S.A.F. Rostom et al. / European Journal of Medicinal Chemistry 76 (2014) 170e181
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CH3), 2.52 (s, 3H, ThiazoleC4eCH3), 3.22 (s, 3H, NeCH3), 4.27 (q,
4.1.11.3. 1-Benzyl-3-(5-(hydrazinecarbonyl)-4-methylthiazol-2-yl)
thiourea (12c). 1H NMR (
-ppm): 2.61 (s, 3H, ThiazoleC4eCH3),
4.93 (s, 2H, CH2), 5.54 (brs, 1H, NH), 6.14 (brs,1H, NH), 7.21e7.78 (m,
5H, AreH), 8.06 (brs, 1H, NH). 13C NMR (
-ppm): 7.5 (CH3), 55.9
J ¼ 9 Hz, 2H, estereCH2), 6.21 (brs, 2H, 2 NH). 13C NMR (
d-ppm): 6.8
d
(CH3), 13.7 (CH3), 34.0 (NeCH3), 59.1 (CH2), 103.2, 149.1, 172.0
(Thiazole C), 167.0 (CO), 179.6 (CS).
d
(CH2), 103.2, 148.8, 171.7 (Thiazole C), 126.5, 127.2, 128.4, 142.6 (Ar
C), 167.1 (CO), 180.1 (CS).
4.1.10.2. Ethyl 2-(3-cyclohexylthioureido)-4-methylthiazole-5-
carboxylate (11b). 1H NMR (
d
-ppm): 1.32 (t, J ¼ 9 Hz, 3H, estere
CH3), 1.52e1.69 (m, 10H, cyclohexyleH), 2.26 (m, 1H, cyclohexyle
H), 2.52 (s, 3H, ThiazoleC4eCH3), 4.29 (q, J ¼ 9 Hz, 2H, estereCH2),
4.1.11.4. 1-(5-(Hydrazinecarbonyl)-4-methylthiazol-2-yl)-3-
phenylthiourea (12d). 1H NMR (
d
-ppm): 2.48 (s, 3H, ThiazoleC4e
CH3), 5.66 (brs, 1H, NH), 5.98 (brs, 1H, NH), 7.34e7.84 (m, 5H, Are
H), 8.10 (brs, 1H, NH). 13C NMR (
-ppm): 7.5 (CH3), 103.4, 149.1, 172.0
6.1 (brs, 2H, 2 NH). 13C NMR (
d-ppm): 6.8 (CH3), 13.6 (CH3), 22.5,
27.1, 33.5, 52.2 (cyclohexyl C) 59.2 (CH2), 105.0, 148.9, 172.4 (Thia-
zole C), 167.3 (CO), 179.6 (CS).
d
(Thiazole C), 124.6, 125.8, 128.8, 139.4 (Ar C), 167.2 (CO), 179.8 (CS).
4.1.10.3. Ethyl 2-(3-benzylthioureido)-4-methylthiazole-5-
4.1.11.5. 1-(5-(Hydrazinecarbonyl)-4-methylthiazol-2-yl)-3-(p-tolyl)
carboxylate (11c). 1H NMR (
d
-ppm): 1.35 (t, J ¼ 9 Hz, 3H, estere
thiourea (12e). 1H NMR (
d
-ppm): 2.32 (s, 3H, tolyleCH3), 2.51 (s, 3H,
ThiazoleC4eCH3), 4.45 (brs,1H, NH), 5.8 (brs,1H, NH), 7.11e7.48 (m,
4H, AreH), 8.11 (brs, 1H, NH). 13C NMR (
-ppm): 6.7 (CH3), 20.9
CH3), 2.53 (s, 3H, ThiazoleC4eCH3), 2.64 (s, 2H, benzyleCH2), 4.34
(q, J ¼ 9 Hz, 2H, estereCH2), 6.35 (brs, 2H, 2 NH), 7.09e7.36 (m, 5H,
d
AreH). 13C NMR (
d
-ppm): 6.9 (CH3), 13.7 (CH3), 55.8 (CH2), 59.2
(CH3), 103.8, 149.2, 172.0 (Thiazole C), 125.4, 129.7, 133.7, 136.8 (Ar
C), 167.6 (CO), 180.1 (CS).
