Design, synthesis, and in vitro evaluation of epigoitrin derivatives as neuraminidase…
166.63, 164.60, 134.55, 133.79, 132.28, 129.65, 129.06,
127.92, 124.18, 115.62, 61.12, 48.44 ppm; IR (KBr):
J = 8.5 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), 6.61 (d,
J = 15.5 Hz, 1H), 6.05 (dd, J = 15.5, 9.0 Hz, 1H), 4.87–
4.83 (m, 1H), 4.63–4.59 (m, 1H), 4.52–4.48 (m, 1H), 3.91
(s, 3H), 3.85 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3):
d = 197.30, 164.50, 160.08, 134.38, 133.84, 131.64,
128.04, 120.75, 115.10, 114.20, 114.01, 61.76, 55.76,
55.34, 48.07 ppm; IR (KBr): mꢀ = 3010, 2922, 1785, 1685,
1586, 1488, 1330, 1291, 1211, 980/cm; HRMS: m/z calcd
for C19H19NO5S2K ([M?K]?) 444.0336, found 444.0346.
ꢀ
m = 3000, 2922, 1785, 1685, 1586, 1488, 1330, 1291, 1211,
880/cm; HRMS: m/z calcd for C18H13ClFNO2SK
([M?K]?) 399.9971, found 400.0004.
(E)-3-[[4-(Benzyloxy)phenyl]sulfonyl]-5-styryloxazolidine-2-
thione (27, C24H21NO4S2) White solid; 72% yield in four
steps; m.p.: 119–120 °C; Rf = 0.73 (hexane/EtOAc = 4:1);
1H NMR (500 MHz, CDCl3): d = 8.03 (d, J = 9.0 Hz, 2H),
7.45–7.43 (m, 4H), 7.41–7.35 (m, 5H), 7.33 (d,
J = 15.5 Hz, 1H), 7.08 (d, J = 8.5 Hz, 2H), 6.67 (d,
J = 15.5 Hz, 1H), 6.22 (d, J = 15.5, 9.0 Hz, 1H), 5.15 (s,
2H), 4.87–4.84 (m, 1H), 4.64–4.59 (m, 1H), 4.55–4.51 (m,
1H) ppm; 13C NMR (125 MHz, CDCl3): d = 197.05,
163.68, 135.54, 135.24, 134.87, 131.67, 128.81, 128.78,
128.72, 128.50, 128.09, 127.55, 126.74, 123.20, 114.81,
(E)-5-(4-Chlorostyryl)-3-[(4-methoxyphenyl)sulfonyl]oxazo-
lidine-2-thione (31, C18H16ClNO4S2) Yellow solid; 65%
yield in four steps; m.p.: 129–131 °C; Rf = 0.33 (hexane/
1
EtOAc = 4:1); H NMR (500 MHz, CDCl3): d = 8.06 (d,
J = 8.5 Hz, 2H), 7.38–7.32 (m, 4H), 7.04 (d, J = 8.5 Hz,
2H), 6.65 (d, J = 15.5 Hz, 1H), 6.25–6.20 (m,1H), 4.89–
4.85 (m, 1H), 4.63–4.55 (m, 2H), 3.94 (s, 3H) ppm; 13C
NMR (125 MHz, CDCl3): d = 196.74, 164.56, 134.48,
133.74, 133.49, 131.64, 128.98, 127.93, 127.81, 124.02,
ꢀ
70.57, 61.63, 47.76 ppm; IR (KBr): m = 2922, 1785, 1685,
1586, 1488, 1330, 1291, 1211/cm; HRMS: m/z calcd for
C24H21NO4S2K ([M?K]?) 490.0543, found 490.0565.
ꢀ
114.03, 61.53, 55.77, 47.49 ppm; IR (KBr): m = 3000,
2922, 1785, 1685, 1586, 1488, 1330, 1291, 1211, 980/cm;
HRMS: m/z calcd for C18H16ClNO4S2K ([M?K]?)
