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Y. Xie et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
tion of compound 12 (0.66 g, 1.30 mmol) in dry CH2Cl2 was added
TiCl4 (290 L, 2.60 mmol). The mixture was stirred at room tem-
perature under the atmosphere of N2. The crude product was puri-
fied by column chromatography (chloroform-methanol, 60:1) to
yield T2 as light green solid (0.32 g, 58.18%). Mp: 151–153 °C. EI-
MS (m/z): 432.1 (M+). 1H NMR (400 MHz, DMSO-d6) d 10.07 (s,
1H, Ar-OH), 8.01 (d, 2H, J = 7.3 Hz, Ar0-H), 7.85 (t, 1H, J = 7.5 Hz,
Ar0-H), 7.69 (t, 2H, J = 7.9 Hz, Ar0-H), 7.61(d, 1H, J = 15.9 Hz, Ar-
CH = CH–), 7.60–7.50 (m, 2H, Ar-H), 6.82 (d, 2H, J = 8.6 Hz, Ar-H),
6.43 (d, 1H, J = 15.9 Hz, Ar-CH = CH–), 4.75–4.62 (m, 2H, –COOCH2-
Ar-H), 4.73 (d, 2H, J = 4.5 Hz, COOCH2CH2O), 4.58 (d, 2H,
l
J = 4.3 Hz, COOCH2CH2O) ppm. 13C NMR (101 MHz, DMSO-d6) d
165.94, 159.22, 151.19, 145.62, 137.70, 136.47, 130.32, 128.65,
122.53, 120.62, 116.96, 115.80, 110.91, 69.95, 61.99.
4.1.7. 4-(2-(2-(3,4-Dihydroxyphenyl)acetoxy)ethoxy)-3-
(phenylsulfonyl)-1,2,5-oxadiazole 2-oxide (T6)
Compound T6 was prepared following the procedure described
above. Mp: 125–127 °C. EI-MS (m/z): 436.1 (M+). 1H NMR
(400 MHz, DMSO-d6)
d 8.85 (s, 2H, Ar-OH), 8.01 (dd, 2H,
J1 = 8.5 Hz, J2 = 1.1 Hz, Ar0-H), 7.90 (t, 1H, J = 7.5 Hz, Ar0-H), 7.73
(t, 2H, J = 7.9 Hz, Ar0-H), 6.67 (d, 1H, J = 2.1 Hz, Ar-H), 6.65 (d, 1H,
J = 8.0 Hz, Ar-H), 6.50 (dd, 1H, J1 = 8.3 Hz, J2 = 2.1 Hz, Ar-H), 4.64–
4.59 (m, 2H, COOCH2CH2O), 4.42–4.38 (m, 2H, COOCH2CH2O),
CH2O–), 4.56–4.42 (m, 2H, –COOCH2CH2O–) ppm, 13C NMR
(101 MHz, DMSO-d6) d 166.84, 160.53, 159.19, 145.92, 137.68,
136.50, 130.90, 130.38, 128.78, 125.43, 116.33, 113.97, 110.94,
70.06, 61.68.
3.50 (s, 2H, ArCH2COO–) ppm. 13C NMR (101 MHz, DMSO-d6) d
171.93, 159.14, 145.57, 144.75, 137.63, 136.56, 130.41, 128.82,
125.14, 120.52, 117.23, 115.91, 110.93, 79.60, 69.78, 62.04.
4.1.4. (E)-4-(2-((3-(4-Hydroxy-3-methoxyphenyl)acryloyl)oxy)
ethoxy)-3-(phenylsulfonyl)-1,2,5-oxadiazole 2-oxide (T3)
Compound T3 was prepared following the procedure described
above. Mp: 130–132 °C. EI-MS (m/z): 462.1 (M+). 1H NMR
4.2. Biological evaluation
(400 MHz, DMSO-d6)
d 9.68 (s, 1H, Ar-OH), 8.01 (dd, 2H,
J1 = 8.4 Hz, J2 = 1.1 Hz, Ar0-H), 7.85 (t, 1H, J = 7.5 Hz, Ar0-H), 7.73–
7.66 (m, 2H, Ar0-H), 7.60 (d, 1H, J = 15.9 Hz, Ar-CH = CH–), 7.37
(d, 1H, J = 1.8 Hz, Ar-H), 7.15 (dd, 1H, J1 = 8.2 Hz, J2 = 1.8 Hz, Ar-
H), 6.82 (d, 1H, J = 8.2 Hz, Ar-H), 6.54 (d, 1H, J = 15.9 Hz, Ar-
CH = CH–), 4.74–4.63 (m, 2H, –COOCH2CH2O–), 4.56–4.47 (m, 2H,
–COOCH2CH2O–), 3.83 (s, 3H, Ar-OCH3) ppm, 13C NMR (101 MHz,
4.2.1. Antioxidant activity
The antioxidant activity of the newly synthetic compounds
were evaluated towards scavenging radicals (DPPHÅ and OHÅ) and
inhibiting lipid peroxidation.
4.2.1.1. DPPH radical scavenging activity. DPPHÅ is based on the
nitrogen atom as the center of the structure and can be existed sta-
bly in organic reagents.31 The absorption of the DPPHÅ solution
after addition of the antioxygen is reduced at the wavelength of
517 nm. An aliquot (0.5 mL) of 0.08 g/mL DPPHÅ solution was com-
bined with 0.5 mL anhydrous alcohol, pH 5.5 and 0.1 M acetate
sodium acetate buffer solution and 0.5 mL sample (antioxygen or
anhydrous alcohol reagent). After addition of each component,
the solution should be mixed well, then placed at r. t. for 30 min
in the dark. The absorption is monitored at 517 nm and the results
are expressed as follows:
DMSO-d6)
d 166.90, 159.22, 150.04, 148.46, 146.27, 137.66,
136.53, 130.41, 128.78, 125.94, 123.83, 116.03, 114.27, 111.66,
110.97, 69.98, 61.71, 56.16.
