Synthesis and antimicrobial activity of 3,4-dihydropyrimidin-2(1H)-one derivatives containing a hydrazone moiety

Article abstract of DOI:10.1515/hc-2017-0227

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.

Full text of DOI:10.1515/hc-2017-0227

Heterocycl. Commun. 2018; aop
HSuya-nNatnhPeengs*i,sLi-MainnYde, MainngtZihmangi,cYarno-CbhuinaYlanagcantdiJvieiZthyenog f
3,4-dihydropyrimidin-2(1H)-one derivatives
containing a hydrazone moiety
https://doi.org/10.1515/hc-2017-0227
Results and discussion
Received October 24, 2017; accepted January 5, 2018
Abstract: The title compounds were synthesized and The preparation of target compounds 3a–r is shown in
1
characterized by IR, H NMR, 13C NMR and HRMS data. Scheme 1. First, 5-methoxycarbonyl-4-[(4-methoxycar-
Their antimicrobial activities against bacterial strains bonyl)phenyl]-6-methyl-3,4-dihydropyrimidin-2(1H)-one
Escherichia coli and fungal strains Aspergillus niger were (1a) and its 5-ethoxycarbonyl analog 1b were synthesized by
evaluated.
three-component condensation reaction of ethyl acetoac-
etate or methyl acetoacetate, urea and 4-methoxycarbonylb-
enzaldehyde 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
Keywords: 3,4-dihydropyrimidin-2(1H)-ones; antimicro-
bial activity; hydrazone; synthesis.
Introduction
3,4-Dihydropyrimidin-2(1H)-ones have attracted consider- did not react with hydrazine to give the hypothetical com-
able attention due their wide range of biological activities, pound 4. In the final step, the target compounds 3a–r were
including antitumor [1], antioxidative [2], antibacterial [3], prepared by a condensation reaction of 2a or 2b with differ-
antifungal [4], anti-inflammatory [5] and antihypertensive ent aromatic aldehydes in ethanol in the presence of acetic
properties [6]. They have also been identified as calcium acid. Structures of all synthetic compounds were confirmed
channel modulators [7], A2B adenosine receptor antago- by analysis of IR, 1H NMR, 13C NMR and HRMS data.
nists [8], HIV-1 replication inhibitors [9] and human DNA
All synthesized compounds were evaluated for their
ligase 1 inhibitors [10]. Hydrazones also exhibit a wide antimicrobial activities against bacterial strains E. coli
range of diverse biological activities [11–17]. In view of and fungal strains A. niger. All compounds show mod-
the biological significance of 3,4-dihydropyrimidin-2(1H)- erate inhibitory effect against the bacterial and fungal
ones and hydrazones, we designed and synthesized a strains. Most of them show better inhibitory activity than
series of novel 3,4-dihydropyrimidin-2(1H)-one derivatives the starting materials 1a and 1b. Compounds 3b, 3f, 3i,
bearing a hydrazone moiety and evaluated their antimi- 3j and 3l demonstrate good antibacterial activity which
crobial activities against bacterial strains Escherichia coli is nearly equal to that of the reference antibiotic cipro-
and fungal strains Aspergillus niger.
floxacin. Compound 3a is an excellent antifungal agent,
the activity of which is comparable to that of the reference
antibiotic fluconazole.
*Corresponding author: Hua-Nan Peng, Key Laboratory of Applied
Organic Chemistry, Higher Institutions of Jiangxi Province,
Shangrao Normal University, Shangrao 334001, China,
e-mail: huananpeng@126.com
Li-Min Ye: College of Life Sciences, Shangrao Normal University,
Shangrao 334001, China
Ming Zhang and Jie Zheng: Key Laboratory of Applied Organic
Chemistry, Higher Institutions of Jiangxi Province, Shangrao Normal
University, Shangrao 334001, China
Yan-Chun Yang: Jiangxi Provincial Research of Targeting
Pharmaceutical Engineering Technology, Shangrao 334001, China
Conclusions
New 3,4-dihydropyrimidin-2(1H)-ones containing a hydra-
zone 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 excel-
lent antifungal agent.