447.9840, found 447.9856.
(E)-3-[(4-Fluorophenyl)sulfonyl]-5-styryloxazolidine-2-
thione (28, C17H14FNO3S2) Yellow solid; 69% yield in
four steps; m.p.: 85–87 °C; Rf = 0.28 (hexane/EtOAc =
4:1); 1H NMR (500 MHz, CDCl3): d = 8.13–8.10 (m,
2H), 7.39–7.38 (m, 5H), 7.25–7.22 (m, 2H), 6.69 (d,
J = 15.5 Hz, 1H), 6.22 (dd, J = 15.5, 9.0 Hz, 1H), 4.89–
4.85 (m, 1H), 4.67–4.63 (m, 1H), 4.56–4.52 (m, 1H) ppm;
13C NMR (125 MHz, CDCl3): d = 196.95, 167.33, 165.28,
134.58, 133.79, 132.47, 132.28, 129.03, 127.96, 123.62,
Ligand preparation
The structures of compounds were built by SYBYL 2.0
[30]. Then, all compounds were energy minimized using
the Tripos force field by the Powell gradient algorithm
(Gasteiger–Hu¨ckel charges) [31]. The energy gradient
ꢀ
116.35, 61.44, 47.72 ppm; IR (KBr): m = 3000, 2922,
˚
criterion was set up 20.9 J/mol A and the maximum iter-
1785, 1685, 1586, 1488, 1330, 1291, 1221, 980/cm;
HRMS: m/z calcd for C17H14FNO3S2K ([M?K]?)
402.0030, found 402.0047.
ations were set at 10000.
CoMFA and CoMSIA modeling
Methyl (E)-4-[5-(4-chlorostyryl)-2-thioxooxazolidine-3-car-
bonyl]benzoate (29, C20H16ClNO4S) Yellow solid; 68%
yield in 4 steps; m.p.: 155–156 °C; Rf = 0.37 (hexane/
The energy minimized conformations were aligned and 21
Xu’s compounds were sorted into training set and test set
randomly to build CoMFA and CoMSIA models, and then,
the final CoMFA and CoMFSIA models were selected
based on statistical parameters. The 3D contour maps of
CoMFA and CoMFSIA models were graphed using the
SYBYL 2.0 program.
1
EtOAc = 4:1); H NMR (500 MHz, CDCl3): d = 8.09 (d,
J = 8.5 Hz, 2H), 7.75 (d, J = 8.5 Hz, 2H), 7.36 (s, 4H),
6.72 (d, J = 15.5 Hz, 1H), 6.31 (dd, J = 15.5, 8.5 Hz, 1H),
4.78–4.74 (m, 1H), 4.72–4.68 (m, 1H), 4.51–4.47 (m, 1H),
3.96 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3):
d = 201.34, 170.44, 166.15, 137.79, 135.27, 134.91,
133.32, 129.58, 129.14, 128.87, 128.80, 126.76, 123.30,
Molecular docking
ꢀ
60.96, 52.49, 48.82 ppm; IR (KBr): m = 3000, 2922, 1785,
1685, 1586, 1488, 1330, 1291, 1211, 880/cm; HRMS: m/z
calcd for C20H16ClNO4SK ([M?K]?) 440.0120, found
440.0161.
The X-ray crystal structure of neuraminidase was retrieved
waters and the original bound ligands were removed from
the protein prior to the docking process, and the protein
was prepared using Biopolymer module implemented in
SYBYL. Each docking generated 20 conformations [32]
(E)-3-[(4-Methoxyphenyl)sulfonyl]-5-(4-methoxystyryl)oxa-
zolidine-2-thione (30, C19H19NO5S2) White solid; 67%
yield in four steps; m.p.: 79–80 °C; Rf = 0.35 (hexane/
1
EtOAc = 4:1); H NMR (500 MHz, CDCl3): d = 8.03 (d,
J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.01 (d,
123