Synthesis and antimicrobial activity of 3,4-dihydropyrimidin-2(1H)-one derivatives containing a hydrazone moiety
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Hua-Nan Peng
,
Li-Min Ye
Abstract
The title compounds were synthesized and characterized by IR, 1H NMR, 13C NMR and HRMS data. Their antimicrobial activities against bacterial strains Escherichia coli and fungal strains Aspergillus niger were evaluated.
Introduction
3,4-Dihydropyrimidin-2(1H)-ones have attracted considerable attention due their wide range of biological activities, including antitumor [1], antioxidative [2], antibacterial [3], antifungal [4], anti-inflammatory [5] and antihypertensive properties [6]. They have also been identified as calcium channel modulators [7], A2B adenosine receptor antagonists [8], HIV-1 replication inhibitors [9] and human DNA ligase 1 inhibitors [10]. Hydrazones also exhibit a wide range of diverse biological activities [11], [12], [13], [14], [15], [16], [17]. In view of the biological significance of 3,4-dihydropyrimidin-2(1H)-ones and hydrazones, we designed and synthesized a series of novel 3,4-dihydropyrimidin-2(1H)-one derivatives bearing a hydrazone moiety and evaluated their antimicrobial activities against bacterial strains Escherichia coli and fungal strains Aspergillus niger.
Results and discussion
The preparation of target compounds 3a–r is shown in Scheme 1. First, 5-methoxycarbonyl-4-[(4-methoxycarbonyl)phenyl]-6-methyl-3,4-dihydropyrimidin-2(1H)-one (1a) and its 5-ethoxycarbonyl analog 1b were synthesized by three-component condensation reaction of ethyl acetoacetate or methyl acetoacetate, urea and 4-methoxycarbonylbenzaldehyde in ethanol in the presence of p-toluenesulfonic acid as catalyst. Then, products 1a and 1b were allowed to react with hydrazine in ethanol under reflux to afford the corresponding hydrazine derivatives 2a and 2b. Apparently for steric reasons, the methoxycarbonyl or ethoxycarbonyl group (COR1) at the dihydropyrimidinone ring of 1a and 1b did not react with hydrazine to give the hypothetical compound 4. In the final step, the target compounds 3a–r were prepared by a condensation reaction of 2a or 2b with different aromatic aldehydes in ethanol in the presence of acetic acid. Structures of all synthetic compounds were confirmed by analysis of IR, 1H NMR, 13C NMR and HRMS data.
All synthesized compounds were evaluated for their antimicrobial activities against bacterial strains E. coli and fungal strains A. niger. All compounds show moderate inhibitory effect against the bacterial and fungal strains. Most of them show better inhibitory activity than the starting materials 1a and 1b. Compounds 3b, 3f, 3i, 3j and 3l demonstrate good antibacterial activity which is nearly equal to that of the reference antibiotic ciprofloxacin. Compound 3a is an excellent antifungal agent, the activity of which is comparable to that of the reference antibiotic fluconazole.
Conclusions
New 3,4-dihydropyrimidin-2(1H)-ones containing a hydrazone moiety were designed, synthesized and evaluated for antimicrobial activities against E. coli and A. niger. All compounds show moderate inhibitory activities against E. coli and A. niger. Compounds 3b, 3f, 3i, 3j and 3l show good antibacterial activity and compound 3a is an excellent antifungal agent.
Experimental
Reagents were purchased from commercial sources and used without further purification. Melting points were determined on a Yanaco micro melting point apparatus and are uncorrected. Infrared spectra were recorded on a Nicolet 6700 infrared spectrometer. NMR spectra were recorded at 400 MHz (1H) and 100 MHz (13C) on a Bruker spectrometer using TMS as an internal standard and DMSO-d6 as solvent. High resolution mass spectra (HRMS) were obtained on a Thermo Scientific spectrometer using electrospray ionization (ESI).
General procedure for the preparation of 1a and 1b
These compounds were prepared using the following modification of a published procedure [18]. A mixture of ethyl acetoacetate or methyl acetoacetate (20 mmol), urea (20 mmol), 4-methoxycarbonylbenzaldehyde (20 mmol) and p-toluenesulfonic acid (10 mol%) in ethanol (100 mL) was stirred and heated under reflux. After cooling, the resulting solid product was filtered and crystallized from ethanol to afford pure compound 1a,b.
4-[4-(Methoxycarbonyl)phenyl]-5-methoxycarbonyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one (1a)
White solid; yield 71%; mp 247–249°C; 1H NMR: δ 9.28 (s, 1H, -NH), 7.92 (d, 2H, J=7 Hz, Ar-H), 7.82 (s, 1H, NH), 7.37 (d, 2H, J=7 Hz, Ar-H), 5.21 (s, 1H, CH), 3.84 (s, 3H, OCH3), 3.53 (s, 3H, OCH3), 2.25 (s, 3H, CH3). HRMS. Calcd for C15H16N2O5, [M]+: m/z 304.1054. Found: m/z 304.1052.
