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I.N. Cvijetic et al. / European Journal of Medicinal Chemistry xxx (2017) 1e15
4
Calculated for C20H29O [MþH]þ 285.2213, found 285.2206; 1H NMR
189.11.
(Z)-2-hydroxy-4-oxo-4-(4-(pyrrolidin-1-yl)phenyl)but-2-
(200 MHz, CD3OD)
d (ppm): 1.43 (m, 12 H), 1.88 (m, 8 H), 2.54 (m,
1 H), 2.60 (s, 3 H), 3.02 (m, 1 H), 7.16 (d, br, 1 H), 7.30 (d, br, 1 H), 7.32
(s, 1 H).
enoic acid (17):
C
14H15NO4, Mr
¼
261.27, red powder,
mp ¼ 160e162 ꢀC (crystallized from EtOH/PhMe), ESI-MS: Calcu-
(Z)-4-(2,5-dicyclohexylphenyl)-2-hydroxy-4-oxobut-2-enoic
acid (12): C22H28O4, Mr ¼ 356.46, white powder (1.30 g, 64%),
mp. ¼ 146e148 ꢀC, dcc (crystallized from AcOEt/hexane), ESI-MS:
lated for C14H16NO4 [MþH]þ 262.1074, found 262.1063; IR (
n,
cmꢁ1): 3155 br, 1716, 1599, 1272; 1H NMR (200 MHz, CDCl3/DMSO-
d6)
d
(ppm): 2.06 (qn, J ¼ 6.18 Hz, 4 H), 3.40 (t, J ¼ 6.18 Hz, 4 H), 6.56
Calculated for C22H29O4 [MþH]þ 357.2060, found 357.2062, IR (
n
,
(d, J ¼ 8.99 Hz, 2 H), 7.02 (s, 1 H), 7.89 (d, J ¼ 8.99 Hz, 2 H); 13C NMR
cmꢁ1): 2976 br, 1722, 1630, 1264; 1H NMR (200 MHz, CDCl3)
(50 MHz, CDCl3/DMSO-d6) d (ppm): 25.22, 47.54, 97.54, 111.25,
d
(ppm): 1.29e1.34 (m, 2 H), 1.36e1.45 (m, 8 H), 1.75 (d br, 2 H), 1.78
121.39, 130.52, 151.84, 164.61, 165.96, 189.61.
(m, 8 H), 2.51 (m, 1 H), 3.00 (m, 1 H), 3.94 (s, CH2 of diketo form),
(Z)-2-hydroxy-4-(4-morpholinophenyl)-4-oxobut-2-enoic
6.83 (s, 1 H, CH of enol form), 7.31 (s, 1 H), 7.33 (s, 2 H); 13C NMR
acid (18):
C
14H15NO5, Mr
¼
277.27, pale orange powder,
(50 MHz, CDCl3)
d
(ppm): 26.00, 26.13, 26.76, 26.83, 34.28, 34.68,
mp ¼ 164e165 ꢀC (crystallized from EtOH/PhMe), ESI-MS: Calcu-
40.10, 43.92, 101.38, 127.09, 127.35, 130.75, 134.50, 144.99, 145.62,
163.57, 170.60, 195.05.
lated for C14H16NO5 [MþH]þ 278.1023, found 278.1019. IR (
n
, cmꢁ1):
3320 br, 1713, 1604, 1268; 1H NMR (200 MHz, D2O)
d (ppm): 3.35 (t,
4-(2,5-dicyclohexylphenyl)-4-oxobutanoic
acid
(1a):
J ¼ 5.05 Hz, 4 H), 3.85 (t, J ¼ 5.05 Hz, 4 H), 3.92 (s, CH2 of diketo
C
22H30O3, Mr
¼
342.47, white powder (0.92 g, 71%),
form), 6.88 (d, J ¼ 8.99 Hz, 2 H), 7.01 (s, 1 H), 7.93 (d, J ¼ 8.99 Hz,
mp ¼ 122e124 ꢀC, dcc (crystallized from PhMe); ESI-MS: Calculated
2 H), 15.64 (sb, 1 H); 13C NMR (50 MHz, CDCl3)
d (ppm): 47.21, 53.19,
for
C
22H31O3 [MþH]þ 343.2268, found 343.2260; 1H NMR
66.57, 97.90, 113.39, 124.96, 130.37, 154.96, 163.35, 167.19, 190.04.