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ꢀꢀꢀꢁ
2ꢀ
ꢀH.-N. Peng et al.: 3,4-Dihydropyrimidin-2(1H)-one derivatives containing a hydrazone moiety
CONHNH2
O
HN
NH
NHNH2
4
O
NH2NH2 H2O
EtOH, ∆
CHO
CO2R1
O
O
O
O
PTSA
NH2NH2 H2O
+
+
HN
OR1
H2N
NH3
EtOH, ∆
EtOH, ∆ 12 h
NH
OCH3
CO2CH3
O
1a: R1 = Me; 71%
1b: R1 = Et; 82%
CO2R1
CO2R1
O
O
R2CHO
AcOH, EtOH, ∆ 5 h
HN
O
HN
O
NH
NHNH2
NH
NHN CH R2
(53–86%)
2a: R1 = Me; 70%
2b: R1 = Et; 76%
3a–r
3a: R1 = Me; R2 = Ph
3j: R1 = Et; R2 = Ph
3k: R1 = Et; R2 = 4-methoxy-C6H4
3b: R1 = Me; R2 = 4-methoxy-C6H4
3c: R1 = Me; R2 = 4-(N,N-dimethylamino)-C6H4
3d: R1 = Me; R2 = 2-hydroxy-C6H4
3e: R1 = Me; R2 = 4-nitro-C6H4
3l: R1 = Et; R2 = 4-(N,N-dimethylamino)-C6H4
3m: R1 = Et; R2 = 2-hydroxy-C6H4
3n: R1 = Et; R2 = 4-nitro-C6H4
3f: R1 = Me; R2 = 4-chloro-C6H4
3g: R1 = Me; R2 = 4-bromo-C6H4
3h: R1 = Me; R2 = 3-nitro-C6H4
3o: R1 = Et; R2 = 4-chloro-C6H4
3p: R1 = Et; R2 = 4-bromo-C6H4
3q: R1 = Et; R2 = 3-nitro-C6H4
3i: R1 = Me; R2 = 2,4-dichloro-C6H4
3r: R1 = Et; R2 = 2,4-dichloro-C6H4
Scheme 1ꢀ
3H, OCH3), 3.53 (s, 3H, OCH3), 2.25 (s, 3H, CH3). HRMS. Calcd for
+
Experimental
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, Jꢁ=ꢁ8 Hz, Ar-H), 7.82
(s, 1H, -NH), 7.38 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H), 5.22 (d, 1H, Jꢁ=ꢁ3 Hz, CH), 3.99–
3.96 (m, 2H, OCH2), 3.83 (s, 3H, OCH3), 2.26 (s, 3H, CH3), 1.08 (t, 3H,
Reagents were purchased from commercial sources and used with-
out 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 spectro-
meter 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).
+
Jꢁ=ꢁ7 Hz, OCH2CH3). HRMS. Calcd for C16H19N2O5, [Mꢁ+ꢁH] : m/z 319.1288.
Found: m/z 319.1299.
General procedure for the preparation of 2a and 2b
General procedure for the preparation of 1a and 1b
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 crystal-
ized from ethanol to give the hydrazide derivative 2a,b.
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-methoxycarbon-
ylbenzaldehyde (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-(Hydrazinocarbonyl)phenyl]-5-methoxycarbonyl-6-methyl-
3,4-dihydropyrimidin-2(1H)-one (2a)ꢀWhite solid; yield 70%; mp
1
273–275°C; H NMR: δ 9.69 (s, 1H, NH), 9.25 (s, 1H, NH), 7.78 (s, 1H,
NH), 7.74 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H), 7.27 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H), 5.17 (d, 1H,
Jꢁ=ꢁ3.5 Hz, CH), 4.47 (s, 2H, NH2), 3.53 (s, 3H, OCH3), 2.25 (s, 3H, CH3).
+
HRMS. Calcd for C14H17N4O4, [Mꢁ+ꢁH] : m/z 305.1224. Found: m/z 305.1235.