5-Ethoxycarbonyl-4-[4-(methoxycarbonyl)phenyl]-6-methyl-3,4-dihydropyrimidin-2(1H)-one (1b)
White solid; yield 82%; mp 191–193°C; 1H NMR: δ 9.27 (s, 1H, -NH), 7.93 (d, 2H, J=8 Hz, Ar-H), 7.82 (s, 1H, -NH), 7.38 (d, 2H, J=8 Hz, Ar-H), 5.22 (d, 1H, J=3 Hz, CH), 3.99–3.96 (m, 2H, OCH2), 3.83 (s, 3H, OCH3), 2.26 (s, 3H, CH3), 1.08 (t, 3H, J=7 Hz, OCH2CH3). HRMS. Calcd for C16H19N2O5, [M+H]+: m/z 319.1288. Found: m/z 319.1299.
General procedure for the preparation of 2a and 2b
A solution of 1a or 1b (10 mmol) and hydrazine hydrate (80%, 50 mmol) in absolute ethanol (20 mL) was heated under reflux for 12 h. Upon cooling, the resultant precipitate was filtered and crystalized from ethanol to give the hydrazide derivative 2a,b.
4-[4-(Hydrazinocarbonyl)phenyl]-5-methoxycarbonyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one (2a)
White solid; yield 70%; mp 273–275°C; 1H NMR: δ 9.69 (s, 1H, NH), 9.25 (s, 1H, NH), 7.78 (s, 1H, NH), 7.74 (d, 2H, J=8 Hz, Ar-H), 7.27 (d, 2H, J=8 Hz, Ar-H), 5.17 (d, 1H, J=3.5 Hz, CH), 4.47 (s, 2H, NH2), 3.53 (s, 3H, OCH3), 2.25 (s, 3H, CH3). HRMS. Calcd for C14H17N4O4, [M+H]+: m/z 305.1224. Found: m/z 305.1235.
5-Ethoxycarbonyl-4-[4-(hydrazinocarbonyl)phenyl]-6-methyl-3,4-dihydropyrimidin-2(1H)-one (2b)
White solid; yield 76%; mp 268–269°C; 1H NMR: δ 9.71 (s, 1H, NH), 9.24 (s, 1H, NH), 7.77 (d, 3H, J=8 Hz, Ar-H, NH), 7.30 (d, 2H, J=8 Hz, Ar-H), 5.19 (s, 1H, CH), 4.49 (s, 1H, NH2), 3.98 (d, 2H, J=7 Hz, OCH2), 2.26 (s, 3H, CH3), 1.08 (t, 3H, J=7 Hz, OCH2CH3); 13C NMR: δ 166.2, 165.7, 152.5, 149.1, 148.1, 132.8, 127.6, 126.6, 99.3, 59.7, 54.2, 18.2, 14.5. HRMS. Calcd for C15H19N4O4, [M+H]+: m/z 319.1401. Found: m/z 319.1415.
General procedure for the preparation of 3a–r
A mixture of 2a or 2b (2 mmol) and aromatic aldehyde (2.2 mmol) in ethanol/DMF was heated under reflux for 5 h in the presence of catalytic amount of glacial acetic acid, then cooled and poured into ice water. The resultant precipitate was filtered and crystalized from ethanol/DMF to obtain the target compound 3a–r.
4-[4-(2-Benzylidenehydrazinocarbonyl)phenyl]-5-methoxycarbonyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one (3a)
White solid; yield 83%; mp 274–277°C; IR: ν 3286, 3253, 3054, 2954, 1696, 1643, 1606, 1540, 1434, 1335, 1270, 1235, 1084 cm−1; 1H NMR: δ 11.82 (s, 1H, CH), 9.32 (s, 1H, NH), 8.45 (s, 1H, NH), 7.87 (d, 3H, J=7 Hz, Ar-H, -NH), 7.74 (d, 2H, J=6 Hz, Ar-H), 7.46 (d, 3H, J=6 Hz, Ar-H), 7.39 (d, 2H, J=7 Hz, Ar-H), 5.24 (d, 1H, J=2.8 Hz, CH), 3.56 (s, 3H, OCH3), 2.29 (s, 3H, CH3); 13C NMR: δ 166.2, 163.5, 152.5, 149.5, 148.7, 148.2, 134.8, 133.1, 130.5, 129.3, 128.4, 127.6, 126.7, 99.0, 54.2, 51.3, 18.4. HRMS. Calcd for C21H21N4O4, [M+H]+: m/z 393.1557. Found: m/z 393.1555.
4-[4-(2-(4-Methoxybenzylidene)hydrazinocarbonyl)phenyl]-5-methoxycarbonyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one (3b)
White solid; yield 76%; mp 258–260°C; IR: ν 3344, 3232, 3145, 3037, 2946, 2838, 1684, 1645, 1607, 1512, 1455, 1439, 1292, 1234, 1106 cm−1; 1H NMR: δ 11.67 (s, 1H, CH), 9.30 (s, 1H, NH), 8.38 (s, 1H, NH), 7.84 (d, 3H, J=7 Hz, Ar-H, NH), 7.68 (d, 2H, J=8 Hz, Ar-H), 7.37 (d, 2H, J=8 Hz, Ar-H), 7.03 (d, 2H, J=8 Hz, Ar-H), 5.23 (d, 1H, J=2.4 Hz, CH), 3.82 (s, 3H, OCH3), 3.55 (s, 3H, OCH3), 2.28 (s, 3H, CH3); 13C NMR: δ 166.2, 163.3, 161.3, 152.5, 149.5, 148.5, 148.1, 133.3, 129.2, 128.3, 127.4, 126.7, 114.8, 99.1, 55.8, 54.2, 51.3, 18.3. HRMS. Calcd for C22H23N4O5, [M+H]+: m/z 423.1663. Found: m/z 423.1657.