(Z)-4-(4-(1H-imidazol-1-yl)phenyl)-2-hydroxy-4-oxobut-2-
enoic acid (19): C13H10N2O4, Mr ¼ 258.23, pale yellow solid,
mp ¼ 184e186 ꢀC (crystallized from AcOEt/PhMe), ESI-MS: Calcu-
(200 MHz, DMSO-d6) d (ppm): 1.32 (m), 1.75 (m), 2.57 (m, 3 H), 2.93
(m, 1 H), 3.06 (t, J ¼ 5.62, 12.36 Hz), 3.21 (t, J ¼ 5.62, 12.36 Hz), 7.10
(d, J ¼ 7.86 Hz), 7.23 (s), 7.28 (s), 7.36 (d, J ¼ 8.42 Hz), 7.51 (d,
J ¼ 7.86 Hz), 7.90 (d, J ¼ 8.42 Hz), 12.16 (s, br). Two forms are visible
in solution, ratio 8:5 calculated according to the signals of aromatic
H-atoms. We assumed the presence of two conformers in solution.
(Z)-2-hydroxy-4-(2-methoxyphenyl)-4-oxobut-2-enoic acid
lated for C13H11N2O4 [MþH]þ 259.0713, found 259.0722; IR (
n,
cmꢁ1): 3452 br, 1710, 1608, 1277; 1H NMR (200 MHz, CDCl3)
d
(ppm): 7.10 (s, 1 H), 7.27 (m, 1 H), 7.38 (m, 1 H), 7.56 (d, J ¼ 8.99 Hz,
2 H), 7.99 (s,1 H), 8.14 (d, J ¼ 8.42 Hz, 2 H); 13C NMR (50 MHz, CDCl3)
(13):
C
11H12O4, Mr
¼
208.21, white powder (2.54 g, 70%),
d (ppm): 98.07, 117.76, 121.06, 130.09, 131.43, 133.68, 135.49, 141.40,
mp ¼ 129e131 ꢀC (crystallized from EtOH), ESI-MS: Calculated for
162.66, 169.81, 189.18.
C
11H11O5 [MþH]þ 223.0601, found 223.0600; IR (
n
, cmꢁ1): 2998 br,
d (ppm): 3.90 (s,
(Z)-2-hydroxy-4-(4-(4-methylpiperazin-1-yl)phenyl)-4-
oxobut-2-enoic acid (20): C15H18N2O4, Mr ¼ 290.31, pale yellow
powder, mp ¼ 162e163 ꢀC (crystallized from EtOH/PhMe); ESI-MS:
1711, 1634, 1259; 1H NMR (200 MHz, DMSO-d6)
3 H), 4.35 (s, br, CH2 of diketo form), 7.08 (t, J ¼ 7.30, 15.16 Hz, 1 H),
7.13 (s, 1 H, CH of enol form), 7.20 (d, J ¼ 7.86 Hz, 1 H), 7.59 (dt,
Calculated for C15H19N2O4 [MþH]þ 291.1339, found 291.1347. IR (
n,
J ¼ 7.30, 15.72 Hz, 1.68 Hz, 1 H), 7.78 (dd, J ¼ 7.86, 1.68 Hz, 1 H); 13
C
cmꢁ1):3420 (br), 1645, 1599, 1247; 1H NMR (200 MHz, DMSO-d6)
NMR (50 MHz, DMSO-d6)
d
(ppm): 53.87, 56.06, 102.76, 112.79,
d (ppm): 2.78 (s, 3 H), 3.33 (m, br, overlapped with residual water
120.88, 124.12, 130.13, 135.18, 158.91, 163.53, 170.14, 189.72.
(Z)-2-hydroxy-4-(3-methoxyphenyl)-4-oxobut-2-enoic acid
signal from solvent), 4.44 (s, CH2 of diketo form), 7.03 (s, 1 H, CH of
enol form), 7.10 (d, J ¼ 9.0 Hz, 2 H), 7.98 (d, J ¼ 9.0 Hz, 2 H), 11.42 (s
(14):
C
11H10O5, Mr
¼
222.19, white powder (2.64 g, 67%),
br, 1 H); 13C NMR (50 MHz, DMSO-d6)
d (ppm): 40.77, 41.86, 43.66,
mp ¼ 139e140 ꢀC (crystallized from EtOH), ESI-MS: Calculated for
51.62, 97.43, 114.03, 124.35, 130.27, 153.44, 163.53, 168.20, 189.64.
C
11H11O5 [MþH]þ 223.0601, found 223.0602; IR (
n
, cmꢁ1): 3256 br,
(Z)-4-(4-(dimethylamino)phenyl)-2-hydroxy-4-oxobut-2-
1687, 1626, 1258; 1H NMR (200 MHz, DMSO-d6)
d
(ppm): 3.83 (s,
enoic acid (21):
C
12H13NO4, Mr
¼
235.24, pale red solid,
3 H), 4.54 (s, br, CH2 of diketo form), 7.03 (s, 1 H, CH of enol form),
7.24 (dd, J1,3 ¼ 7.86 Hz, J1,2 ¼ 2.25 Hz, 1 H), 7.46 (t, J ¼ 7.86 Hz, 1 H),
7.48 (s, 1 H, overlapped with t at 7.46 ppm), 7.62 (d, J ¼ 7.86 Hz,1 H);
mp ¼ 155e157 ꢀC (crystallized from EtOH/PhMe); ESI-MS: Calcu-
lated for C12H14NO4 [MþH]þ 236.0917, found 236.0918. IR (
n
, cmꢁ1):
3382 br, 1719, 1602, 1274. 1H NMR (200 MHz, CD3OD)
d (ppm): 3.10
13C NMR (50 MHz, DMSO-d6)
d
(ppm): 53.14, 55.47, 98.15, 112.15,
(s, 6 H), 6.78 (d, J ¼ 8.99 Hz, 2 H), 7.01 (s, 1 H), 7.91 (d, J ¼ 8.99 Hz,
120.14, 120.42, 130.35, 136.29, 159.74, 163.34, 170.78, 189.88.
