Synthesis and antibacterial activities of para-alkoxy phenyl-β- ketoaldehyde derivatives

Article abstract of DOI:10.1007/s00044-012-0429-8

A series of para-alkoxy phenyl-β-ketoaldehyde derivatives were synthesized and evaluated for antimicrobial activities. Preliminary results showed that some compounds had moderate antibacterial activities, especially, 3-(4-methoxyphenyl)-3-oxopropanal O-methyl oxime (4) showed more potent antibacterial activity against Staphylococcus aureus and resistant Helicobacter pylori than the other compounds. Compound 4 showed more active antibacterial activities against methicillin-resistant S. aureus than Houttuynin and levofloxacin. Compound 4 was also investigated and its antibacterial activities against the strains clinical separated of Staphylococcus aureus. The preliminary structure-activity relationships were obtained. The maximum tolerance dose value for acute toxicity of compound 4 was 5,000 mg/kg. It indicated that compound 4 should be safe in clinical treatment. Graphical Abstract: A series of para-alkoxy phenyl-β-ketoaldehyde derivatives were designed, synthesized and evaluated for antimicrobial activities. 3-(4-Methoxyphenyl)-3-oxopropanal O-methyl oxime (4) showed more potent antibacterial activities against Staphylococcus aureus and resistant Hp than the other compounds. The maximum tolerance dose values for acute toxicity of compound 4 was 5,000 mg/kg. It indicated that compound 4 should be safe in clinical treatment. [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00044-012-0429-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:4228–4238
DOI 10.1007/s00044-012-0429-8
ORIGINAL RESEARCH
Synthesis and antibacterial activities of para-alkoxy
phenyl-b-ketoaldehyde derivatives
•
Jinbing Liu Fengyan Wu Huacan Song
•
•
•
Zhihou Wang Liangzhong Zhao
Received: 26 May 2012 / Accepted: 15 December 2012 / Published online: 3 January 2013
Ó Springer Science+Business Media New York 2012
Abstract A series of para-alkoxy phenyl-b-ketoaldehyde
derivatives were synthesized and evaluated for antimicro-
bial activities. Preliminary results showed that some com-
pounds had moderate antibacterial activities, especially,
3-(4-methoxyphenyl)-3-oxopropanal O-methyl oxime (4)
showed more potent antibacterial activity against Staphy-
lococcus aureus and resistant Helicobacter pylori than the
other compounds. Compound 4 showed more active anti-
bacterial activities against methicillin-resistant S. aureus
than Houttuynin and levofloxacin. Compound 4 was also
investigated and its antibacterial activities against the
strains clinical separated of Staphylococcus aureus. The
preliminary structure–activity relationships were obtained.
The maximum tolerance dose value for acute toxicity of
compound 4 was 5,000 mg/kg. It indicated that compound
4 should be safe in clinical treatment.
Keywords Para-alkoxy phenyl-b-ketoaldehyde
derivatives Á Antibacterial activity Á Synthesis Á
Structure–activity relationship (SAR) analysis
Introduction
The increasing incidence of bacterial resistance to currently
available antibacterial agents is a growing global health
problem. Therefore, modern medicine is engaged in an
eager quest for new antibiotics, which can treat the infec-
tions caused by constantly emerging antibiotic resistant
bacteria (Barbachyn et al., 2003; Haug et al., 2004; Phillips
et al., 2007). So far, many efforts have been spent in the
search for effective and safe antibacterial drugs, and a large
number of naturally occurring and synthetic antibiotics
have already been reported. However, most of them are not
potent enough to put into practical use due to their weak
individual activities or safety concerns. For example, due
to undesirable side effects, Grepafloxacin and Trovafloxa-
cin were removed from the market and their use is now
prohibited in several countries (Srivastava et al., 2007;
Noguchi et al., 2005).
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-012-0429-8) contains supplementary
material, which is available to authorized users.
In addition, more than 60 % of the world’s population is
infected with the pathogenic, Gram-negative bacterium
Helicobacter pylori (Hp). The persistence of Hp leads to the
development of a subset of gastric pathologies, including
chronic active gastritis, peptic ulceration, and the promotion
of malignant disorders (Franco et al., 2007). Hence since
1994, the World Health Organization (WHO) has classified
Hp as a Class 1 carcinogen responsible for its leading role in
the development of gastric neoplasia in humans, since it has
been demonstrated that chronic infection is strongly asso-
ciated with the development of malignant gastric diseases
(Logan 1994).