4-[4-(2-(4-N,N-Dimethylaminophenylbenzylidene)hydrazinocarbonyl)phenyl]-5-methoxycarbonyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one (3c)
Yellow solid; yield 75%; mp 188–190°C; IR: ν 3435, 3232, 3124, 2942, 1682, 1653, 1627, 1611, 1597, 1523, 1432, 1366, 1337, 1241, 1188, 1088 cm−1; 1H NMR: δ 11.51 (s, 1H, -CH), 9.31 (s, 1H, NH), 8.29 (s, 1H, NH), 7.83 (d, 3H, J=8 Hz, Ar-H, -NH), 7.54 (d, 2H, J=8 Hz, Ar-H), 7.36 (d, 2H, J=8 Hz, Ar-H), 6.76 (d, 2H, J=8 Hz, Ar-H), 5.23 (d, 1H, J=2.4 Hz, CH), 3.55 (s, 3H, OCH3), 2.98 (s, 6H, N(CH3)2), 2.28 (s, 3H, CH3); 13C NMR: δ 166.2, 163.1, 152.5, 152.0, 149.5, 149.1, 148.3, 133.5, 128.9, 128.3, 126.7, 122.1, 112.3, 99.1, 54.2, 51.3, 40.2, 18.3. HRMS. Calcd for C23H26N5O4, [M+H]+: m/z 436.1979. Found: m/z 436.1961.
4-[4-(2-(2-Hydroxybenzylidene)hydrazinocarbonyl)phenyl]-5-methoxycarbonyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one (3d)
White solid; yield 85%; mp 292–294°C; IR: ν 3419, 3232, 3158, 3067, 2954, 1690, 1659, 1646, 1619, 1565, 1494, 1436, 1341, 1300, 1245, 1088 cm−1; 1H NMR: δ 12.07 (s, 1H, OH), 11.28 (s, 1H, CH), 9.32 (s, 1H, NH), 8.63 (s, 1H, NH), 7.89 (d, 1H, J=8 Hz, Ar-H), 7.86 (s, 1H, NH),7.55 (d, 1H, J=8 Hz, Ar-H), 7.39 (d, 2H, J=8 Hz, Ar-H), 7.31 (t, 1H, J=8 Hz, Ar-H), 6.95–6.91 (m, 2H, Ar-H), 5.23 (d, 1H, J=3.2 Hz, CH), 3.55 (s, 3H, OCH3), 2.28 (s, 3H, CH3); 13C NMR: δ 166.2, 163.2, 157.9, 152.5, 149.6, 148.9, 148.7, 132.5, 131.9, 130.0, 128.5, 126.8, 119.8, 119.1, 116.9, 99.0, 54.2, 51.3, 18.4. HRMS. Calcd for C21H21N4O5, [M+H]+: m/z 409.1506. Found: m/z 409.1501.
5-Methoxycarbonyl-6-methyl-4-[4-(2-(4-nitrobenzylidene)hydrazinocarbonyl)phenyl]-3,4-dihydropyrimidin-2(1H)-one (3e)
White solid; yield 86%; mp 188–190°C; IR: ν 3311, 3211, 3108, 3058, 2954, 2838, 1701, 1661, 1607, 1556, 1515, 1431, 1386, 1283, 1222, 1091 cm−1; 1H NMR: δ 12.12 (s, 1H, CH), 9.32 (s, 1H, NH), 8.54 (s, 1H, NH), 8.31 (d, 2H, J=8 Hz, Ar-H), 8.00 (d, 2H, J=8 Hz, Ar-H), 7.88 (d, 3H, J=8 Hz, Ar-H, NH), 7.40 (d, 2H, J=8 Hz, Ar-H), 5.24 (d, 1H, J=3.2 Hz, CH), 3.55 (s, 3H, OCH3), 2.28(s, 3H, CH3); 13C NMR: δ 166.2, 163.8, 152.5, 149.6, 149.0, 148.3, 145.7, 141.1, 132.8, 128.6, 128.5, 126.8, 124.5, 99.0, 54.2, 51.3, 18.3. HRMS. Calcd for C21H20N5O6, [M+H]+: m/z 438.1408. Found: m/z 438.1412.
4-[4-(2-(4-Chlorobenzylidene)hydrazinocarbonyl)phenyl]-5-methoxycarbonyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one (3f)
White solid; yield 85%; mp 288–290°C; IR: ν 3365, 3253, 3112, 2975, 2822, 1718, 1693, 1654, 1638, 1613, 1539, 1431, 1283, 1231, 1088 cm−1; 1H NMR: δ 11.88 (s, 1H, CH), 9.31 (s, 1H, NH), 8.43 (s, 1H, NH), 7.76 (d, 3H, J=6 Hz, Ar-H, NH), 7.76 (d, 2H, J=8 Hz, Ar-H), 7.53 (d, 2H, J=8 Hz, Ar-H), 7.38 (d, 2H, J=8 Hz, Ar-H), 5.23 (d, 1H, J=2.8 Hz, CH), 3.55 (s, 3H, OCH3), 2.28 (s, 3H, CH3); 13C NMR: δ 166.2, 163.6, 152.5, 149.6, 148.7, 146.8, 135.0, 133.8, 133.0, 129.4, 129.2, 128.4, 126.8, 99.0, 54.2, 51.3, 18.3. HRMS. Calcd for C21H20ClN4O4, [M+H]+: m/z 427.1168. Found: m/z 427.1178.