2 H); 13C NMR (50 MHz, CD3OD)
d
(ppm): 40.10, 98.19, 112.26,
(Z)-4-(3-bromophenyl)-2-hydroxy-4-oxobut-2-enoic
acid
123.02, 131.44, 155.98, 165.72, 168.36, 191.03.
(15): C10H7BrO4, Mr ¼ 271.06, white powder (3.35 g, 68%),
The CAS numbers for already reported compounds are: 113416-
61-8 for 1; 1224740-28-6 for 2; 1224740-52-6 for 3; 1224740-57-1
for 4; 149281-53-8 for 5; 1799810-91-5 for 6; 1799810-93-7 for 7;
1799811-01-0 for 8; 1207167-72-3 for 9; 1799811-06-5 for 10;
760207-27-0 for 13; 868616-56-2 for 14; 260558-95-0 for 15;
1224740-53-7 for 16; 1799811-04-3 for 17; 927904-77-6 for 18;
1224739-86-9 for 19; 1146317-98-7 for 22; 1207167-69-8 for 23;
1207167-70-1 for 24; 1207167-71-2 for 25; 160428-91-1 for 26;
36330-85-5 for 3a; 2234-14-2 for 5a.
mp ¼ 143e144 ꢀC (crystallized from EtOH/PhMe), ESI-MS: Calcu-
lated for C10H6BrO4 [MeH]- 268.9455, found 268.9453; IR (
n
, cmꢁ1):
3524, 1628, 1301, 1237; 1H NMR (200 MHz, DMSO-d6)
d (ppm): 4.57
(s, br, CH2 of diketo form), 7.08 (s, 1 H, CH of enol form), 7.49 (t,
J ¼ 7.86 Hz, 1 H), 7.85 (dd, J1,2 ¼ 7.86 Hz, J1,3 ¼ 2.25 Hz, 1 H), 8.03 (d,
J ¼ 8.42 Hz, 1 H), 8.14 (s, 1 H); 13C NMR (50 MHz, DMSO-d6)
d (ppm):
49.24, 97.64, 122.56, 127.02, 130.31, 131.33, 136.54, 136.97, 163.18,
170.43, 188.79.
(Z)-2-hydroxy-4-oxo-4-(3-(trifluoromethyl)phenyl)but-2-
enoic acid (16): C11H7F3O4, Mr ¼ 260.17, white powder (0.62 g,
61%), mp ¼ 135e137 ꢀC (crystallized from AcOEt/PhMe), ESI-MS:
The full characterization of compounds 8, 10 and 17 is, for the
first time, given in this manuscript.
Calculated for C11H8F3O4 [MþH]þ 261.0369, found 261.0373; IR (
n
,
2.1.1. Antibacterial activity
cmꢁ1): 3439 br, 1673, 1622, 1228; 1H NMR (200 MHz, CDCl3)
Bacterial Strains. Antimicrobial susceptibility testing control
organisms Escherichia coli NCTC 12241, Staphylococcus aureus (NCTC
12981 and NCTC 13373), Enterococcus faecalis NCTC 12697 and Ba-
cillus subtilis NCTC 10400 were obtained from the National
Collection of Type Cultures (Public Health England, UK).
Tetracycline-resistant MRSA isolate XU212 (expressing a TetK efflux
d
(ppm): 7.10 (s, 1 H, CH of enol form), 7.20 (s, 1 H, CH of second enol
form), 7.67 (dt, J ¼ 7.86 Hz, 1 H), 7.87 (dd, J ¼ 7.86 Hz, 1 H), 8.24 (s br,
1 H), 8.18 (d, J ¼ 7.86 Hz, 1 H); 13C NMR (50 MHz, CDCl3)
d (ppm):
96.07, 98.13, 124.83, 124.91, 129.79, 129.91, 130.25, 130.32, 130.54,
130.61, 131.10, 134.30, 135.72, 161.91, 162.53, 170.39, 174.75, 185.76,
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Please cite this article in press as: I.N. Cvijetic, et al., Design, synthesis and biological evaluation of novel aryldiketo acids with enhanced
j.ejmech.2017.10.045