N. M. Raghavendra et al. / Bioorg. Med. Chem. Lett. 22 (2012) 820–823
823
cmÀ1): 3270, 3030, 2901, 2878, 1685, 1600, 1567, 821; MS (API-ES) m/z for
Acknowledgments
C
15H20N4OS
(M+H)+
305.
N-(benzo[d]thiazol-2-yl)-2-(1,4-diazepan-1-
yl)acetamide (A3): Yield 30%, mp 227 °C; 1H NMR (400 MHz, DMSO-d6): d
1.25 (s, 1H), 1.96–2.10 (m, 2H, J = 7.3 Hz), 2.9–3.0 (m, 8H, J = 7.3 Hz), 3.45 (s,
We are thankful to DST (SR/FT/CS-079/2009) and AICTE (8023/
BOR/RID/RPS-102/2009-10) for providing molecular modelling
softwares and other financial assistance for this project. We also
thank Gokaraju Rangaraju Educational Society for providing labo-
ratory facilities and Laila Impex R&D Center, Vijaywada, Andhra
Pradesh, India for the spectral analysis.
2H), 7.3–7.8 (m, 4H, J = 7.4 Hz), 10.60 (br r, 1H); IR (KBr,
m
cmÀ1): 3323, 3049,
2883, 2823, 1697, 1600, 1529, 827; MS (API-ES) m/z for C14H18N4OS (M+H)+
291. N-(5-methoxybenzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide (B1):
Yield 26%, mp 119 °C; 1H NMR (400 MHz, DMSO-d6): d 1.3 (s, 1H), 3.82 (s,
8H), 3.88 (s, 3H), 4.29 (s, 1H), 7.11 (d, 1H, J = 7.4 Hz), 7.45 (d, 1H, J = 7.6 Hz),
7.69 (d, 1H, J = 7.5 Hz); IR (KBr,
m
cmÀ1): 3280, 3095, 2920, 2845, 1690, 1603,
1571, 823; MS (API-ES) m/z for C14H18N4O2S (M+H)+ 307. 2-(4-ethylpiperazin-
1-yl)-N-(5-methoxybenzo[d]thiazol-2-yl)acetamide (B2): Yield 23%, mp
212 °C; 1H NMR (400 MHz, DMSO-d6): d 1.2 (s, 3H), 2.0 (br r, 8H), 3.9 (s, 2H),
6.90 (d, 1H, J = 7.1 Hz), 7.1 (d, 1H, J = 7.5 Hz), 7.45 (d, 1H, J = 7.4 Hz), 7.5 (s, 1H);
Supplementary data
IR (KBr,
(API-ES) m/z for
m
cmÀ1): 3287, 3095, 2971, 2922, 2848, 1641, 1545, 1466, 821; MS
16H22N4O2S (M+H)+ 335. 2-(1,4-diazepan-1-yl)-N-(5-
Supplementary data associated with this article can be found, in
C
methoxybenzo[d]thiazol-2-yl)acetamide (B3): Yield 33%; mp 222 °C; 1H NMR
(400 MHz, DMSO-d6): d 0.8 (br r, 2H), 2.00 (q, 4H, J = 6.5 Hz), 2.9-3.04 (m, 4H),
3.45 (t, 2H), 3.89 (s, 3H), 7.01 (d, 1H, J = 7.3 Hz), 7.28 (d, 1H, J = 7.5 Hz), 7.68 (s,
m
cmÀ1): 3280, 3095, 2920, 2896, 2848, 1690, 1537, 1470, 820; MS
References and notes
1H); IR (KBr,