4-[4-(Methoxycarbonyl)phenyl]-5-methoxycarbonyl-6-methyl-
3,4-dihydropyrimidin-2(1H)-one (1a)ꢀWhite solid; yield 71%; mp
1
5-Ethoxycarbonyl-4-[4-(hydrazinocarbonyl)phenyl]-6-methyl-
3,4-dihydropyrimidin-2(1H)-one (2b)ꢀWhite solid; yield 76%; mp
247–249°C; H NMR: δ 9.28 (s, 1H, -NH), 7.92 (d, 2H, Jꢁ=ꢁ7 Hz, Ar-H),
7.82 (s, 1H, NH), 7.37 (d, 2H, Jꢁ=ꢁ7 Hz, Ar-H), 5.21 (s, 1H, CH), 3.84 (s,
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H.-N. Peng et al.: 3,4-Dihydropyrimidin-2(1H)-one derivatives containing a hydrazone moietyꢂ ꢂ3
1
268–269°C; H NMR: δ 9.71 (s, 1H, NH), 9.24 (s, 1H, NH), 7.77 (d, 3H, OCH3), 2.28 (s, 3H, CH3); 13C NMR: δ 166.2, 163.2, 157.9, 152.5, 149.6,
Jꢁ=ꢁ8 Hz, Ar-H, NH), 7.30 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H), 5.19 (s, 1H, CH), 4.49 148.9, 148.7, 132.5, 131.9, 130.0, 128.5, 126.8, 119.8, 119.1, 116.9, 99.0,
+
(s, 1H, NH2), 3.98 (d, 2H, Jꢁ=ꢁ7 Hz, OCH2), 2.26 (s, 3H, CH3), 1.08 (t, 3H, 54.2, 51.3, 18.4. HRMS. Calcd for C21H21N4O5, [Mꢁ+ꢁH] : m/z 409.1506.
Jꢁ=ꢁ7 Hz, OCH2CH3); 13C NMR: δ 166.2, 165.7, 152.5, 149.1, 148.1, 132.8, Found: m/z 409.1501.
127.6, 126.6, 99.3, 59.7, 54.2, 18.2, 14.5. HRMS. Calcd for C15H19N4O4,
+
[Mꢁ+ꢁH] : m/z 319.1401. Found: m/z 319.1415.
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,
General procedure for the preparation of 3a–r
1
1091 cm−1; H NMR: δ 12.12 (s, 1H, CH), 9.32 (s, 1H, NH), 8.54 (s, 1H,
NH), 8.31 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H), 8.00 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H), 7.88
(d, 3H, Jꢁ=ꢁ8 Hz, Ar-H, NH), 7.40 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H), 5.24 (d, 1H,
Jꢁ=ꢁ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,
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.
+
124.5, 99.0, 54.2, 51.3, 18.3. HRMS. Calcd for C21H20N5O6, [Mꢁ+ꢁH] : m/z
438.1408. Found: m/z 438.1412.
4-[4-(2-Benzylidenehydrazinocarbonyl)phenyl]-5-methoxycar-
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,
bonyl-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, Jꢁ=ꢁ7 Hz, Ar-H,
-NH), 7.74 (d, 2H, Jꢁ=ꢁ6 Hz, Ar-H), 7.46 (d, 3H, Jꢁ=ꢁ6 Hz, Ar-H), 7.39 (d, 2H,
Jꢁ=ꢁ7 Hz, Ar-H), 5.24 (d, 1H, Jꢁ=ꢁ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
1
1088 cm−1; H NMR: δ 11.88 (s, 1H, CH), 9.31 (s, 1H, NH), 8.43 (s, 1H,
NH), 7.76 (d, 3H, Jꢁ=ꢁ6 Hz, Ar-H, NH), 7.76 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H), 7.53 (d,
2H, Jꢁ=ꢁ8 Hz, Ar-H), 7.38 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H), 5.23 (d, 1H, Jꢁ=ꢁ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,
+
C21H21N4O4, [Mꢁ+ꢁH] : m/z 393.1557. Found: m/z 393.1555.
+
54.2, 51.3, 18.3. HRMS. Calcd for C21H20ClN4O4, [Mꢁ+ꢁH] : m/z 427.1168.
Found: m/z 427.1178.
