Nitazoxanide-Based Antimicrobial Agents
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(79 mg, 46%) as a pale yellow solid: H NMR (300 MHz, [D6]DMSO):
J=9.2 Hz, 1H); 13C NMR (75 MHz, [D6]DMSO): d=162.6, 157.5,
144.4, 142.4, 127.4, 123.3, 120.5, 114.1, 113.3, 95.8, 91.6 ppm; HRMS
(ESI): m/z calcd for [C12H6N4O6S+H]+: 335.0081, found 335.0088.
d=13.82 (s, 1H), 8.72 (s, 1H), 8.35 (s, 1H), 8.32 (s, 1H), 7.82–7.67
(m, 3H), 7.50 ppm (d, J=3.8 Hz, 1H); 13C NMR (75 MHz,
[D6]DMSO): d=162.1, 156.3, 155.5, 144.5, 142.6, 142.1, 130.2, 129.7,
N-(5-Nitrothiazol-2-yl)thiophene-3-carboxamide (74): Method B
yielded compound 74 (76 mg, 38%) as a yellow solid: 1H NMR
(500 MHz, [D6]DMSO): d=13.43 (br s, 1H), 8.75–8.68 (m, 1H), 8.65
(s, 1H), 7.75–7.72 (m, 1H), 7.72–7.67 ppm (m, 1H); 13C NMR
(125 MHz, [D6]DMSO): d=162.4, 161.2, 142.6, 142.0, 133.7, 133.4,
127.9, 127.2 ppm; HRMS (ESI): m/z calcd for [C8H5N3O3S2 +H]+:
255.9845, found 255.9848.
128.8, 125.6 (q, JCF =3.9 Hz), 124.0 (q, JCF =271 Hz), 121.3 (q, JCF
3.8 Hz), 120.8, 110.2 ppm; HRMS (ESI): m/z calcd for
[C15H8F3N3O4S+H]+: 384.0260, found 384.0275.
=
5-(3-Nitrophenyl)-N-(5-nitrothiazol-2-yl)furan-2-carboxamide
(69): Method B yielded compound 69 (31 mg, 20%) as a bright
yellow solid: 1H NMR (500 MHz, [D6]DMSO): d=13.83 (br s, 1H),
8.75 (s, 1H), 8.67 (s, 1H), 8.41 (d, J=7.8 Hz, 1H), 8.23–8.19 (m, 1H),
7.76 (t, J=8.0 Hz, 1H), 7.72 (d, J=3.8 Hz, 1H), 7.51 ppm (d, J=
3.7 Hz, 1H); 13C NMR (125 MHz, [D6]DMSO): d=162.1, 156.2, 154.7,
148.4, 144.7, 142.5, 142.1, 131.0, 130.6, 130.2, 123.6, 120.7, 119.1,
110.7 ppm; HRMS (ESI): m/z calcd for [C14H8N4O6S+H]+: 361.0237,
found 361.0241.
2,5-Dichloro-N-(5-nitrothiazol-2-yl)thiophene-3-carboxamide
(75): Method B yielded compound 75 (109 mg, 66%) as a tan
solid: 1H NMR (300 MHz, [D6]DMSO): d=13.47 (br s, 1H), 8.69 (s,
1H), 7.72 ppm (d, J=0.7 Hz, 1H); 13C NMR (75 MHz, [D6]DMSO):
d=161.7, 159.8, 142.4, 132.9, 129.4, 126.9, 125.6 ppm; HRMS (ESI):
m/z calcd for [C8H3Cl2N3O3S2 +H]+: 323.9066, found 323.9074.
N-(5-Nitrothiazol-2-yl)-2,3’-bifuran-5-carboxamide (70): Method D
yielded the intermediate Suzuki coupling product (133 mg, 95%)
as a pale yellow solid: 1H NMR (500 MHz, [D6]DMSO): d=8.22 (s,
1H), 7.84–7.77 (m, 1H), 7.36 (d, J=3.6 Hz, 1H), 6.92–6.89 (m, 1H),
6.85 (d, J=3.6 Hz, 1H), 3.81 ppm (s, 3H). Method E yielded the in-
N-(5-Nitrothiazol-2-yl)thiophene-2-carboxamide (76): Method A
yielded compound 76 (85 mg, 36%) as a light yellow solid:
1H NMR (300 MHz, [D6]DMSO): d=13.70 (br s, 1H), 8.72 (s, 1H),
8.32 (dd, J=3.8, 1.1 Hz, 1H), 8.09 (dd, J=5.0, 1.1 Hz, 1H), 7.30 ppm
(dd, J=5.0, 3.9 Hz, 1H); 13C NMR (125 MHz, [D6]DMSO): d=162.5,
160.8, 142.6, 142.0, 135.7, 135.3, 132.4, 128.9 ppm; HRMS (ESI): m/z
calcd for [C8H5N3O3S2 +H]+: 255.9845, found 255.9846.