(CH2), 103.2, 148.8, 171.7 (Thiazole C), 126.5, 127.2, 128.4, 142.6 (Ar
C), 167.1 (CO), 180.1 (CS).
4.1.11.6. 1-(4-Fluorophenyl)-3-(5-(hydrazinecarbonyl)-4-
4.1.10.4. Ethyl 4-methyl-2-(3-phenylthioureido)thiazole-5-
methylthiazol-2-yl)thiourea (12f). 1H NMR (
d
-ppm): 2.45 (s, 3H,
ThiazoleC4eCH3), 4.05 (brs, 1H, NH), 5.14 (brs, 1H, NH), 7.12e7.62
(m, 4H, AreH), 7.99 (brs,1H, NH). 13C NMR (
-ppm): 6.9 (CH3),103.7,
carboxylate (11d). 1H NMR (
d
-ppm): 1.34 (t, J ¼ 9 Hz, 3H, estere
CH3), 2.53 (s, 3H, ThiazoleC4eCH3), 4.31 (q, J ¼ 9 Hz, 2H, estere
CH2), 6.29 (brs, 2H, 2 NH), 7.12e7.41 (m, 5H, AreH). 13C NMR (
d
d-
148.2, 171.7 (Thiazole C), 115.7, 126.6, 135.3, 158.4 (Ar C), 167.5 (CO),
180.0 (CS).
ppm): 6.9 (CH3), 13.6 (CH3), 59.0 (CH2), 103.4, 149.1, 172.0 (Thiazole
C), 124.3, 125.2, 128.8, 139.6 (Ar C), 167.0 (CO), 179.9 (CS).
4.1.12. 2-Amino-4-methyl-N-substituted-thiazole-5-carboxamides
(13aec)
4.1.10.5. Ethyl 4-methyl-2-(3-(p-tolyl)thioureido)thiazole-5-
carboxylate (11e). 1H NMR (
d
-ppm): 1.35 (t, J ¼ 9 Hz, 3H, estere
To a solution of the thiazole 1 (0.93 g, 5 mmol) in ethanol
(15 mL), the appropriate amine was added and the mixture was
heated under reflux for 10e12 h. After being cooled to room tem-
perature, the separated solid was filtered, washed with cold
ethanol, dried and recrystallized. Physicochemical and analytical
data are recorded in Table 3. IR (cmꢀ1): 3540e2775 (NH, OH),
1685e1645 (C]O).
CH3), 2.27 (s, 3H, tolyleCH3), 2.50 (s, 3H, ThiazoleC4eCH3), 4.33 (q,
J ¼ 9 Hz, 2H, estereCH2), 6.45 (brs, 2H, 2NH), 6.98e7.23 (m, 4H, Are
H). 13C NMR (
d-ppm): 6.7 (CH3), 13.6 (CH3), 20.9 (CH3), 59.1 (CH2),
104.1, 149.3, 172.1 (Thiazole C), 125.2,129.5, 133.6, 136.4 (Ar C), 167.0
(CO), 180.3 (CS).
4.1.10.6. Ethyl 2-(3-(4-fluorophenyl)thioureido)-4-methylthiazole-5-
carboxylate (11f). 1H NMR (
d
-ppm): 1.37 (t, J ¼ 9 Hz, 3H, estere
CH3), 2.49 (s, 3H, ThiazoleC4eCH3), 4.3 (q, J ¼ 9 Hz, 2H, estereCH2),
6.32 (brs, 2H, 2NH), 6.97e7.19 (m, 4H, AreH). 13C NMR (
-ppm): 6.9
4.1.12.1. 2-Amino-N-(4-hydroxyethyl)-4-methylthiazole-5-
carboxamide (13a). 1H NMR (
d
-ppm): 2.51 (s, 3H, ThiazoleC4eCH3),
2.90 (m, 2H, CH2), 3.46 (m, 2H, CH2), 3.85 (brs, 1H, OH), 6.13 (brs,
2H, NH2), 8.16 (brs, 1H, NH). 13C NMR (
-ppm): 6.5 (CH3), 103.5,
d
(CH3), 13.5 (CH3), 59.2 (CH2), 103.3, 149.2, 172.3 (Thiazole C), 115.9,
126.8, 135.1, 158.3 (Ar C), 167.0 (CO), 180.2 (CS).
d
149.2, 172.2 (Thiazole C), 45.4 (CH2eN), 64.5 (CH2eOH), 167.9 (CO).