J. Liu (&) Á F. Wu Á L. Zhao
Department of Biology and Chemical Engineering,
Shaoyang University, Shao Shui Xi Road, Shaoyang 422100,
People’s Republic of China
e-mail: xtliujb@yahoo.com.cn
J. Liu Á H. Song
School of Chemistry and Chemical Engineering,
Sun Yat-sen University, 135 Xin Gang Xi Road,
Guangzhou 510275, People’s Republic of China
Z. Wang
Centre for Drug Evaluation, State Drug Administration,
Beijing 100050, People’s Republic of China
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Med Chem Res (2013) 22:4228–4238
4229
Pharmacological treatment of Hp infections includes
administration of a proton pump inhibitor and a combina-
tion of two or more antibiotics, among which the most
active ones are amoxicillin, clarithromycin, metronidazole,
and tetracyclines. However, high dose and long-term
administration are required for complete eradication. Fur-
thermore, this therapy occasionally provokes side effects
such as diarrhea, including pseudomembranous enteroco-
litis in serious cases (Ryoichi et al., 2001). Several studies
have demonstrated that even two consecutive regiments
failed to eradicate Hp in some patient. In addition, an
increasing emergence of drug resistance, which is more
frequent and more severe in the case of quadruple therapy,
can lead to treatment failure (Sorberg et al., 1998; Tomas
et al., 1996). Obviously, this is still needed to search and
develop novel antibacterial drugs with better activities
together with lower side effects.
relationships (SARs) and probing structural requirements
for the potent antibacterial activities of these compounds.
A series of para-alkoxy phenyl-b-ketoaldehyde and deriv-
atives were synthesized, their in vitro antibacterial activities
against S. aureus (ATTC-25923), E. coli (ATTC-25922),
P. aeruginosa (ATTC-27853), clinical isolates of S. aureus,
methicillin-resistant S. aureus (MRSA) and resistant Hp
were evaluated. Acute toxicity of compound 4 was also
evaluated.
Materials and methods
Chemistry
Most of chemicals were purchased from Darui Chemical
Co. (Shanghai, China). THF and toluene were dried
over molecular sieve. The other commercially available
reagents and solvents were used without further purifica-
tion. All reactions were monitored by TLC (Merck Kie-
selgel 60, F254). Melting points (mp) were determined
with WRS-1B melting point apparatus and are uncorrected.
NMR spectra were recorded on Mercury-Plus300 spec-
trometers at 25 °C using CDCl3 or DMSO-d6 as a solvent.
All chemical shifts (d) are quoted in ppm downfield from
TMS and coupling constants (J) are given in Hz. Infrared
(IR) spectra were recorded on a Perkin-Elmer Infracord
221 spectrometer and reported in cm-1. LC–MS spectra
were recorded using the LCMS-2010A.
Houttuynia cordata Thunb. (Saururaceae) (HC) is a tra-
ditional Chinese medicine (TCM) used to relieve lung-
related symptoms such as lung abscess, phlegm, cough,
and dyspnea, and is effective in treating pneumonia, infec-
tious disease, refractory hemoptysis as well as malignant
pleural effusion (Lau et al., 2008). Houttuynin (Fig. 1),
n-nonyl-b-oxoaldehyde, was first isolated from HC as the
major active constituent. Pharmacological study shows that
b-ketoaldehyde unit is its important pharmacological moi-
ety. Houttuynin possesses broad spectrum pharmacological
properties including antibacterial, antivirus, anti-inflam-
mation, and increasing immunity. Sodium houttuyfonate
(Fig. 1) which was derived from Houttuynin has been
clinically used in the treatment of bacterial infections for
many years in China (Wang, 2002; Ye et al., 2006; Wang
et al., 2004). We always reported that 4-alkylphenyl-
b-ketoaldehyde derivatives could perform high antibacterial
activities (Liu et al., 2009) and all the synthesized com-
pounds were tested for their in vitro antibacterial activities
against both Gram-positive bacteria Staphylococcus aureus
(ATTC-25923) and Gram-negative bacteria Escherichia
coli (ATTC-25922) and Pseudomonas aeruginosa (ATTC-
27853). But the antibacterial activities against resistant
Hp and toxicities were not evaluated. The present investi-
gation aimed at further elucidating the structure–activity
General procedure 1 for the preparation
of 3-hydroxy-1-(4-methoxyphenyl)
prop-2-en-1-one (Clerici et al., 2001)
4-Methoxy acetophenone (0.05 mol) was dissolved in dry
THF (50 mL) or toluene (50 mL), and stirred in ice bath.