4-[4-(2-(4-Bromobenzylidene)hydrazinocarbonyl)phenyl]-5-methoxycarbonyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one (3g)
White solid; yield 83%; mp>300°C; IR: ν 3365, 3249, 3116, 2971, 2813, 1718, 1693, 1656, 1639, 1606, 1536, 1432, 1285, 1231, 1092 cm−1; 1H NMR: δ 11.88 (s, 1H, CH), 9.31 (s, 1H, NH), 8.41 (s, 1H, NH), 7.86 (d, 3H, J=7 Hz, Ar-H, NH), 7.67 (t, 4H, J=8 Hz, Ar-H), 7.38 (d, 2H, J=8 Hz, Ar-H), 5.23 (d, 1H, J=2.8 Hz, CH), 3.55 (s, 3H, OCH3), 2.28 (s, 3H, CH3); 13C NMR: δ 166.2, 163.6, 152.5, 149.6, 148.7, 146.9, 134.1, 133.0, 132.3, 129.4, 128.4, 126.8, 123.8, 99.0, 54.2, 51.3, 18.3. HRMS. Calcd for C21H20BrN4O4, [M+H]+: m/z 471.0662. Found: m/z 471.0649.
5-Methoxycarbonyl-6-methyl-4-[4-(2-(3-nitrobenzylidene)hydrazinocarbonyl)phenyl]-3,4-dihydropyrimidin-2(1H)-one (3h)
White solid; yield 79%; mp 296–298°C; IR: ν 3357, 3220, 3091, 2945, 1707, 1642, 1606, 1529, 1432, 1350, 1286, 1229, 1094 cm−1; 1H NMR: δ 12.09 (s, 1H, CH), 9.31 (s, 1H, -NH), 8.56 (s, 2H, NH, Ar-H), 8.28 (d, 1H, J=7 Hz, Ar-H), 8.17 (d, 1H, J=7 Hz, Ar-H), 7.87 (d, 3H, J=8 Hz, NH, Ar-H), 7.78 (t, 1H, J=7 Hz, Ar-H), 7.39 (d, 2H, J=8 Hz, Ar-H), 5.23 (d, 1H, J=2.4 Hz, CH), 3.81 (s, 3H, OCH3), 3.55 (s, 3H, OCH3), 2.28 (s, 3H, CH3); 13C NMR: δ 166.2, 163.7, 152.5, 149.6, 148.9, 148.7, 145.8, 136.7, 133.9, 132.8, 131.0, 128.6, 126.8, 124.7, 121.4, 99.0, 54.2, 51.3, 18.3. HRMS. Calcd for C21H20N5O6, [M+H]+: m/z 438.1408. Found: m/z 438.1413.
4-[4-(2-(2,4-Dichlorobenzylidene)hydrazinocarbonyl)phenyl]-5-methoxycarbonyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one (3i)
White solid; yield 77%; mp 279-281°C; IR: ν 3353, 3216, 3104, 2942, 1700, 1652, 1611, 1559, 1436, 1294, 1226, 1100 cm−1; 1H NMR: δ 12.09 (s, 1H, -CH), 9.31 (s, 1H, NH), 8.80 (s, 1H, NH), 8.03 (d, 1H, J=8 Hz, Ar-H), 7.88 (d, 2H, J=8 Hz, Ar-H), 7.86 (s, 1H, NH), 7.73 (s, 1H, Ar-H), 7.53 (d, 1H, J=8 Hz, Ar-H), 7.39 (d, 2H, J=8 Hz, Ar-H), 5.23 (d, 1H, J=3.2 Hz, CH), 3.55 (s, 3H, OCH3), 2.28 (s, 3H,-CH3); 13C NMR: δ 166.1, 163.5, 152.5, 149.6, 148.9, 143.0, 135.5, 134.3, 132.7, 131.2, 129.9, 128.5, 126.8, 99.0, 54.2, 51.3, 18.4. HRMS. Calcd for C21H19Cl2N4O4, [M+H]+: m/z 461.0778. Found: m/z 461.0744.