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termediate carboxylic acid (92 mg, 99%) as a white solid: H NMR
(500 MHz, [D6]DMSO): d=13.08 (br s, 1H), 8.22–8.16 (m, 1H), 7.77
(t, J=1.7 Hz, 1H), 7.27 (d, J=3.5 Hz, 1H), 6.88 (dd, J=1.9, 0.8 Hz,
1H), 6.80 ppm (d, J=3.5 Hz, 1H). Method B yielded compound 70
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(42 mg, 32%) as a yellow solid: H NMR (500 MHz, [D6]DMSO): d=
5-Chloro-N-(5-nitrothiazol-2-yl)thiophene-2-carboxamide
(77):
13.55 (s, 1H), 8.66 (s, 1H), 8.33–8.28 (m, 1H), 7.82 (d, J=1.5 Hz,
1H), 7.73 (d, J=3.7 Hz, 1H), 6.99 (d, J=0.6 Hz, 1H), 6.92 ppm (d,
J=3.7 Hz, 1H); 13C NMR (125 MHz, [D6]DMSO): d=162.2, 156.1,
152.1, 144.8, 143.0, 142.6, 142.0, 141.1, 120.5, 116.5, 108.4,
108.0 ppm; HRMS (ESI): m/z calcd for [C12H7N3O5S+H]+: 306.0179,
found 306.0189.
Method B yielded compound 77 (122 mg, 69%) as a yellow solid:
1H NMR (500 MHz, [D6]DMSO): d=13.79 (s, 1H), 8.71 (s, 1H), 8.17
(d, J=4.2 Hz, 1H), 7.35 ppm (d, J=4.2 Hz, 1H); 13C NMR (125 MHz,
[D6]DMSO): d=162.4, 160.0, 142.3, 142.0, 137.1, 134.9, 132.4,
129.1 ppm; HRMS (ESI): m/z calcd for [C8H4ClN3O3S2 +H]+:
289.9455, found 289.9465.
N-(5-Nitrothiazol-2-yl)-5-(thiophen-3-yl)furan-2-carboxamide
(71): Method D yielded the intermediate Suzuki coupling product
(128 mg, 84%) as a yellow solid: 1H NMR (300 MHz, [D6]DMSO):
d=7.97 (dd, J=2.9, 1.2 Hz, 1H), 7.70 (dd, J=5.1, 2.9 Hz, 1H), 7.54
(dd, J=5.1, 1.2 Hz, 1H), 7.40 (d, J=3.6 Hz, 1H), 6.99 (d, J=3.6 Hz,
1H), 3.83 ppm (s, 3H). Method E yielded the intermediate carboxyl-
3-Chloro-N-(5-nitrothiazol-2-yl)thiophene-2-carboxamide
(78):
Method B yielded compound 78 (133 mg, 75%) as a yellow solid:
1H NMR (500 MHz, [D6]DMSO): d=8.74 (s, 1H), 8.02 (d, J=5.2 Hz,
1H), 7.25 ppm (d, J=5.2 Hz, 1H); 13C NMR (125 MHz, [D6]DMSO):
d=163.0, 161.9, 140.5, 139.9, 132.3, 129.9, 129.0, 128.0 ppm; HRMS
(ESI): m/z calcd for [C8H4ClN3O3S2 +H]+: 289.9455, found 289.9467.