Sodium (0.075 mol) was added to the solution and the
mixture was stirred for 30 min in ice bath. Ethyl formate
(0.1 mol) was then added dropwise to the mixture below
5 °C. After the addition, the reaction mixture was stirred
for another 2 h. The reaction mixture was warmed to room
temperature and stirred overnight. 150 mL of water was
added into the mixture, and the mixture was stirred for
another 30 min. Then it was portioned between organic
layer and water. The water layer was extracted with
dichloromethane (29, 50 mL). The aqueous phase was
acidified with acetic acid or 5 % hydrochloric acid and
extracted with dichloromethane (39, 50 mL). This extract
was washed with water and brine, dried over sodium sul-
fate, and the solvent was removed under reduced pressure.
A thick yellow oil product was obtained. It was purified by
crystallization from hexane or separated by silica gel
O
O
H3C
Houttuynin
Fig. 1 Structures of houttuynin and sodium houttuyfonate
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Med Chem Res (2013) 22:4228–4238
column chromatography to afford the 3-hydroxy-1-(4-
methoxyphenyl)prop-2-en-1-one.
dissolved in 1 mL of water, the solution was added drop-
wise to the solution of 4-substituted phenyl-b-ketoaldehyde
in ethanol at -5 °C. After the addition, the reaction mix-
ture was stirred at room temperature for 5–6 h. The solvent
was removed by rotary evaporation under reduced pres-
sure; the residue was separated by silica gel column
chromatography.
3-Hydroxy-1-(4-methoxyphenyl)prop-2-en-1-one (1)
Yield 72 %, white solid; mp 63–65 °C; IR (KBr): 2968, 1672,
1602, 1258, 1174, 1030,825 cm-1 1H-NMR (300 MHz,
.
CDCl3): d 8.14 (d, 1H, J = 4.3 Hz, = CH), 7.91 (d,
J = 9.0 Hz, 2H, PhH), 6.97 (d, J = 9.0 Hz, 2H, PhH), 6.17
(d, H, J = 4.3 Hz, = CH), 3.90 (s, 1H, OH), 3.89 (s, 3H,
CH3). ESI–MS m/z: 179 (M?1).
Method B
4-Substituted acetophenone (0.05 mol) was dissolved in
dry THF (50 mL) or toluene (50 mL) and the mixture was
stirred in ice bath; sodium (0.075 mol) was added into the
reaction solution and stirred for 30 min. Ethyl formate
(0.1 mol) was added dropwise to the reaction mixture at
5 °C. After the addition, the reaction mixture was stirred
for another 2 h. The reaction mixture was warmed to room
temperature and stirred overnight (about 15 h). The pre-
cipitate was separated by filtration; the corresponding
enolic sodium was obtained.
General procedure 2 for the preparation of 1-hydroxy-
3-(4-alkoxy phenyl)-3-oxopropane-1-sulfonate
The enolic sodium was added to the saturated sodium
bisulfite. The reaction mixture was stirred at room tem-
perature for 2 h; the precipitate formed was separated by
filtration. The product was purified by crystallization from
50 % ethanol.
3-(4-Methoxyphenyl)-1-Hydroxy-3-oxopropane-1-
Enolic sodium (10 mmol) was added to anhydrous eth-
anol (20 mL) and the mixture was stirred at room tem-
perature. The corresponding hydroxylamine hydrochloride
(10 mmol) or alkoxyamine hydrochloride (10 mmol) was
added to the mixture. The mixture was stirred at room
temperature for 6–9 h, and the reaction was monitored by
TLC (ethyl acetate/petroleum ether = 1:10). After com-
pletion of the reaction, alcohol was evaporated under
reduced pressure, and the residue was purified by chro-
matography on silica gel to give the corresponding target
compound.
sulfonate sodium (2)
Yield 24 %, white solid; mp 189–191 °C; IR (KBr): 3423,
3256, 1668, 1603, 1575, 1413, 1413, 1257, 1178, 821 cm-1
.