4-[4-(2-Benzylidenehydrazinocarbonyl)phenyl]-5-ethoxycarbonyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one (3j)
White solid; yield 76%; mp 228–230°C; IR: ν 3241, 3112, 2983, 2934, 1715, 1685, 1646, 1610, 1559, 1536, 1450, 1370, 1287, 1226, 1096 cm−1; 1H NMR: δ 11.79 (s, 1H, CH), 9.26 (s, 1H, NH), 8.44 (s, 1H, NH), 7.86 (d, 2H, J=8 Hz, Ar-H), 7.82 (s, 1H, NH), 7.72 (d, 2H, J=7 Hz, Ar-H), 7.45~7.37 (m, 5H, Ar-H), 5.23 (d, 1H, J=3.2 Hz, CH), 4.02–3.97 (m, 2H, OCH2), 2.27 (s, 3H, CH3), 1.11 (t, 3H, J=7 Hz, OCH2CH3); 13C NMR: δ 165.7, 163.5, 152.5, 149.3, 148.8, 148.2, 134.8, 133.0, 130.5, 129.3, 128.4, 127.5, 126.8, 99.3, 59.7, 54.3, 18.3, 14.5. HRMS. Calcd for C22H23N4O4, [M+H]+: m/z 407.1714. Found: m/z 407.1694.
5-Ethoxycarbonyl-4-[4-(2-(4-methoxybenzylidene)hydrazinocarbonyl)phenyl]-6-methyl-3,4-dihydropyrimidin-2(1H)-one (3k)
White solid; yield 70%; mp 173–175°C; IR: ν 3240, 3109, 2978, 2837, 1704, 1652, 1607, 1511, 1453, 1366, 1287, 1254, 1226, 1093 cm−1; 1H NMR: δ 11.68 (s, 1H, CH), 9.27 (s, 1H, NH), 8.38 (s, 1H, NH), 7.86 (d, 2H, J=8 Hz, Ar-H), 7.83 (s, 1H, NH), 7.66 (d, 2H, J=8 Hz, Ar-H), 7.38 (d, 2H, J=8 Hz, Ar-H), 7.00 (d, 2H, J=8 Hz, Ar-H), 5.25 (s, 1H, CH), 4.00–3.97 (m, 2H, OCH2), 3.79 (s, 3H, OCH3), 2.28 (s, 3H, CH3), 1.10 (t, 3H, J=7 Hz, OCH2CH3); 13C NMR: δ 165.7, 163.3, 161.3, 152.5, 149.2, 148.7, 148.2, 133.2, 129.2, 128.3, 127.3, 126.8, 114.8, 99.3, 59.7, 55.7, 54.3, 18.2, 14.5. HRMS. Calcd. for C23H25N4O5, [M+H]+: m/z 437.1819. Found: m/z 437.1828.
5-Ethoxycarbonyl-4-[4-(2-(4-N,N-dimethylaminophenylbenzylidene)hydrazinocarbonyl)phenyl]-6-methyl-3,4-dihydropyrimidin-2(1H)-one (3l)
Yellow solid; yield 53%; mp 184–186°C; IR: ν 3238, 3116, 2979, 2801, 1705, 1680, 1652, 1607, 1523, 1364, 1286, 1225, 1092 cm−1; 1H NMR: δ 11.50 (s, 1H, CH), 9.26 (s, 1H, NH), 8.29 (s, 1H, NH), 7.83 (s, 3H, NH, Ar-H), 7.53 (d, 2H, J=6 Hz, Ar-H), 7.37 (d, 2H, J=6 Hz, Ar-H), 6.73 (d, 2H, J=6 Hz, Ar-H), 5.24 (s, 1H, CH), 4.00-3.98 (m, 2H, OCH2), 2.95 (s, 6H, N(CH3)2), 2.28 (s, 3H, CH3), 1.10 (s, 3H, OCH2CH3); 13C NMR: δ 165.7, 163.3, 152.5, 152.0, 149.2, 149.1, 148.5, 133.4, 128.9, 128.2, 126.7, 122.0, 112.2, 99.3, 59.8, 54.3, 40.1, 18.3, 14.5. HRMS. Calcd for C24H28N5O4, [M+H]+: m/z 450.2136. Found: m/z 450.2112.
5-Ethoxycarbonyl-4-[4-(2-(2-hydroxybenzylidene)hydrazinocarbonyl)phenyl]-6-methyl-3,4-dihydropyrimidin-2(1H)-one (3m)
White solid; yield 73%; mp 270–272°C; IR: ν 3356, 3219, 3107, 2971, 1716, 1689, 1654, 1641, 1614, 1531, 1490, 1456, 1278, 1228, 1087 cm−1; 1H NMR: δ 12.06 (s, 1H, OH), 11.31 (s, 1H, CH), 9.28 (s, 1H, NH), 8.63 (s, 1H, NH), 7.90 (s, 2H, Ar-H), 7.83 (s, 1H, NH), 7.52~7.29 (m, 4H, Ar-H), 6.93 (s, 2H, Ar-H), 5.25 (s, 1H, CH), 3.99 (s, 2H, OCH2), 2.28 (s, 3H, CH3), 1.11 (s, 3H, OCH2CH3); 13C NMR: δ 165.7, 163.2, 158.0, 152.5, 149.3, 149.1, 148.8, 132.4, 131.8, 130.0, 128.4, 126.9, 119.8, 119.1, 116.9, 99.3, 59.8, 54.3, 18.3, 14.5. HRMS. Calcd for C22H23N4O5, [M+H]+: m/z 423.1663. Found: m/z 423.1657.
