Journal of Medicinal Chemistry
ARTICLE
J = 10.8 Hz), 7.76 (s, 2H), 7.59 (d, 2H, J = 8.4 Hz), 7.16 (d, 2H, J = 8.4
Hz), 4.86 (s, 2H), 2.53 (s, 3H). MS (ESI), m/z: 395.26 [ M - H]-.
(Z)-N-Cyclohexyl-2-(4-((2,4-dioxothiazolidin-5-ylidene)
methyl)phenoxy)acetamide (3Q). Yield 78.3%; analytical HPLC
purity = 98.61%; light-yellow solid. H NMR (400 MHz, DMSO-d6):
1
(Z)-2-(4-((2,4-Dioxothiazolidin-5-ylidene)methyl)pheno-
xy)-N-(3-fluorophenyl)acetamide (3G). Yield 73.7%; analytical
HPLC purity = 99.11%; white solid. 1H NMR (400 MHz, DMSO-d6):
δ 12.53 (s, 1H), 10.33 (s, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.58 (d, 2H, J =
8.4 Hz), 7.52 (d, 1H, J = 8.4 Hz), 7.36 (t, 1H, J = 8.0 Hz), 7.15 (d, 3H, J =
8.4 Hz), 4.82 (s, 2H). MS (ESI), m/z: 371.01 [M - H]-.
(Z)-2-(4-((2,4-Dioxothiazolidin-5-ylidene)methyl)pheno-
xy)-N-(4-fluorophenyl)acetamide (3H). Yield 71.8%; analytical
HPLC purity = 99.40%; yellow solid. 1H NMR (400 MHz, DMSO-d6):
δ 12.54 (s, 1H), 10.21 (s, 1H), 7.76 (s, 1H), 7.67-7.63 (m, 2H), 7.59
(d, 4H, J = 8.8 Hz), 7.17 (t, 2H, J = 8.4 Hz), 4.80 (s,2H). MS (ESI), m/z:
372.06 [M - H]-.
(Z)-N-(3-Chlorophenyl)-2-(4-((2,4-dioxothiazolidin-5-yli-
dene)methyl)phenoxy)acetamide (3I). Yield 92.8%; analytical
HPLC purity = 98.53%; white solid. 1H NMR (400 MHz, DMSO-d6): δ
12.55 (s, 1H), 10.35(s, 1H), 7.84 (s, 1H), 7.77 (s, 1H), 7.59(d, 2H, J = 8.4
Hz), 7.53 (d, 1H, J = 8.0 Hz), 7.37 (t, 1H, J = 8.2 Hz), 7.16 (d, 2H, J = 8.4
Hz), 4.83 (s, 2H). MS (ESI), m/z: 386.98 [M - H]-.
(Z)-N-(4-Chlorophenyl)-2-(4-((2,4-dioxothiazolidin-5-yli-
dene)methyl)phenoxy)acetamide (3J). Yield 73.4%. analytical
HPLC purity = 98.06%; yellow solid. 1H NMR (400 MHz, DMSO-d6):
δ 12.54 (s, 1H), 10.30 (s, 1H), 7.76 (s, 1H), 7.67 (m, 2H, J = 8.8 Hz), 7.59
(d, 2H, J = 8.8 Hz), 7.39 (d, 2H, J = 9.2 Hz), 7.16 (d, 2H, J = 8.8 Hz), 4.81
(s,2H). MS (ESI), m/z: 387.06 [ M - H]-.
δ 12.53 (s, 1H), 7.95 (d, 1H, J = 8.0 Hz), 7.75 (s, 1H), 7.56 (d, 2H, J = 8.8
Hz), 7.09 (d, 2H, J = 8.8 Hz), 4.54 (s, 2H), 3.61 (t,1H, J = 3.6 Hz), 1.74 -
1.64 (m, 4H), 1.58-1.55 (m, 1H), 1.31-1.19 (m, 4H), 1.15-1.06 (m,
1H). MS (ESI), m/z: 359.07 [M - H]-.