4.1.5. (E)-4-(2-((3-(3,4-Dihydroxyphenyl)acryloyl)oxy)ethoxy)-3-
(phenylsulfonyl)-1,2,5-oxadiazole 2-oxide (T4)
Compound 17 was prepared according to the literature proce-
dure.30 Compound 17 (0.72 g, 2.10 mmol) in DMF solution was
mixed with M1(0.50 g, 1.75 mmol), EDCI (0.60 g, 2.52 mmol),
DMAP (0.025 g, 0.21 mmol). The mixture was stirred at room tem-
perature for 8–12 h. The crude product was purified by column
chromatography (petroleum ether-ethyl acetate, 4:1) to yield 20
as light yellow oil (0.62 g, 48.43%). Compound 20 (0.62 g,
1.01 mmol) was dissolved in acetic acid-water (24 mL:6 mL). The
mixture was stirred at room temperature under the atmosphere
of N2. The crude product was purified by column chromatography
(chloroform-methanol, 90:1) to yield T4 as white solid (0.23 g,
51.11%). Mp: 154–156 °C. EI-MS (m/z): 448.1 (M+). 1H NMR
(400 MHz, DMSO-d6) d 9.64 (s, 1H, Ar-OH), 9.17 (s, 1H, Ar-OH),
8.05–7.97 (m, 2H, Ar0-H) 7.85 (t, 1H, J = 7.5 Hz, Ar0-H), 7.70 (t, 2H,
J = 7.9 Hz, Ar0-H), 7.53 (d, 1H, J = 15.9 Hz, Ar-CH = CHCOO–), 7.08
(d, 1H, J = 2.0 Hz, Ar-H), 7.04 (dd, 1H, J1 = 8.1 Hz, J2 = 2.0 Hz, Ar-H),
6.79 (d, 1H, J = 8.1 Hz, Ar-H), 6.30 (d, 1H, J = 15.9 Hz, Ar-
CH = CHCOO–), 4.72–4.64 (m, 2H, COOCH2CH2–), 4.54–4.47 (m,
DPPH radical scavenging activity ð%Þ ¼ ½ðAo ꢀ A1Þ=AoÞꢁ ꢂ 100
wherein Ao is the absorbance of the solvent control reaction and A1
is the absorbance of varying concentrations of samples. Each absor-
bance was corrected by using blank solution. All tests were per-
formed as parallel for three times.
4.2.1.2. Hydroxyl radical scavenging activity. The assay is based on
the reduction of ferrous ions while the color of solution change.32
Hydroxyl radicals were generated in the Fe2+-Phenanthroline-
H2O2 system (Fenton reaction). The reaction mixture contained
2.1 mM phenanthroline, 50 mM KH2PO4-NaOH buffer (pH 7.4),
2.1 mM freshly prepared FeSO4, 0.03% H2O2 (V/V), 100 mM ascor-
bic acid, solvent, and varying concentrations of tested target com-
pounds. The 10 mL tubes covering reaction solutions were
incubated for 60 min at 37 °C. After incubation, the absorbance
was measured at 536 nm against an appropriate blank group
(without target compounds replaced by an equal amount of dis-
tilled water). Hydroxyl radical scavenging percentage was evalu-
ated by comparing the test and blank solutions and the results
are calculated as follows:
2H, COOCH2CH2O–) ppm. 13C NMR (101 MHz, DMSO-d6) d 166.78,
159.20, 149.09, 146.32, 146.10, 137.68, 136.55, 130.42, 128.78,
125.85, 122.01, 116.26, 115.38, 113.77, 110.96, 69.95, 61.65.
4.1.6. 4-(2-((3,4-Dihydroxybenzoyl)oxy)ethoxy)-3-(phenylsulfonyl)-
1,2,5-oxadiazole 2-oxide (T5)
Hydroxyl radical scavenging activity ð%Þ
¼ ½1 ꢀ ðAs0 ꢀ As1Þ=ðAb0 ꢀ Ab1Þꢁ ꢂ 100:
Compound T5 was prepared following the procedure described
above. Mp: 145–147 °C. EI-MS (m/z): 422.0 (M+). 1H NMR
(400 MHz, DMSO-d6) d 9.91 (s, 1H, Ar-OH), 9.42 (s, 1H, Ar-OH),
7.96 (dd, 2H, J1 = 8.5 Hz, J2 = 1.1 Hz, Ar0-H), 7.82 (t, 1H, J = 7.5 Hz,
Ar0-H), 7.61 (t, 2H, J = 7.9 Hz, Ar0-H), 7.40 (d, 1H, J = 2.1 Hz, Ar-H),
7.33 (dd, 1H, J1 = 8.3 Hz, J2 = 2.1 Hz, Ar-H), 6.84 (d, 1H, J = 8.3 Hz,
wherein As0 is the absorbance of the sample reaction which not
contain the H2O2 solution and As1 is the absorbance of the sample
reaction which contains the H2O2 solution and Ab0 is the absorbance
of the control reaction which not contain the H2O2 solution and As1