1H-NMR (300 MHz, DMSO-d6): d 7.90 (d, J = 8.7 Hz, 2H,
PhH), 7.04 (d, J = 8.7 Hz, 2H, PhH), 5.73 (s, 1H, OH),
4.49–4.45 (m, H, CH), 3.82 (s, 3H, CH3), 3.21 (d,
J = 8.1 Hz, 2H, CH2). 13C-NMR (75 MHz, DMSO-d6): d
197.0, 163.6, 131.1, 130.7, 114.5, 80.8, 56.3, 42.2. ESI–MS
m/z: 259 (M-23).
General procedure 3 for the preparation of the schiff
bases of 4-alkoxy phenyl-b-ketoaldehyde (3–20) (Liu
et al., 2010; Jeong et al., 2006; Jeong et al., 2005; Li
et al., 2005):
3-(4-Methoxyphenyl)-3-oxopropanal oxime (3)
Yield 34 %, yellow solid; mp 56–58 °C; IR (KBr): 3134,
3097, 2938, 1608, 1509, 1458, 1257, 1175, 831 cm-1. H-
1
NMR (300 MHz, CDCl3): d 8.33 (d, 1H, OH), 7.58 (d,
J = 8.7 Hz, 2H, PhH), 6.99 (d, J = 8.7 Hz, 2H, PhH),
5.73–5.68 (m, H, CH), 3.78 (s, 3H, CH3), 3.44 (d,
J = 8.7 Hz, 2H, CH2). ESI–MS m/z: 194 (M?1).
Method A
A1: The corresponding 4-substituted phenyl-b-ketoalde-
hyde (5 mmol) was dissolved in anhydrous ethanol
(10 mL). Semicarbazide (5 mmol) or thiosemicarbazide
(5 mmol) was added to the reaction solution. The mixture
was stirred for 5–8 h under refluxing conditions and then
the mixture was cooled to room temperature; the precipi-
tate was separated by filtration, and the target compound
was purified by recrystallized from 95 % ethanol.
3-(4-Methoxyphenyl)-3-oxopropanal O-methyl oxime (4)
Yield 82 %, yellow solid; mp 52–54 °C; IR (KBr): 2962,
1669, 1602, 1259, 1176, 1032, 815 cm-1
.
1H-NMR
(300 MHz, CDCl3): d 7.96 (d, J = 9.0 Hz, 2H, PhH), 7.67,
7.21(t, J = 6.0, 4.8 Hz, 1H, CH), 6.95(d, J = 9.0 Hz, 2H,
PhH), 3.98–3.87(m, 8H, 2CH3, CH2); 13C NMR(75 MHz,
CDCl3): d 193.2, 166.3,162.7, 132.6, 129.0, 118.5, 61.0,
55.3 34.1; ESI–MS m/z: 208 (M?1).
A2: The corresponding 4-substituted phenyl-b-ketoalde-
hyde (5 mmol) was dissolved in anhydrous ethanol (10 mL),
and the mixture was cooled with ice–salt bath. The corre-
sponding hydroxylamine hydrochloride (5 mmol) or alk-
oxyamine hydrochloride (5 mmol) and KOH (5 mmol) were
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Med Chem Res (2013) 22:4228–4238
4231
3-(4-Methoxyphenyl)-3-oxopropanal O-ethyl oxime (5)
Yield 67 %, yellow oil; IR (KBr): 2976, 2934, 1677, 1600,
3-(4-Ethoxyphenyl)-3-oxopropanal O-methyl oxime (10)
Yield 41.6 %, yellow solid; mp 58–60 °C; IR (KBr):
858, 1036, 1173, 1215, 1257, 1597, 1681, 2897, 2939,
.
2982 cm-1 1H-NMR (300 MHz, CDCl3): d 7.91 (d,
J = 8.7 Hz, 2H, PhH), 7.63, 7.18 (t, J = 7.2, 6.3 Hz, 1H,
CH), 6.93 (d, J = 8.7 Hz, 2H, PhH), 4.11 (q, J = 6.9 Hz,
2H, CH2), 3.9–3.84 (m, 5H, CH3, CH2),1.47 (t,
J = 6.9 Hz, 3H, CH3). ESI–MS m/z: 222 (M?1).