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ic acid (92 mg, 99%) as a pink solid: H NMR (500 MHz, [D6]DMSO):
d=13.08 (br s, 1H), 7.93 (dd, J=2.9, 1.3 Hz, 1H), 7.69 (dd, J=5.1,
2.9 Hz, 1H), 7.52 (dd, J=5.1, 1.3 Hz, 1H), 7.29 (d, J=3.6 Hz, 1H),
6.94 ppm (d, J=3.6 Hz, 1H). Method B yielded compound 71
5-Bromo-N-(5-nitrothiazol-2-yl)thiophene-2-carboxamide
(79):
Method B yielded compound 79 (128 mg, 75%) as a tan solid:
1H NMR (300 MHz, [D6]DMSO): d=13.77 (br s, 1H), 8.71 (s, 1H),
8.11 (d, J=4.1 Hz, 1H), 7.44 ppm (d, J=4.1 Hz, 1H); 13C NMR
(75 MHz, [D6]DMSO): d=162.3, 159.9, 142.3, 142.0, 137.5, 133.1,
132.5, 121.4 ppm; HRMS (ESI): m/z calcd for [C8H4BrN3O3S2 +H]+:
333.8950, found 333.8959.
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(23 mg, 19%) as a yellow solid: H NMR (500 MHz, [D6]DMSO): d=
13.66 (br s, 1H), 8.71 (s, 1H), 8.17 (dd, J=2.9, 1.2 Hz, 1H), 7.74 (d,
J=3.7 Hz, 1H), 7.72 (dd, J=5.0, 2.9 Hz, 1H), 7.67 (dd, J=5.0,
1.2 Hz, 1H), 7.07 ppm (d, J=3.7 Hz, 1H); 13C NMR (125 MHz,
[D6]DMSO): d=162.3, 156.4, 154.5, 143.1, 142.8, 142.0, 130.7, 128.0,
125.3, 123.6, 120.8, 108.2 ppm; HRMS (ESI): m/z calcd for
[C12H7N3O4S2 +H]+: 321.9951, found 321.9953.
N-(5-Nitrothiazol-2-yl)-5-phenylthiophene-2-carboxamide
(80):
Method D yielded the intermediate Suzuki coupling product
(92 mg, 94%) as a white solid:[39] 1H NMR (300 MHz, [D6]DMSO):
d=7.81 (d, J=3.9 Hz, 1H), 7.78–7.69 (m, 2H), 7.62 (d, J=4.0 Hz,
1H), 7.52–7.36 (m, 3H), 3.84 ppm (s, 3H). Method E yielded the in-
N-(5-Nitrothiazol-2-yl)benzofuran-2-carboxamide (72): Method C
followed by Method A yielded compound 72 (57 mg, 32%) as a
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light orange solid: H NMR (300 MHz, [D6]DMSO): d=8.71 (s, 1H),
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termediate carboxylic acid (74 mg, 95%) as a white solid: H NMR
8.16 (s, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.61–
7.49 (m, 1H), 7.39 ppm (t, J=7.6 Hz, 1H); 13C NMR (75 MHz,
[D6]DMSO): d=162.0, 157.7, 155.1, 145.9, 142.5, 142.1, 128.4, 126.7,
124.3, 123.6, 113.9, 112.2 ppm; HRMS (ESI): m/z calcd for
[C12H7N3O4S+H]+: 290.0230, found 290.0241.
(500 MHz, [D6]DMSO): d=13.17 (br s, 1H), 7.78–7.69 (m, 3H), 7.58
(d, J=3.9 Hz, 1H), 7.49–7.43 (m, 2H), 7.42–7.37 ppm (m, 1H). Meth-
od B yielded compound 80 (68 mg, 57%) as a yellow solid:
1H NMR (300 MHz, [D6]DMSO): d=13.73 (br s, 1H), 8.72 (s, 1H),
8.32 (d, J=4.1 Hz, 1H), 7.84–7.76 (m, 2H), 7.71 (d, J=4.1 Hz, 1H),
7.61–7.29 ppm (m, 3H); 13C NMR (75 MHz, [D6]DMSO): d=162.6,
160.7, 151.6, 142.7, 142.0, 134.5, 133.5, 132.5, 129.4, 126.11,
125.3 ppm; HRMS (ESI): m/z calcd for [C14H9N3O3S2 + H]+: 332.0158,
found 332.0161.
5-Nitro-N-(5-nitrothiazol-2-yl)benzofuran-2-carboxamide
(73):
Method B yielded compound 73 (16 mg, 10%) as a light orange
solid: 1H NMR (300 MHz, [D6]DMSO): d=8.91 (d, J=2.4 Hz, 1H),
8.75 (s, 1H), 8.39 (dd, J=9.2, 2.4 Hz, 1H), 8.32 (s, 1H), 8.01 ppm (d,
ChemMedChem 2011, 6, 362 – 377
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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