(API-ES) m/z for C15H20N4O2S (M+H)+ 321. N-(5-methoxybenzo[d]thiazol-2-yl)-
2-(4-phenylpiperazin-1-yl)acetamide (B4): Yield 36%, mp 199 °C; 1H NMR
(400 MHz, DMSO-d6): d 2.70 (s, 4H), 3.19 (s, 4H), 3.43 (s, 2H), 3.79 (s, 3H), 6.78
(t, 1H, J = 7.8 Hz), 6.96 (d, 2H, J = 7.3 Hz), 7.20 (t, 2H, J = 7.3 Hz), 7.58 (s, 1H),
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7.62–7.69 (m, 2H, J = 7.5 Hz), 11.9 (s, 1H); IR (KBr,
m
cmÀ1): 3261, 3088, 2987,
2931, 2824, 1699, 1540, 1501, 813; MS (API-ES) m/z for C20H22N4O2S (M+Na)+
405. N-(5-nitrobenzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide (C1): Yield
45%, mp 268 °C; 1H NMR (400 MHz, DMSO-d6): d 1.3 (s, 1H), 2.62–2.67 (m, 4H,
J = 8.5 Hz), 2.50 (s, 4H), 3.40 (s, 2H), 7.90 (d, 1H, J = 7.3 Hz), 8.30 (d, 1H,
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13H15N5O3S (M+H)+ 322. 2-(4-
1514, 1442, 848; MS (API-ES) m/z for
C
ethylpiperazin-1-yl)-N-(5-nitrobenzo[d]thiazol-2-yl)acetamide (C2): Yield
25%, mp 179 °C; 1H NMR (400 MHz, DMSO-d6): d 1.40 (t, 3H, J = 7.3 Hz), 3.10
(br r, 4H), 3.25 (q, 2H, J = 7.0 Hz), 3.40 (br r, 4H), 3.62 (s, 2H), 7.78 (d, 1H,
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J = 7.3 Hz), 8.25 (d, 1H, J = 7.3 Hz), 8.75 (s, 1); IR (KBr,
m
cmÀ1): 3402, 3170,
2876, 2831, 1705, 1573, 1506, 1442, 819; MS (API-ES) m/z for C15H19N5O3S
(M+H)+ 350. 2-(1,4-diazepan-1-yl)-N-(5-nitrobenzo[d]thiazol-2-yl)acetamide
(C3): Yield 38%, mp 229 °C; 1H NMR (400 MHz, DMSO-d6): d 1.1–1.3 (m, 2H,
J = 7.9 Hz), 2.0 (br r, 1H), 2.93–3.0 (m, 4H, J = 7.8 Hz), 3.6 (s, 4H), 3.85 (s, 2H),
7.69 (d, 2H, J = 7.5 Hz), 8.15 (d, 1H, J = 7.5 Hz), 8.8 (s, 1H); IR (KBr,
3394, 3170, 2918, 2878, 1708, 1573, 1500, 1448, 827; MS (API-ES) m/z for
m
cmÀ1):
C
14H17N5O3S
(M+H)+
334.
N-(5-nitrobenzo[d]thiazol-2-yl)-2-(4-
phenylpiperazin-1-yl)acetamide (C4): Yield 72%, mp 230 °C; 1H NMR
(400 MHz, DMSO-d6): d 2.80 (br r, 4H), 3.12 (s, 2H), 3.20 (br r, 4H), 6.9–7.1
(m, 3H, J = 7.0 Hz), 7.3–7.4 (m, 2H, J = 7.5 Hz), 8.1 (d, 2H, J = 7.3 Hz), 8.5 (s, 1H);
IR (KBr,
m
cmÀ1): 3311, 3040, 2916, 2864, 1651, 1570, 1516, 1442, 852; MS
(API-ES) m/z for C19H19N5O3S (M+H)+ 398.