5-Ethoxycarbonyl-6-methyl-4-[4-(2-(4-nitrobenzylidene)hydrazinocarbonyl)phenyl]-3,4-dihydropyrimidin-2(1H)-one (3n)
White solid; yield 85%; mp 251–253°C; IR: ν 3246, 3116, 2979, 1726, 1698, 1646, 1606, 1520, 1457, 1343, 1286, 1225, 1096 cm−1; 1H NMR: δ 12.09 (s, 1H, CH), 9.26 (s, 1H, NH), 8.53 (s, 1H, NH), 8.29 (d, 2H, J=8 Hz, Ar-H), 7.98 (d, 2H, J=8 Hz, Ar-H), 7.87 (d, 2H, J=8 Hz, Ar-H), 7.82 (s, 1H, NH), 7.39 (d, 2H, J=8 Hz, Ar-H), 5.23 (d, 1H, J=2.4 Hz, CH), 4.02-3.97 (m, 2H, OCH2), 2.26 (s, 3H, CH3), 1.11 (t, 3H, J=7 Hz, OCH2CH3); 13C NMR: δ 165.7, 163.7, 152.5, 149.3, 149.1, 148.3, 145.7, 141.1, 132.7, 128.4, 126.8, 124.5, 99.2, 59.7, 54.3, 18.3, 14.5. HRMS. Calcd for C22H22N5O6, [M+H]+: m/z 452.1565. Found: m/z 452.1530.
4-[4-(2-(4-Chlorobenzylidene)hydrazinocarbonyl)phenyl]-5-ethoxycarbonyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one (3o)
White solid; yield 83%; mp 279–281°C; IR: ν 3356, 3220, 3119, 2971, 2817, 1717, 1689, 1655, 1641, 1606, 1540, 1494, 1453, 1370, 1284, 1228, 1087 cm−1; 1H NMR: δ 11.85 (s, 1H, CH), 9.26 (s, 1H, NH), 8.43 (s, 1H, NH), 7.86 (d, 2H, J=8 Hz, Ar-H), 7.82 (s, 1H, NH), 7.74 (d, 2H, J=8 Hz, Ar-H), 7.50 (d, 2H, J=8 Hz, Ar-H), 7.38 (d, 2H, J=8 Hz, Ar-H), 5.23 (d, 1H, J=3.2 Hz, CH), 4.02~3.97 (m, 2H, OCH2), 2.27 (s, 3H, CH3), 1.11 (t, 3H, J=7 Hz, OCH2CH3); 13C NMR: δ 165.7, 163.5, 152.5, 149.3, 148.9, 146.9, 135.0, 133.7, 132.9, 129.4, 129.1, 128.4, 126.8, 99.3, 59.7, 54.3, 18.3, 14.5. HRMS. Calcd for C22H22ClN4O4, [M+H]+: m/z 441.1324. Found: m/z 441.1341.
4-[4-(2-(4-Bromobenzylidene)hydrazinocarbonyl)phenyl]-5-ethoxycarbonyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one (3p)
White solid; yield 79%; mp 286–287°C; IR: ν 3240, 3104, 2978, 2929, 1702, 1664, 1646, 1610, 1532, 1486, 1460, 1370, 1286, 1222, 1092 cm−1; 1H NMR: δ 11.87 (s, 1H, CH), 9.27 (s, 1H, NH), 8.41 (s, 1H, NH), 7.87 (d, 2H, J=8 Hz, Ar-H), 7.83 (s, 1H, NH), 7.67 (d, 2H, J=8 Hz, Ar-H), 7.62 (d, 2H, J=8 Hz, Ar-H), 7.39 (d, 2H, J=8 Hz, Ar-H), 5.25 (d, 1H, J=2.8 Hz, CH), 4.02–3.97 (m, 2H, OCH2), 2.28 (s, 3H, CH3), 1.10 (t, 3H, J=7 Hz, OCH2CH3); 13C NMR: δ 165.7, 163.6, 152.5, 149.2, 148.9, 147.0, 134.1, 132.9, 132.3, 129.4, 128.4, 126.8, 123.8, 99.3, 59.7, 54.3, 18.3, 14.5. HRMS. Calcd for C22H22BrN4O4, [M+H]+: m/z 485.0819. Found: m/z 485.0824.
5-Ethoxycarbonyl-6-methyl-4-[4-(2-(3-nitrobenzylidene)hydrazinecarbonyl)phenyl]-3,4-dihydropyrimidin-2(1H)-one (3q)
White solid; yield 78%; mp 271–273°C; IR: ν 3344, 3236, 3108, 2979, 2929, 1699, 1654, 1610, 1561, 1531, 1353, 1287, 1225, 1092 cm−1; 1H NMR: δ 12.05 (s, 1H, CH), 9.26 (s, 1H, NH), 8.54 (s, 2H, NH, Ar-H), 8.23 (d, 1H, J=7 Hz, Ar-H), 8.13 (d, 1H, J=7 Hz, Ar-H), 7.87 (d, 2H, J=8 Hz, Ar-H), 7.82 (s, 1H, NH), 7.73 (t, 1H, J=7 Hz, Ar-H), 7.39 (d, 2H, J=8 Hz, Ar-H), 5.23 (d, 1H, J=2.8 Hz, CH), 4.02-3.97 (m, 2H, OCH2), 2.27 (s, 3H, CH3), 1.11 (t, 3H, J=7 Hz, OCH2CH3); 13C NMR: δ 165.7, 163.7, 152.5, 149.2, 149.1, 145.7, 136.7, 133.8, 132.7, 130.9, 128.5, 126.8, 124.6, 121.3, 99.3, 59.7, 54.3, 18.3, 14.5. HRMS. Calcd for C22H22N5O6, [M+H]+: m/z 452.1565. Found: m/z 452.1528.
