2454 Brindha et al.
Asian J. Chem.
acetylcoumarin (3). It was then brominated using bromine in
acetic acid (0.01 mmol). The crystals of 3-bromoacetyl coumarin
(4) formed were collected, washed with minimum quantity of
glacial acetic acid, dried and recrystallized [19].
General procedure for the synthesis of 2-alkylamino-
4-(3-coumarinyl)thiazoles (5a-d):A solution of 3-bromoacetyl-
coumarin (0.005 mol) in hot ethanol was treated with alkyl-
thiourea (0.01 mol), a mild exothermic reaction giving a clear
solution that soon deposited as crystals. The crystals were
separated, washed with ethanol and boiled with water containing
sodium acetate, which yielded 2-alkylamino-4-(3-coumarinyl)-
thiazoles and the product obtained was recrystallized with
ethanol.
2-Ethylamino-4-(3-coumarinyl)thiazole (5a): Orange
solid, yield: 70 %; m.w.: 272 g/mol; IR (KBr, νmax, cm-1): 3130
(Ar-C-H), 1729 (C=O of lactone), 1555, 1488 (Ar C=C), 1450,
1401 (alkyl C-H), 1302 (C-N), 757 (C-S); 1H NMR (400 MHz,
DMSO-d6) δ: 8.893 (s, 1H, H1-coumarin), 8.012-8.082 (d, 1H,
H2-coumarin), 7.738-7.849 (m, 2H, H3 & H5-coumarin), 7.868-
7.991 (t, 1H, H4-coumarin), 8.974 (s, 2H, thiazole & -NH), 3.411-
3.463 (q, 2H, -CH2), 1.034-1.226 (t, 3H, -CH3); 13C NMR (400
MHz, CDCl3): 149.74, 135.45, 135.33, 130.76, 130.64, 125.59,
125.52, 122.52, 117.13, 50.24, 35.77; MS (ESI-MS) m/z: 273
(MH+).
2-Propylamino-4-(3-coumarinyl)thiazole (5b): Orange
solid, yield: 62 %; m.w.: 286 g/mol; IR (KBr, νmax, cm-1): 3251
(-NH-), 3043 (Ar- C-H), 1730 (C=O of lactone), 1487 (Ar C=C),
1451, 1370 (alkyl C-H), 1279 (C-N), 1217 (C-O), 757 (C-S);
1H NMR (400 MHz, DMSO-d6) δ: 8.740 (s, 1H, H1-coumarin),
7.994-8.013 (d, 1H, H2-coumarin), 7.393-7.546 (m, 2H, H3 &
H5-coumarin), 7.740-7.838 (t, 1H, H4-coumarin), 8.956 (s, 1H,
thiazole), 8.832 (s, 1H, -NH), 3.586-3.618 (m, 2H, -CH2), 1.152-
1.228 (m, 2H, -CH2), 1.036-1.071 (t, 3H, -CH3).
was obtained from Protein Data Bank (PDB code: 1KE9). The
docking study was performed using AutoDock Vina in PyRx
and Pymol for visualization.
RESULTS AND DISCUSSION
The synthesis of 2-alkylamino-4-(3-coumarinyl)thiazoles
was carried out as outlined in Scheme-I. The starting compound
of 3-acetylcoumarin was prepared by refluxing a mixture of
ethylacetoacetate and salicylaldehyde in ethanol in the presence
of a catalytic amount of piperidine, acetic acid and brominated
using bromine in acetic acid. The N-alkylthiourea was prepared
by heating the mixture of alkylamine, ammonium thiocyanate,
hydrochloric acid and water. 2-Alkylamino-4-(3-coumarinyl)-
thiazoles were synthesized by reaction of 3-bromoacetylcoumarin
with N-alkylthioureas in hot ethanol and crystals obtained were
boiled with water containing sodium acetate. The yields of
the final compounds (5a-d) ranged from 62 to 74 % after
recrystallization with ethanol. The purity of compounds were
checked throughout by thin layer chromatography (TLC).