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,
4-[4-(2-(4-Bromobenzylidene)hydrazinocarbonyl)phenyl]-
5-methoxycarbonyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one
(3g)ꢀWhite solid; yield 83%; mpꢁꢁ>ꢁꢁ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, Jꢁ=ꢁ7 Hz, Ar-H, NH), 7.67 (t, 4H, Jꢁ=ꢁ8 Hz, Ar-H), 7.38 (d, 2H,
Jꢁ=ꢁ8 Hz, Ar-H), 5.23 (d, 1H, Jꢁ=ꢁ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
1
1106 cm−1; H NMR: δ 11.67 (s, 1H, CH), 9.30 (s, 1H, NH), 8.38 (s, 1H,
NH), 7.84 (d, 3H, Jꢁ=ꢁ7 Hz, Ar-H, NH), 7.68 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H), 7.37 (d,
2H, Jꢁ=ꢁ8 Hz, Ar-H), 7.03 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H), 5.23 (d, 1H, Jꢁ=ꢁ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,
+
+
[Mꢁ+ꢁH] : m/z 423.1663. Found: m/z 423.1657.
C21H20BrN4O4, [Mꢁ+ꢁH] : m/z 471.0662. Found: m/z 471.0649.
4-[4-(2-(4-N,N-Dimethylaminophenylbenzylidene)hydrazino-
carbonyl)phenyl]-5-methoxycarbonyl-6-methyl-3,4-dihydropy-
rimidin-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,
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, Jꢁ=ꢁ7 Hz, Ar-H), 8.17 (d, 1H, Jꢁ=ꢁ7 Hz, Ar-H), 7.87 (d, 3H, Jꢁ=ꢁ8 Hz, NH,
Ar-H), 7.78 (t, 1H, Jꢁ=ꢁ7 Hz, Ar-H), 7.39 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H), 5.23 (d,
1H, Jꢁ=ꢁ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
1
1337, 1241, 1188, 1088 cm−1; H NMR: δ 11.51 (s, 1H, -CH), 9.31 (s, 1H,
NH), 8.29 (s, 1H, NH), 7.83 (d, 3H, Jꢁ=ꢁ8 Hz, Ar-H, -NH), 7.54 (d, 2H,
Jꢁ=ꢁ8 Hz, Ar-H), 7.36 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H), 6.76 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H),
5.23 (d, 1H, Jꢁ=ꢁ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, [Mꢁ+ꢁH] : m/z 436.1979. Found: m/z 436.1961.
for C21H20N5O6, [Mꢁ+ꢁH] : m/z 438.1408. Found: m/z 438.1413.
4-[4-(2-(2-Hydroxybenzylidene)hydrazinocarbonyl)phenyl]- 4-[4-(2-(2,4-Dichlorobenzylidene)hydrazinocarbonyl)phenyl]-
5-methoxycarbonyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one 5-methoxycarbonyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one
(3d)ꢀWhite solid; yield 85%; mp 292–294°C; IR: ν 3419, 3232, 3158, (3i)ꢀWhite solid; yield 77%; mp 279-281°C; IR: ν 3353, 3216, 3104,
1
3067, 2954, 1690, 1659, 1646, 1619, 1565, 1494, 1436, 1341, 1300, 1245, 2942, 1700, 1652, 1611, 1559, 1436, 1294, 1226, 1100 cm−1; H NMR:
1
1088 cm−1; H NMR: δ 12.07 (s, 1H, OH), 11.28 (s, 1H, CH), 9.32 (s, 1H, δ 12.09 (s, 1H, -CH), 9.31 (s, 1H, NH), 8.80 (s, 1H, NH), 8.03 (d, 1H,
NH), 8.63 (s, 1H, NH), 7.89 (d, 1H, Jꢁ=ꢁ8 Hz, Ar-H), 7.86 (s, 1H, NH),7.55 Jꢁ=ꢁ8 Hz, Ar-H), 7.88 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H), 7.86 (s, 1H, NH), 7.73 (s,
(d, 1H, Jꢁ=ꢁ8 Hz, Ar-H), 7.39 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H), 7.31 (t, 1H, Jꢁ=ꢁ8 Hz, 1H, Ar-H), 7.53 (d, 1H, Jꢁ=ꢁ8 Hz, Ar-H), 7.39 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H), 5.23
Ar-H), 6.95–6.91 (m, 2H, Ar-H), 5.23 (d, 1H, Jꢁ=ꢁ3.2 Hz, CH), 3.55 (s, 3H, (d, 1H, Jꢁ=ꢁ3.2 Hz, CH), 3.55 (s, 3H, OCH3), 2.28 (s, 3H,-CH3); 13C NMR:
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4ꢀ ꢀH.-N. Peng et al.: 3,4-Dihydropyrimidin-2(1H)-one derivatives containing a hydrazone moiety
132.7, 128.4, 126.8, 124.5, 99.2, 59.7, 54.3, 18.3, 14.5. HRMS. Calcd for
δ 166.1, 163.5, 152.5, 149.6, 148.9, 143.0, 135.5, 134.3, 132.7, 131.2, 129.9,
+
C22H22N5O6, [Mꢁ+ꢁH] : m/z 452.1565. Found: m/z 452.1530.