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28. Molecular modelling and docking simulations: The X-ray crystal structure of
COX-2-naproxen complex (PDB code: 3NT1; resolution 1.73 Å) was optimized
by deleting the identical B chain of the protein and retaining respective A chain
for docking studies. Mislabelled atom types from the pdb file were corrected,
subsequently, proline F angles were fixed at 70°, side chain amides were
checked to maximize potential hydrogen bonding, side chains were checked
for close van der Waals contacts, and essential hydrogens were added. The
model was checked for conformational problems using the module ProTable
from Sybyl. Ramachandran plot29 of the backbone torsion angles PHI and PSI,
local geometry and the location of buried polar residues/exposed non-polar
residues were examined. The protein and synthesised compounds, including
naproxen and rofecoxib were subjected to energy minimization following the
gradient termination of the Powell method for 3000 iterations using Kollman
united force field with non-bonding cut-off set at 9.0 and the dielectric
constant set at 4.0.30,31 The synthesised compounds and the standard
compounds tested in this study were docked to COX-2 (PDB code: 3NT1)
using Surflex-Dock GeomX programme in Sybyl software by incremental
construction approach of building the structure in the active site so as to favour
the binding affinity.32,33 Finally, the docked ligands were ranked based on a
variety of scoring functions that have been compiled into the single consensus
score (C-score).34,35
16. Shashank, D.; Vishawanth, T.; Arif Pasha, Md.; Balasubramaniam, V.; Nagendra,
A.; Perumal, P.; Suthakaran, R. Int. J. Chem. Tech. Res. 2009, 1, 1224.
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Arch. Pharm. 2007, 340, 635.
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23. Synthesis of N-(benzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide analogs
(A1–C4):
A mixture of equimolar quantities of substituted 2-chloro-N-
(benzo[d]thiazol-2-yl)acetamides (A–C), various piperazine derivatives,
dioxane (10 ml) and triethylamine (0.2 ml) were heated at 100 °C with
stirring for 2–6 h. The reaction was monitored by TLC using mobile phase
petroleum ether/ethyl acetate (2:8). The excess of ethanol was removed by
distillation. To the residue add warm distilled water. The solid thus obtained is
filtered, washed with 5% NaHCO3 to remove excess acidic impurities, filtered,
washed and dried. The product obtained was recrystallized and further
purified by flash chromatograph.
29. Edsall, J. T.; Flory, P. J.; Kendrew, J. C.; Liquori, A. M.; Nemethy, G.;
Ramachandran, G. N.; Scheraga, H. A. J. Biol. Chem. 1966, 241, 1004.
30. Purcell, W.; Singer, J. A. J. Chem. Eng. Data. 1967, 12, 235.
31. Cieplak, P.; Cornell, W. D.; Bayly, C.; Kollman, P. A. J. Comput. Chem. 1995, 16,
1357.
24. Spectral data of N-(benzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide analogs
(A1–C4): N-(benzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide (A1): Yield
22%, mp 196 °C; 1H NMR (400 MHz, DMSO-d6): d 0.9 (br r, 1H), 1.2 (br r, 8H),
3.36 (s, 2H), 7.35 (d, 2H, J = 7.50 Hz), 7.67 (d, 2H, J = 7.50 Hz), 7.9 (br r, 1H); IR
(KBr,
m
cmÀ1): 3282, 3060, 2872, 2848, 1690, 1600, 1533, 842; MS (API-ES) m/z
32. Leach, A. R.; Kuntz, I. J. Comput. Chem. 1992, 13, 730.
for C13H16N4OS (M+H)+ 277. N-(benzo[d]thiazol-2-yl)-2-(4-ethylpiperazin-1-
yl)acetamide (A2): Yield 28%, mp 132 °C; 1H NMR (400 MHz, DMSO-d6): d 1.12
(t, 3H, J = 7.0 Hz), 2.3 (q, 2H, J = 6.8 Hz), 2.7 (br r, 8H), 3.33 (s, 2H), 5.5 (br r, 1H),
33. Rarey, M.; Kramer, B.; Lengauer, T. J. Comput.-Aided Mol. Des. 1997, 11, 369.
34. Rarey, M.; Kramer, B.; Lengauer, T.; Klebe, G. A. J. Mol. Biol. 1996, 261, 470.
35. Jones, G.; Willett, P.; Glen, R.; Leach, A. R.; Taylor, R. J. Mol. Biol. 1997, 267, 727.
7.0 (d, 1H, J = 7.4 Hz), 7.15 (t, 1H, J = 7.5 Hz), 7.58 (d, 2H, J = 7.3 Hz); IR (KBr,
m