1261, 1261, 1172, 829 cm-1
.
1H-NMR (300 MHz,
CDCl3): d 7.97–7.92(m, 2H, PhH), 7.66,7.19(t, J = 6.0,
5.1 Hz,1H, CH), 6.95 (d, J = 9.0 Hz, 2H, PhH), 4.21–4.10
(m, 2H, CH2), 3.99, 3.84 (d, J = 6.0, 4.8 Hz, 2H, CH2),
3.87 (s, 3H, CH3), 1.31 (d, J = 6.9 Hz, 3H, CH3). ESI–MS
m/z: 222 (M?1).
3-(4-Ethoxyphenyl)-3-oxopropanal O-ethyl oxime (11)
3-(Methoxyimino)-3-(4-methoxyphenyl)propanal
O-methyl oxime (6)
Yield 53.6 %, yellow solid; mp 50–51 °C; IR (KBr): 807,
867, 925, 1045, 1172, 1206, 1266, 1512, 1588, 1681, 2888,
1
2930, 2982, 3066 cm-1. H-NMR (300 MHz, CDCl3): d
Yield 56 %, yellow oil; IR (KBr): 2939, 2902, 1607, 1514,
1
1303, 1253, 1180, 1049, 836 cm-1. H-NMR (300 MHz,
7.96 (d, J = 9.0 Hz, 2H, PhH), 7.67, 7.19 (t, J = 6.0,
4.8 Hz, 1H, CH), 6.94 (d, J = 9.0 Hz, 2H, PhH), 4.07–4.22
(m, 4H, 2CH2), 3.99, 3.84 (d, J = 6.0, 4.8 Hz, 2H, CH2),
1.48 (t, J = 6.9 Hz, 3H, CH3), 1.24 (t, J = 6.9 Hz, 3H,
CH3). ESI–MS m/z: 236 (M?1).
CDCl3): d 7.64 (t, J = 9.0 Hz, 2H, PhH), 7.44, 6.68 (t,
J = 6.3, 5.1 Hz, 1H, CH), 6.97 (d, J = 8.7 Hz, 2H, PhH),
3.99 (s, 3H, CH3), 3.93, 3.83 (s, 6H, 2CH3), 3.76, 3.64
(J = 5.1, 6.3 Hz, 2H, CH2). ESI–MS m/z: 237 (M?1).
3-(Ethoxyimino)-3-(4-methoxyphenyl)propanal
3-(4-Ethoxyphenyl)-3-(methoxyimino)propanal
O-ethyl oxime (7)
O-methyl oxime (12)
1
Yield 52 %, yellow oil; H-NMR (300 MHz, CDCl3): d
Yield 69 %, yellow oil; IR (KBr): 840, 1053, 1181, 1248,
1512, 1614, 2819, 2897, 2939, 2982 cm-1 1H-NMR
.
7.97 (d, J = 9.0 Hz, 2H, PhH), 7.66, 7.19 (t, 1H, CH), 6.95
(d, J = 9.0 Hz, 2H, PhH), 4.19–4.08 (m, 4H, 2CH2), 4.00,
4.86 (d, 2H, CH2), 3.87 (s, 3H, CH3), 1.31 (t, 6H, 2CH3).
ESI–MS m/z: 265 (M?1).
(300 MHz, CDCl3): d 7.60 (d, J = 9.0 Hz, 2H, PhH), 7.42,
6.66 (t, J = 6.3 Hz, 1H, CH), 7.21 (d, J = 9.0 Hz, 2H,
PhH), 4.00 (3 s, 6H, 2CH3), 3.77, 3.65 (d, J = 6.9, 6.0 Hz,
2H, CH2), 2.70 (q, J = 7.5 Hz, 2H, CH2), 1.27 (t,
J = 7.5 Hz, 3H, CH3). ESI–MS m/z: 251 (M?1).
3-(4-Methoxyphenyl)-3-oxopropanal semicarbazone (8)
Yield 43 %, yellow solid; mp 186–188 °C; IR (KBr): 3364,
3-(Ethoxyimino)-3-(4-ethoxyphenyl)propanal
1735, 1614, 1575, 1404, 1249, 820 cm-1
.