O
O
CHO
OH
Piperidine
CH3COOH
+
O
3
Br in
O
O
O
1
2
CH3COOH
NHR
S
O
N
O
Br
NH2-CS-NHR
C2H5OH
O
O
O
4
5
2-Isopropylamino-4-(3-coumarinyl)thiazole (5c): Orange
brown solid, yield: 68 %; m.w.: 286 g/mol; IR (KBr, νmax, cm-1):
3042 (Ar-C-H), 2957 (alkyl C-H), 1730 (C=O of lactone), 1554
(Ar C=C), 1450, 1368 (alkyl C-H), 1302 (C-N), 1249 (C-O),
757 (C-S); 1H NMR (400 MHz, DMSO-d6) δ: 8.745 (s, 1H, H1-
coumarin), 8.035-8.095 (d, 1H, H2-coumarin), 7.400-7.535 (m,
2H, H3 & H5-coumarin), 7.745-7.831 (t, 1H, H4-coumarin), 8.965
(s, 1H, thiazole), 3.592 - 3.426 (m, 1H, -CH), 0.980-1.093 (d,
6H, -CH3), 8.832 (s, 1H, -NH).
2-Butylamino-4-(3-coumarinyl)thiazole (5d): Orange
brown solid, yield: 74 %; m.w.: 300 g/mol; IR (KBr, νmax, cm-1):
3130 (Ar-C-H), 1730 (C=O of lactone), 1554, 1487 (Ar C=C),
1449, 1369 (alkyl C-H), 1302 (C-N), 1181 (C-O), 757 (C-S);
1H NMR (400 MHz, DMSO-d6) δ: 8.692 (s, 1H, H1-coumarin),
7.970-8.009 (d, 1H, H2-coumarin), 7.408-7.507 (m, 2H, H3 &
H5-coumarin), 7.738-7.807 (t, 1H, H4-coumarin), 8.830 (s, 1H,
thiazole), 3.962-4.009 (q, 2H, -CH2), 1.556-1.630 (m, 2H, -CH2),
1.110-1.234 (m, 2H, -CH2), 1.033-1.068 (t, 3H, -CH3); 8.738
(s, 1H, -NH).
R = 5a - Ethyl, 5b - Propyl, 5c - Isopropyl & 5d - butyl
Scheme-I
The FT-IR, 1H NMR, 13C NMR and ESI-MS were used to
characterize the synthesized compounds. The spectral data
obtained were in good agreement with the proposed structures.
The FT-IR spectrum of the synthesized compounds showed
the presence of strong characteristic band at 3130-3042 cm-1
corresponding to the aromatic C-H stretching band. The band
at 1451-1368 cm-1 represents the alkyl C-H bending band. The
other prominent absorption bands observed in the IR spectrum
were 1730 (C=O), 1555 (Ar C=C) and 1370 cm-1 (C-N), respec-
tively.
The 1H NMR spectra recorded for these compounds clearly
supported the proposed structures. Thiazole protons of the
synthesized compounds were observed at 8.974, 8.956, 8.965
and 8.830 ppm respectively. All the other additional peaks
observed were in agreement with the protons on the corres-
ponding substituents and coumarin ring. The 13C NMR spectra
of the compounds confirmed the number of carbon atoms present
in the synthesized compounds. The ESI-MS spectrometric data
value is also in full accordance with the proposed structures.
The molecular docking studies of 2-alkylamino-4-(3-
coumarinyl)thiazoles were carried to identify binding affinity
and interactions between the ligand and the active site of target.
Molecular docking studies: The structures of 2-alkyl-
amino-4-(3-coumarinyl)thiazoles were modeled, optimized
and energy minimized using Gaussian 09 software. Ligand
selection depends on the compounds which are obeying Lipinski
rule of five. The optimized compounds were used to perform
molecular docking. The 3D structure of the molecular target