4.1.11. 1-(5-(Hydrazinecarbonyl)-4-methylthiazol-2-yl)-3-
(substituted)thiourea (12aef)
4.1.12.2. 2-Amino-N-(4-methoxyphenyl)-4-methylthiazole-5-
carboxamide (13b). 1H NMR (
d
-ppm): 2.43 (s, 3H, ThiazoleC4eCH3),
3.51 (s, 3H, OCH3), 6.48 (brs, 2H, NH2), 7.14e7.72 (m, 4H, AreH), 8.12
(brs, 1H, NH). 13C NMR (
-ppm): 6.6 (CH3), 56.0 (CH3O), 103.7, 149.0,
To a solution of the appropriate thioureido derivative 11
(5 mmol) in ethanol (15 mL) was added hydrazine hydrate (0.75 g,
15 mmol), and the reaction mixture was heated under reflux for 6 h.
The obtained precipitate, upon cooling, was filtered, washed with
cold water, dried and recrystallized. Physicochemical and analytical
data are recorded in Table 2. IR (cmꢀ1): 3540e2920 (NH), 1670e
1665 (C]O), 990e953 (NCS).
d
172.3 (Thiazole C), 114.3, 121.4, 130.5, 157.5 (Ar C), 165.4 (CO).
4.1.12.3. 2-Amino-N-(4-fluorophenyl)-4-methylthiazole-5-carbox-
amide (13c). 1H NMR (
d
-ppm): 2.48 (s, 3H, ThiazoleC4eCH3), 6.09
(brs, 2H, NH2), 6.88e7.52 (m, 4H, AreH), 8.08 (brs,1H, NH). 13C NMR
-ppm): 6.5 (CH3), 103.5, 149.3, 172.1 (Thiazole C), 115.6, 122.2,
(d
4.1.11.1. 1-(5-(Hydrazinecarbonyl)-4-methylthiazol-2-yl)-3-
133.5, 157.7 (Ar C), 165.2 (CO).
methylthiourea (12a). 1H NMR (
d
-ppm): 2.55 (s, 3H, ThiazoleC4e
CH3), 3.25 (s, 3H, NeCH3), 5.58 (brs, 1H, NH), 6.19 (brs, 1H, NH), 8.12
(brs, 1H, NH). 13C NMR (
-ppm): 7.4 (CH3), 34.2 (NeCH3), 104.4,
4.2. In vitro antibacterial and antifungal screening
d
149.2, 171.9 (Thiazole C), 167.4 (CO), 179.9 (CS).
4.2.1. Inhibition-zone (IZ) measurements
All the synthesized compounds were evaluated by the agar cup
diffusion technique [41] using a 1 mg/mL solution in DMSO. The
test organisms utilized were S. aureus (ATCC 6538), B. subtilis (ATCC
6633) as examples of Gram positive bacteria and E. coli (ATCC
25922), P. aeruginosa (ATCC 27853) as examples of Gram negative
bacteria. They were also evaluated for their in vitro antifungal po-
tential against C. albicans (ATCC 10231) and A. niger (recultured)
4.1.11.2. 1-Cyclohexyl-3-(5-(hydrazinecarbonyl)-4-methylthiazol-2-
yl)thiourea (12b). 1H NMR (
d
-ppm): 1.49e1.58 (m, 10H, cyclo-
hexyleH), 2.17 (m, 1H, cyclohexyleH), 2.59 (s, 3H, ThiazoleC4e
CH3), 6.16 (brs, 1H, NH), 8.09 (brs, 1H, NH). 13C NMR (
-ppm): 7.6
d
(CH3), 22.3, 27.3, 32.9, 51.2 (cyclohexyl C), 104.6, 148.7, 172.0
(Thiazole C), 167.4 (CO), 179.8 (CS).