1H-NMR
O-ethyl oxime (13)
(300 MHz, d6-DMSO): d 10.0 (s, 1H, NH), 7.95 (d,
J = 8.7 Hz, 2H, PhH), 7.32 (t, 1H, CH), 7.03 (d, J = 8.7 Hz,
2H, PhH), 6.24 (s, 2H, NH2), 3.91 (d, 2H, CH2), 3.82 (s, 3H,
CH3); 13C NMR (75 MHz, DMSO-d6): d 193.6, 166.1,
157.6, 154.2, 130.6, 129.0, 115.5, 55.6, 34.3; ESI–MS m/z:
236 (M?1).
Yield 21 %, yellow oil; IR (KBr): 917, 1045, 1248, 1409,
1512, 1563, 1614, 2879, 2930, 2982 cm-1 1H-NMR
.
(300 MHz, CDCl3): d 7.64–7.59 (m, 2H, PhH), 7.47, 6.71
(t, J = 6.3, 5.1 Hz, 1H, CH), 7.21 (d, J = 9.0 Hz, 2H,
PhH), 4.28–4.01 (m, 6H, 3CH2), 3.79, 3.63 (d, J = 5.4,
6.3 Hz, 2H, CH2), 1.45–1.24 (m, 9H, 3CH3). ESI–MS m/z:
279 (M?1).
3-(4-Methoxyphenyl)-3-oxopropanal
thiosemicarbazone (9)
3-(4-Isopropoxyphenyl)-3-oxopropanal O-methyl
Yield 48 %, yellow solid; mp 179–180 °C; IR (KBr): 3405,
oxime (14)
1
3252, 3171, 1662, 1594, 1512, 1166, 1081, 826 cm-1. H-
NMR (300 MHz, d6-DMSO): d 11.18 (s, 1H, NH), 7.96 (d,
J = 8.7 Hz, 2H, PhH), 7.61 (s, 1H, NH2), 7.59 (t,
J = 5.7 Hz, 1H, CH), 7.42 (s, 1H, NH2), 7.06 (d,
J = 8.7 Hz, 2H, PhH), 3.98 (d, J = 5.7 Hz, 2H, CH2), 3.86
(s, 3H, CH3); 13C NMR (75 MHz, DMSO-d6): d 194.2,
181.6, 165.1, 154.6, 131.2, 129.3, 114.9, 55.9, 34.9; ESI–
MS m/z: 252 (M?1).
Yield 65 %, yellow oil; IR (KBr): 832, 867, 952, 1036,
1113, 1181, 1224, 1257, 1418, 1512, 1596, 1681, 2819,
1
2897, 2939, 2982 cm-1. H-NMR (300 MHz, CDCl3): d
7.87 (d, J = 7.2 Hz, 2H, PhH), 7.60, 7.14 (t, 1H, CH), 6.87
(d, J = 7.2 Hz, 2H, PhH), 4.61–4.59 (m, 1H, CH), 3.91,
3.88 (s, 3H, CH3), 3.80 (d, 2H, CH2), 1.32 (s, 6H, 2CH3).
13C NMR (CDCl3, 75 MHz) d: 22.2, 35.0, 39.1, 61.8, 62.1,
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Med Chem Res (2013) 22:4228–4238
70.5, 115.4, 129.0, 130.8, 144.4, 145.5, 162.5, 193.4,
1384, 1512, 1597, 1681, 2870, 2955, 3058 cm-1. 1H-NMR
(300 MHz, CDCl3): d 7.94 (d, J = 8.2 Hz, 2H, PhH), 7.18
(t, J = 3.3 Hz, 1H, CH), 6.93 (d, J = 8.2 Hz, 2H, PhH),
4.20–4.13 (m, 2H, CH2), 4.04 (t, J = 6.3 Hz, 2H, CH2),
3.97 (t, J = 3.6 Hz, 2H, CH2), 1.81–1.76 (m, 2H, CH2),
1.54–1.49 (m, 2H, CH2), 1.30 (t, J = 6.9 Hz, 3H, CH3),
1.00 (t, J = 4.2 Hz, 3H, CH3). ESI–MS m/z: 264 (M?1).