4-[4-(2-(2,4-Dichlorobenzylidene)hydrazinocarbonyl)phenyl]-5-ethoxycarbonyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one (3r)
White solid; yield 76%; mp 297–299°C; IR: ν 3357, 3228, 3108, 2929, 2809, 1695, 1652, 1607, 1590, 1557, 1469, 1378, 1284, 1230, 1101 cm−1; 1H NMR: δ 9.26 (s, 1H, NH), 8.78 (s, 1H, NH), 8.00 (d, 1H, J=8 Hz, Ar-H), 7.88 (d, 2H, J=8 Hz, Ar-H), 7.82 (s, 1H, NH), 7.63 (s, 1H, Ar-H), 7.46 (d, 1H, J=8 Hz, Ar-H), 7.39 (d, 2H, J=8 Hz, Ar-H), 5.24 (d, 1H, J=2.8 Hz, CH), 4.01–3.95 (m, 2H, OCH2), 2.27 (s, 3H, -CH3), 1.09 (t, 3H, J=7 Hz, OCH2CH3); 13C NMR: δ 165.7, 163.5, 152.5, 149.3, 149.1, 143.0, 135.5, 134.3, 132.6, 131.2, 129.8, 128.4, 126.9, 99.3, 59.7, 54.4, 18.3, 14.5. HRMS. Calcd for C22H21Cl2N4O4, [M+H]+: m/z 475.0934. Found: m/z 475.0928.
Antimicrobial activity
The antimicrobial activities were determined against bacterial strain E. coli and fungal strain A. niger by the standardized disk diffusion method [19] at 50 μg/mL concentration in DMSO. The antimicrobial activity was determined by measuring the diameter of inhibition zone. Ciprofloxacin and fluconazole were used as standard drugs against bacterial and fungal strains, respectively, at 50 μg/mL concentration.
Acknowledgements
We acknowledge the financial support from the National Natural Science Foundation of China (No. 61741510) and the Science and Technology Research Program of Education Department of Jiangxi Province, China (No. GJJ12703).
References
[1] Matias, M.; Campos, G.; Santos, A. O.; Falcão, A.; Silvestre, S.; Alves, G. Potential antitumoral 3,4-dihydro- pyrimidin-2-(1H)-ones: synthesis, in vitro biological evaluation and QSAR studies. RSC Adv. 2016, 6, 84943–84958.10.1039/C6RA14596ESearch in Google Scholar
[2] Stefani, H. A.; Oliveira, C. B.; Almeida, R. B.; Pereira, C. M. P.; Braga, R. C.; Cell, R.; Borges, V. C.; Savegnago, L.; Nogueira, C. W. Dihydropyrimidin-(2H)-ones obtained by ultrasound irradiation: a new class of potential antioxidant agents. Eur. J. Med. Chem. 2006, 41, 513–518.10.1016/j.ejmech.2006.01.007Search in Google Scholar PubMed
[3] Ashok, M.; Holla, B. S.; Kumari, N. S. Convenient one pot synthesis of some novel derivatives of thiazolo[2,3-b]dihydropyrimidinone possessing 4-methyl thio-phenyl moiety and evaluation of their antibacterial and antifungal activities. Eur. J. Med. Chem. 2007, 42, 380–385.10.1016/j.ejmech.2006.09.003Search in Google Scholar PubMed
[4] Singh, O. M.; Singh, S. J.; Devi, M. B.; Devi, L. N.; Singh, N. I.; Lee, S. G. Synthesis and in vitro evaluation of the antifungal activities of dihydropyrimidinones. Bioorg. Med. Chem. Lett. 2008, 18, 6462–6467.10.1016/j.bmcl.2008.10.063Search in Google Scholar PubMed
[5] Bahekar, S. S.; Shinde, D. B. Synthesis and anti-inflammatory activity of some [4,6-(4-substituted aryl)-2-thioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-acetic acid derivatives. Bioorg. Med. Chem. Lett. 2004, 14, 1733–1736.10.1016/j.bmcl.2004.01.039Search in Google Scholar PubMed
[6] Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd, D. M.; Moreland, S.; Hedberg, A.; O’Reilly, B. C. Dihydropyrimidine calcium channel blockers. 3. 3-Carbamoyl-4-aryl-1,2,3,4-tetrahydro-6-methyl-5-pyrimidinecarboxylic acid esters as orally effective antihypertensive agents. J. Med. Chem. 1991, 34, 806–811.10.1021/jm00106a048Search in Google Scholar PubMed
[7] Kappe, C. O.; Fabian, W. M. F.; Semones, M. A. Conformational analysis of 4-aryl-dihydropyrimidine calcium channel modulators. A comparison of ab initio, semiempirical and X-ray crystallographic studies. Tetrahedron1997, 53, 2803–2816.10.1016/S0040-4020(97)00022-7Search in Google Scholar