(Z)-N-Benzyl-2-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-
phenoxy)acetamide (3R). Yield 84.3%; analytical HPLC purity =
98.58%; yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 12.54 (s, 1H),
8.70 (t, 1H, J = 6.0 Hz), 7.76 (s, 1H), 7.57 (d, 2H, J = 8.8 Hz), 7.32-7.31
(m, 2H), 7.25-7.21 (m, 3H), 7.12 (d, 2H, J = 8.8 Hz), 4.65 (s, 2H), 4.34
(d, 2H, J = 6.0 Hz). MS (ESI), m/z: 367.15 [M - H]-.
(Z)-2-(4-((2,4-Dioxothiazolidin-5-ylidene)methyl)pheno-
xy)-N-(pyridin-2-yl)acetamide (3S). Yield 65.8%; analytical HPLC
purity = 98.05%; light-yellow solid. 1H NMR (400 MHz, DMSO-d6):
δ 12.53 (s, 1H), 10.62 (s, 1H), 8.35 (d, 1H, J = 8.0 Hz), 8.04 (d, 1H,
J = 8.0 Hz), 7.83-7.75 (m, 2H), 7.75 (s, 1H), 7.58 (d, 2H, J =
8.8 Hz), 7.16-7.12 (m, 3H), 4.89 (s, 2H). MS (ESI), m/z: 354.03
[M - H]-.
(Z)-2-(4-((2,4-Dioxothiazolidin-5-ylidene)methyl)pheno-
xy)-N-(5-methylpyridin-2-yl)acetamide(3T). Yield 74.1%; ana-
lytical HPLC purity = 98.29%; light-yellow solid. 1H NMR (400 MHz,
DMSO-d6): δ 12.54 (s, 1H), 10.53 (s, 1H), 8.18 (q, 1H, J = 3.2 Hz), 7.95
(d, 1H, J = 7.6 Hz), 7.76 (s, 1H), 7.64-7.61 (m, 1H), 7.58 (d, 2H, J = 8.8
Hz), 7.13 (d, 2H, J = 9.2 Hz), 4.88 (s, 2H), 2.26 (s, 3H). MS (ESI), m/z:
368.16 [M - H]-.
(Z)-2-(4-((2,4-Dioxothiazolidin-5-ylidene)methyl)pheno-
xy)-N-(naphthalen-1-yl)acetamide (3U). Yield 68.3%; analytical
HPLC purity = 98.77%; light-yellow solid. 1H NMR (400 MHz, DMSO-
d6): δ 12.54 (s, 1H), 10.21 (s, 1H), 8.00-7.94 (m, 2H), 7.81 (d, 2H, J =
8.0 Hz), 7.78 (s, 1H), 7.66-7.61 (m, 3H), 7.55-7.61 (m, 3H), 7.23 (d,
2H, J = 8.0 Hz), 4.98 (s, 2H). MS (ESI), m/z: 403.05 [M - H]-.
(Z)-2-(4-((2,4-Dioxothiazolidin-5-ylidene)methyl)pheno-
xy)-N-(naphthalen-2-yl)acetamide (3V). Yield 70.0%; analytical
HPLC purity = 99.22%; white solid. 1H NMR (400 MHz, DMSO-d6):
δ 12.54 (s, 1H), 10.38 (s, 1H), 8.32 (s, 1H), 7.90-7.82 (m, 3H), 7.77 (s,
1H), 7.68-7.65 (m, 1H), 7.60 (d, 2H, J = 8.8Hz), 7.48 (t, 1H, J = 7.2 Hz),
7.42 (t, 1H, J = 7.2 Hz), 7.20 (d, 2H, J = 8.8 Hz), 4.88 (s, 2H). MS (ESI),
m/z: 403.10 [M - H]-.
(Z)-N-(4-Bromophenyl)-2-(4-((2,4-dioxothiazolidin-5-yli-
dene)methyl)phenoxy)acetamide (3K). Yield 80.2%; analytical
HPLC purity = 99.45%; light-yellow solid. 1H NMR (400 MHz, DMSO-
d6): δ 12.53 (s, 1H), 10.29 (s,1H), 7.76 (s, 1H), 7.62-7.57 (m, 4H), 7.51
(d, 2H, J= 8.8Hz), 7.15 (d, 2H, J= 8.8Hz), 4.841(s, 2H). MS(ESI), m/z:
431.08 [M - H]-.