128.5, 126.8, 99.0, 54.2, 51.3, 18.4. HRMS. Calcd for C21H19Cl2N4O4,
+
[Mꢁ+ꢁH] : m/z 461.0778. Found: m/z 461.0744.
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,
4-[4-(2-Benzylidenehydrazinocarbonyl)phenyl]-5-ethoxycar-
bonyl-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,
Jꢁ=ꢁ8 Hz, Ar-H), 7.82 (s, 1H, NH), 7.72 (d, 2H, Jꢁ=ꢁ7 Hz, Ar-H), 7.45~7.37
(m, 5H, Ar-H), 5.23 (d, 1H, Jꢁ=ꢁ3.2 Hz, CH), 4.02–3.97 (m, 2H, OCH2),
2.27 (s, 3H, CH3), 1.11 (t, 3H, Jꢁ=ꢁ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,
1
1228, 1087 cm−1; H NMR: δ 11.85 (s, 1H, CH), 9.26 (s, 1H, NH), 8.43
(s, 1H, NH), 7.86 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H), 7.82 (s, 1H, NH), 7.74 (d, 2H,
Jꢁ=ꢁ8 Hz, Ar-H), 7.50 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H), 7.38 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H),
5.23 (d, 1H, Jꢁ=ꢁ3.2 Hz, CH), 4.02~3.97 (m, 2H, OCH2), 2.27 (s, 3H, CH3),
1.11 (t, 3H, Jꢁ=ꢁ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, [Mꢁ+ꢁH] : m/z 441.1324. Found: m/z
99.3, 59.7, 54.3, 18.3, 14.5. HRMS. Calcd for C22H23N4O4, [Mꢁ+ꢁH] : m/z
441.1341.
407.1714. Found: m/z 407.1694.
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,
5-Ethoxycarbonyl-4-[4-(2-(4-methoxybenzylidene)hydrazino-
carbonyl)phenyl]-6-methyl-3,4-dihydropyrimidin-2(1H)-one
(3k)ꢀWhite solid; yield 70%; mp 173–175°C; IR: ν 3240, 3109, 2978,
1
2837, 1704, 1652, 1607, 1511, 1453, 1366, 1287, 1254, 1226, 1093 cm−1; H
1
1092 cm−1; H NMR: δ 11.87 (s, 1H, CH), 9.27 (s, 1H, NH), 8.41 (s, 1H,
NMR: δ 11.68 (s, 1H, CH), 9.27 (s, 1H, NH), 8.38 (s, 1H, NH), 7.86 (d, 2H,
Jꢁ=ꢁ8 Hz, Ar-H), 7.83 (s, 1H, NH), 7.66 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H), 7.38 (d, 2H,
Jꢁ=ꢁ8 Hz, Ar-H), 7.00 (d, 2H, Jꢁ=ꢁ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, Jꢁ=ꢁ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.
NH), 7.87 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H), 7.83 (s, 1H, NH), 7.67 (d, 2H, Jꢁ=ꢁ8 Hz,
Ar-H), 7.62 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H), 7.39 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H), 5.25 (d,
1H, Jꢁ=ꢁ2.8 Hz, CH), 4.02–3.97 (m, 2H, OCH2), 2.28 (s, 3H, CH3), 1.10 (t,
3H, Jꢁ=ꢁ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, [Mꢁ+ꢁH] : m/z 485.0819. Found: m/z
Calcd. for C23H25N4O5, [Mꢁ+ꢁH] : m/z 437.1819. Found: m/z 437.1828.
485.0824.