194.0. ESI–MS m/z: 236 (M?1).
3-(4-Isopropoxyphenyl)-3-oxopropanal O-ethyl
oxime (15)
Yield 50 %, yellow oil; IR (KBr): 832, 874, 952, 1045,
1112, 1172, 1215, 1257, 1384, 1418, 1512, 1597, 1681,
2930, 2982 cm-1. 1H-NMR (300 MHz, CDCl3): d 7.93 (d,
J = 7.8 Hz, 2H, PhH), 7.65, 7.16 (t, J = 5.4, 0.9 Hz, 1H,
CH), 6.90 (d, J = 7.8 Hz, 2H, PhH), 4.68–4.62 (m, 1H,
CH), 4.20–4.09 (m, 2H, CH2), 3.97, 3.84 (d, J = 3.3,
5.1 Hz, 2H, CH2), 1.37 (s, 3H, CH3), 1.36 (s, 3H, CH3),
1.30–1.23 (m, 3H, CH3). ESI–MS m/z: 250 (M?1).
3-(4-Butoxyphenyl)-3-(ethoxyimino)propanal O-ethyl
oxime (20)
Yield 73 %, yellow oil; IR (KBr): 832, 883, 1052, 1181,
1248, 1427, 1469, 1512, 1563, 1614, 2819, 2870, 2939,
.
2955 cm-1 1H-NMR (300 MHz, CDCl3): d 7.60 (d,
J = 8.4 Hz, 2H, PhH), 7.46, 6.70 (t, J = 6.3, 2.7 Hz, 1H,
CH), 6.88 (d, J = 8.4 Hz, 2H, PhH), 4.27–4.04 (m, 4H,
2CH2), 3.99 (t, J = 6.3 Hz, 2H, CH2), 3.78, 3.77 (d,
J = 4.5, 5.4 Hz, 2H, CH2), 1.82–1.73 (m, 2H, CH2),
1.54–1.46 (m, 2H, CH2), 1.35–1.21 (m, 6H, 2CH2),1.00
(t, J = 4.2 Hz, 3H, CH3). ESI–MS m/z: 307 (M?1).
3-(4-Isopropoxyphenyl)-3-(methoxyimino)propanal
O-methyl oxime (16)
Yield 52 %, yellow oil; IR (KBr): 832, 951, 1052, 1113,
1181, 1248, 1427, 1512, 1614, 2819, 2897, 2939,
.
2982 cm-1 1H-NMR (300 MHz, CDCl3): d 7.61 (d,
J = 7.5 Hz, 2H, PhH), 7.44, 6.72 (t, J = 5.0, 3.6 Hz, 1H,
CH), 6.87 (d, J = 7.5 Hz, 2H, PhH), 4.61–4.56 (m, 1H,
CH), 3.98–3.82 (m, 6H, 2CH3), 3.76, 3.63 (d, J = 3.3,
4.8 Hz, 2H, CH2), 1.35 (s, 3H, CH3), 1.34 (s, 3H, CH3).
ESI–MS m/z: 265 (M?1).
Biological evaluation
In vitro antibacterial activity assays
In vitro antimicrobial activity was determined by the agar
dilution method according to the Clinical and Laboratory
Standard Institute (CLSI) (formerly National Committee for
Clinical Laboratory Standards) (NCCLS 1993). The over-
night cultures (after 16–18 h of incubation at 37 °C) of all the
bacteria were used for the assay and adjusted to the turbidity
of a 0.5 McFarland standard. The stock solution (1 mg/ml) of
all the test chemicals was prepared by dissolving 1 mg of the
test chemical in 1 ml of dimethyl sulfoxide (DMSO), DMSO
was used as control for all the test compounds. Twenty
milliliter of Mueller–Hinton Agar (MHA) and 500 ll of each
test bacterial culture of 16–18 h incubation adjusted at 0.5
McFarland were mixed and poured into sterilized and labeled
plates. The wells of 6-mm diameter were punched in the
solidified agar plates. Test chemicals of 100 ll were added to
individual wells. The loaded plats were incubated at 37 °C
for 24 h. The diameter of zone of growth inhibition around
each well was measured after incubation using a vernier
caliper. The minimum inhibitory concentration (MIC) is the
lowest concentration of the antimicrobial agent that prevents
the development of viable growth after 16–18 h incubation.