(Z)-N-(2,4-Dichlorophenyl)-2-(4-((2,4-dioxothiazolidin-5-
ylidene)methyl)phenoxy)acetamide (3L). Yield 80.3%; analyti-
1
cal HPLC purity = 98.16%; light-yellow solid. H NMR (400 MHz,
DMSO-d6): δ 12.55 (s, 1H), 9.81 (s, 1H), 7.84-7.80 (m, 1H), 7.77
(s, 1H), 7.72-7.71 (m, 1H), 7.60 (d, 2H, J = 8.8 Hz), 7.47-7.44
(m, 1H), 7.18 (d, 2H, J = 8.8 Hz), 4.89 (s, 2H). MS (ESI), m/z: 421.10
[M - H]-.
(Z)-N-(3,5-Dichlorophenyl)-2-(4-((2,4-dioxothiazolidin-5-
ylidene)methyl)phenoxy)acetamide (3M). Yield 72.1%; analy-
’ ASSOCIATED CONTENT
1
tical HPLC purity = 98.64%; light-yellow solid. H NMR (400 MHz,
Supporting Information. 1H NMR and MS analysis of
DMSO-d6): δ 12.55 (s, 1H), 10.47 (s, 1H), 7.77 (s, 1H), 7.74 (d, 2H, J =
1.6 Hz), 7.59 (d, 2H, J = 9.2 Hz), 7.33 (t, 1H, J = 1.6 Hz), 7.16 (d, 2H, J =
8.8 Hz), 4.84 (s, 2H). MS (ESI), m/z: 421.01 [M - H]-.
S
b
1A-V, 2A-V, and 3I; the detailed HPLC analysis of 3A-V;
docking results of all molecules with murine iNOS. This material
(Z)-N-(3-Chloro-4-fluorophenyl)-2-(4-((2,4-dioxothiazoli-
din-5-ylidene)methyl)phenoxy)acetamide (3N). Yield 84.5%;
1
analytical HPLC purity = 98.34%; yellow solid. H NMR (400 MHz,
’ AUTHOR INFORMATION
DMSO-d6): δ 12.54 (s, 1H), 10.36 (s, 1H), 7.96-7.94 (m, 2H), 7.76 (s,
1H), 7.60-7.54 (m, 3H), 7.40 (t, 1H, J = 8.8 Hz), 7.16 (d, 2H, J = 8.4Hz),
4.86 (s, 2H). MS (ESI), m/z: 406.08 [M - H]-.
(Z)-N-(3,4-Difluorophenyl)-2-(4-((2,4-dioxothiazolidin-5-
ylidene)methyl)phenoxy)acetamide (3O). Yield 81.5%; analy-
tical HPLC purity = 99.87%; white solid. 1H NMR (400 MHz, DMSO-
d6): δ 12.53 (s, 1H), 10.37 (s, 1H), 7.82-7.77 (m, 1H), 7.75 (s, 1H), 7.58
(d, 2H, J = 8.8 Hz), 7.45-7.38 (m, 2H), 7.15 (d, 2H, J = 8.4 Hz), 4.81 (s,
2H). MS (ESI), m/z: 389.20 [M - H]-.
Corresponding Author
*For M.-L.X.: phone, þ86-28-85164103; E-mail, tmkxiang@
gmail.com. For L.-J.C.: phone, þ86-28-85164063; fax, þ86-28-
85164060; E-mail, lijuan17@hotmail.com.
Author Contributions
§These authors contributed equally and should be considered co-
first authors.
(Z)-2-(4-((2,4-Dioxothiazolidin-5-ylidene)methyl)pheno-
xy)-N-methyl-N-phenylacetamide (3P). Yield 79.6%; analyti-
cal HPLC purity = 99.91%; yellow solid. 1H NMR (400 MHz, DMSO-
d6): δ 12.52 (s, 1H), 7.73 (s, 1H), 7.52-7.50 (m, 6H), 7.41 (s, 1H),
6.93 (s, 2H), 4.53 (s, 2H), 3.20 (s, 3H). MS (ESI), m/z: 367.20
[M - H]-.
’ ACKNOWLEDGMENT
We are grateful to the National Key Programs of China during
the 11th Five-Year Plan period (2009ZX09102-045 and
2009ZX09501-015).
2067
dx.doi.org/10.1021/jm1011534 |J. Med. Chem. 2011, 54, 2060–2068