OEt showed
good antibacterial activity.
Experimental conditions: (a) Triethylamine, MeOH, 20-
25 °C, 4 h; (b) Conc; H2SO4, MeOH, reflux, 5 h; (c) NH2NH2.H2O,
methanol, 50 °C, 15 h; (d) benzaldehydes (6a-p), ethanol,
reflux, 12 h.
ACKNOWLEDGEMENTS
One of the authors (GS) thanks Dr. B. Ram, the Director,
Green Evolution Laboratories for his helpful suggestions.
Antimicrobial testing: Table-1 depicts the antibacterial
activity results. It is observed from the table that most of the
compounds (7a-p) showed significant antibacterial activity
against all the tested bacterial strains. Compounds 7g (R = 2-
OH, 4-OCHF2), 7h (R = 2-NO2), 7i (R = 3-NO2), 7j (R = 4-
NO2) and 7n (4-OH) displayed excellent antibacterial activity
(zone of inhibition: 25-32 mm) against both the Gram positive
and Gram negative bacterial strains. Compounds 7f (R = 2-F,
3-Cl), 7k (R = 2-OMe), 7l (R = 4-OMe), 7m (R = 4-OEt), 7o
(R = 3-OMe), 7p (R = 3,4-OEt) showed good antibacterial
activity (zone of inhibition: 19-26 mm) while the remaining
compounds 7a (R = H), 7b (R = 2-Cl), 7c (R = 3-Cl), 7d (R =
4-Cl), 7e (R = 3-Br) showed moderate antibacterial activity
(zone of inhibition: 14-22 mm). From the Table-1, it can be
generalized that the compounds incorporated with R = 2-OH,
4-CHF2, 2-NO2, 3-NO2, 4-NO2 and 4-OH, exhibited excellent
antibacterial activity while the compounds with R = 2-F, 3-Cl,
2-OMe, 4-OMe, 4-OEt, 3-OMe, 3,4-OEt showed good anti-
bacterial activity, from the above observations it can be stated
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TABLE-1
ANTIBACTERIAL ACTIVITY OF COMPOUNDS 7a-p
E. coli
MTCC
443
P. aeruginosa S. aureus S. pyogenes
Compound
No.
MTCC
424
Zone of inhibition in (mm)b
MTCC
96
MTCC
442
20
22
21
20
20
25
30
31
32
31
24
26
26
30
26
25
27
16
18
17
19
17
22
28
27
29
28
21
20
22
27
21
21
23
19
20
19
18
17
24
30
29
29
30
24
24
23
29
25
25
26
15
16
14
26
15
20
25
26
25
27
19
20
20
25
20
19
21
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
Norfloxacina
aConcentration: 100 µg/mL-1 of DMSO; bValues, including diameter of
the well (8 mm), are means of three replicates; cNo activity