5-Ethoxycarbonyl-4-[4-(2-(4-N,N-dimethylaminophenylben-
zylidene)hydrazinocarbonyl)phenyl]-6-methyl-3,4-dihydropy-
rimidin-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, Jꢁ=ꢁ6 Hz, Ar-H), 7.37 (d,
2H, Jꢁ=ꢁ6 Hz, Ar-H), 6.73 (d, 2H, Jꢁ=ꢁ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.
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,
1
2979, 2929, 1699, 1654, 1610, 1561, 1531, 1353, 1287, 1225, 1092 cm−1; H
NMR: δ 12.05 (s, 1H, CH), 9.26 (s, 1H, NH), 8.54 (s, 2H, NH, Ar-H), 8.23
(d, 1H, Jꢁ=ꢁ7 Hz, Ar-H), 8.13 (d, 1H, Jꢁ=ꢁ7 Hz, Ar-H), 7.87 (d, 2H, Jꢁ=ꢁ8 Hz,
Ar-H), 7.82 (s, 1H, NH), 7.73 (t, 1H, Jꢁ=ꢁ7 Hz, Ar-H), 7.39 (d, 2H, Jꢁ=ꢁ8 Hz,
Ar-H), 5.23 (d, 1H, Jꢁ=ꢁ2.8 Hz, CH), 4.02-3.97 (m, 2H, OCH2), 2.27 (s, 3H,
CH3), 1.11 (t, 3H, Jꢁ=ꢁ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,
+
Calcd for C24H28N5O4, [Mꢁ+ꢁH] : m/z 450.2136. Found: m/z 450.2112.
+
54.3, 18.3, 14.5. HRMS. Calcd for C22H22N5O6, [Mꢁ+ꢁH] : m/z 452.1565.
Found: m/z 452.1528.
5-Ethoxycarbonyl-4-[4-(2-(2-hydroxybenzylidene)hydrazino-
carbonyl)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,
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,
1
1087 cm−1; H 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,
1
1101 cm−1; H NMR: δ 9.26 (s, 1H, NH), 8.78 (s, 1H, NH), 8.00 (d, 1H,
Jꢁ=ꢁ8 Hz, Ar-H), 7.88 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H), 7.82 (s, 1H, NH), 7.63 (s, 1H,
Ar-H), 7.46 (d, 1H, Jꢁ=ꢁ8 Hz, Ar-H), 7.39 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H), 5.24 (d,
1H, Jꢁ=ꢁ2.8 Hz, CH), 4.01–3.95 (m, 2H, OCH2), 2.27 (s, 3H, -CH3), 1.09
(t, 3H, Jꢁ=ꢁ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,
+
99.3, 59.8, 54.3, 18.3, 14.5. HRMS. Calcd for C22H23N4O5, [Mꢁ+ꢁH] : m/z
423.1663. Found: m/z 423.1657.
+
14.5. HRMS. Calcd for C22H21Cl2N4O4, [Mꢁ+ꢁH] : m/z 475.0934. Found:
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,
Jꢁ=ꢁ8 Hz, Ar-H), 7.98 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H), 7.87 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H),
7.82 (s, 1H, NH), 7.39 (d, 2H, Jꢁ=ꢁ8 Hz, Ar-H), 5.23 (d, 1H, Jꢁ=ꢁ2.4 Hz,
CH), 4.02-3.97 (m, 2H, OCH2), 2.26 (s, 3H, CH3), 1.11 (t, 3H, Jꢁ=ꢁ7 Hz,
OCH2CH3); 13C NMR: δ 165.7, 163.7, 152.5, 149.3, 149.1, 148.3, 145.7, 141.1,
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
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ꢁꢀꢀꢀ
H.-N. Peng et al.: 3,4-Dihydropyrimidin-2(1H)-one derivatives containing a hydrazone moietyꢂ ꢂ5
as a novel class of potent and selective A2B adenosine receptor
antagonists. ACS Med. Chem. Lett. 2013, 4, 1031–1036.
[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.
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.
[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.
[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.
[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 deriva-
tives as potential antimicrobial and antitubercular agents. Eur.
J. Med. Chem. 2017, 138, 698–714.
Acknowledgements: We acknowledge the financial sup-
port 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).
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