[8] Crespo, A.; Maatougui, A. E.; Biagini, P.; Azuaje, J.; Coelho, A.; Brea, J.; Loza, M. I.; Cadavid, M. I.; García-Mera, X.; Gutiérrez-de-Terán, H.; et al. Discovery of 3,4-dihydropyrimidin-2(1H)-ones as a novel class of potent and selective A2B adenosine receptor antagonists. ACS Med. Chem. Lett.2013, 4, 1031–1036.10.1021/ml400185vSearch in Google Scholar PubMed PubMed Central
[9] Kim, J.; Ok, T.; Park, C.; So, W.; Jo, M.; Seo, M.; Kim, Y.; Sohn, J. H.; Park, Y.; Ju, M. K.; et al. Discovery of 3,4-dihydropyrimidin-2(1H)-ones with inhibitory activity against HIV-1 replication. Bioorg. Med. Chem. Lett. 2012, 22, 2119–2124.10.1016/j.bmcl.2011.12.090Search in Google Scholar PubMed
[10] Sashidhara, K. V.; Singh, L. R.; Shameem, M.; Shakya, S.; Kumar, A.; Laxman, T. S.; Krishna, S.; Siddiqi, M. I.; Bhatta, R. S.; Banerjee, D. Design, synthesis and anticancer activity of dihydropyrimidinone-semicarbazone hybrids as potential human DNA ligase 1 inhibitors. MedChemComm.2016, 7, 2349–2363.10.1039/C6MD00447DSearch in Google Scholar
[11] Dubs, P.; Bourel-Bonnet, L.; Subra, G.; Blanpain, A.; Melnyk, O.; Pinel, A. M.; Gras-Masse, H.; Martinez, J. Parallel synthesis of a lipopeptide library by hydrazone-based chemical Ligation. J. Comb. Chem. 2007, 9, 973–981.10.1021/cc070033bSearch in Google Scholar PubMed
[12] Abdelrahman, M. A.; Salama, I.; Gomaa, M. S.; Elaasser, M. M.; Abdel-Aziz, M. M .; Soliman, D. H. Design, synthesis and 2D QSAR study of novel pyridine and quinolone hydrazone derivatives as potential antimicrobial and antitubercular agents. Eur. J. Med. Chem. 2017, 138, 698–714.10.1016/j.ejmech.2017.07.004Search in Google Scholar PubMed
[13] Angelova, V. T.; Vassilev, N. G.; Nikolova-Mladenova, B.; Vitas, J.; Malbasa, R.; Momekov, G.; Djukic, M.; Saso, L. Antiproliferative and antioxidative effects of novel hydrazone derivatives bearing coumarin and chromene moiety. Med. Chem. Res.2016, 25, 2082–2092.10.1007/s00044-016-1661-4Search in Google Scholar
[14] Moldovan, C. M.; Oniga, O.; Parvu, A.; Tiperciuc, B.; Verite, P.; Pirnau, A.; Crisan, O.; Bojita, M.; Pop, R. Synthesis and anti-inflammatory evaluation of some new acyl-hydrazones bearing 2-aryl-thiazole. Eur. J. Med. Chem. 2011, 46, 526–534.10.1016/j.ejmech.2010.11.032Search in Google Scholar PubMed
[15] Ulloora, S.; Shabaraya, R.; Ranganathan, R.; Adhikari, A. V. Synthesis, anticonvulsant and anti-inflammatory studies of new 1,4-dihydropyridin-4-yl-phenoxyacetohydrazones. Eur. J. Med. Chem. 2013, 70, 341–349.10.1016/j.ejmech.2013.10.010Search in Google Scholar PubMed
[16] He, H. F.; Wang, X. Y.; Shi, L. Q.; Yin, W. Y.; Yang, Z. W.; He, H. W.; Liang, Y. Synthesis, antitumor activity and mechanism of action of novel 1,3-thiazole derivatives containing hydrazide-hydrazone and carboxamide moiety. Bioorg. Med. Chem. Lett. 2016, 26, 3263–3270.10.1016/j.bmcl.2016.05.059Search in Google Scholar PubMed
[17] Wang, G. C.; Chen, M.; Wang, J.; Peng, Y. P.; Li, L. Y.; Xie, Z. Z.; Deng, B.; Chen, S.; Li, W. B. Synthesis, biological evaluation and molecular docking studies of chromone hydrazone derivatives as a-glucosidase inhibitors. Bioorg. Med. Chem. Lett. 2017, 27, 2957–2961.10.1016/j.bmcl.2017.05.007Search in Google Scholar PubMed
[18] Jin, T. S.; Wang, H. X.; Xing, C. Y.; Li, X. L.; Li, T. S. An efficient one-pot synthesis of 3,4-dihydropyrimidin-2-ones catalyzed by methanesulfonic acid. Synth. Commun. 2004, 34, 3009–3016.10.1081/SCC-200026660Search in Google Scholar
[19] Wang, L. Z.; Zhang, P.; Zhang, X. M.; Zhang, Y. H.; Li, Y.; Wang, Y. X. Synthesis and biological evaluation of a novel series of 1,5-benzothiazepine derivatives as potential antimicrobial agents. Eur. J. Med. Chem. 2009, 44, 2815–2821.10.1016/j.ejmech.2008.12.021Search in Google Scholar PubMed
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