MICs (lg/ml) were determined on MHA with medium
containing dilutions of antibacterial agents by the literature
method. Stock solution of 4 mg/ml was prepared in DMSO
and was appropriately diluted to get final concentrations of
128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, and 0.012 lg/ml. Stan-
dard antibiotics were also diluted in same manner to make
comparison. The minimal bactericidal concentration (MBC)
3-(Ethoxyimino)-3-(4-isopropoxyphenyl)propanal
O-ethyl oxime (17)
Yield 59 %, yellow oil; IR (KBr): 832, 867, 952, 1045,
1112, 1181, 1248, 1384, 1512, 1614, 2879, 2930, 2982,
.
3049 cm-1 1H-NMR (300 MHz, CDCl3): d 7.60 (d,
J = 8.1 Hz, 2H, PhH), 7.46, 6.69 (t, J = 5.1, 3.6 Hz, 1H,
CH), 6.87 (d, J = 8.1 Hz, 2H, PhH), 4.58–4.54 (m, 1H,
CH), 4.25–4.06 (m, 4H, 2CH2), 3.78, 3.64 (d, 2H, CH2),
1.35–1.23 (m, 12H, 4CH3). ESI–MS m/z: 293 (M?1).
3-(4-Butoxyphenyl)-3-oxopropanal O-methyl oxime (18)
Yield 70 %, yellow solid; mp 50–51 °C; IR (KBr): 807,
867, 1036, 1121, 1172, 1215, 1266, 1308, 1351, 1512,
.
1597, 1681, 2819, 2870, 2948, 3058 cm-1 1H-NMR
(300 MHz, CDCl3): d 7.93 (d, J = 8.1 Hz, 2H, PhH), 7.19
(t, J = 2.7 Hz, 1H, CH), 6.92 (d, J = 8.1 Hz, 2H, PhH),
4.04–3.92 (m, 7H, 2CH2, CH3), 1.81–1.76 (m, 2H, CH2),
1.51–1.46 (m, 2H, CH2), 1.00 (t, J = 6.7 Hz, 3H, CH3).
ESI–MS m/z: 250 (M?1).
3-(4-Butoxyphenyl)-3-oxopropanal O-ethyl oxime (19)
Yield 80 %, yellow solid; mp 51–52 °C; IR (KBr): 662,
807, 874, 934, 1052, 1121, 1172, 1206, 1266, 1308, 1342,
123

Med Chem Res (2013) 22:4228–4238
4233
Scheme 1 Synthesis of 4-alkoxy phenyl-b-ketoaldehyde derivatives.
Reagents: (i) ethyl formate/Na/toluene, (ii) 5 % HCl, (iii) saturated
sodium bisulfite solution, (iv) 3-hydroxy-1-(4-alkoxyphenyl)prop-
2-en-1-one/amine = 1:1, RT or refluxing, (v) enolic sodium of
3-hydroxy-1-(4-alkoxy- phenyl)prop-2-en-1-one/amine hydrochlo-
ride, RT
was defined as the minimal concentration of compounds
required to kill of the organisms in the medium after 24 h
incubation.
Results and discussion
The synthesis of 3-(4-alkoxy phenyl)-3-oxopropanal was
carried out according to the Scheme 1. The key intermediate
1-(4-alkoxy phenyl) enolic sodium was obtained by the
Claisen condensation reaction. According to Scheme 1, the
sodium 1-hydroxy-3-(4-alkoxy phenyl)-3-oxopropane-1-
sulfonate was prepared by the addition reaction of
saturated sodium bisulfite with the corresponding 3-hydroxy-
1-(4-alkoxy phenyl)prop-2-en-1-one, and the reaction tem-
perature is RT.
Acute toxicity
Acute toxicity experiments were carried out using KM mice
of both sexes weighing 18–22 g. The food and water were
provided according to EPA OPPTS Harmonized Test
guideline. All animals were provided by Qinlongshan Lab-
oratory Animal Center SCXK(Yu) 2005-0001. Various
doses of the compound 4 were given by intragastric admin-
istration to the healthy KM mice. After the intragastric
administration of the compound, mice were observed con-
tinuously for any gross behavioral changes and deaths and
intermittently for 1 week, the maximum tolerance dose
(MTD) values can be obtained.
The Schiff base derivatives of 3-hydroxy-1-(4-alkoxy
phenyl)prop-2-en-1-one were synthesized via the conden-
sation of 3-hydroxy-1-(4-alkoxy phenyl)prop-2-en-1-one
with corresponding amine. Semicarbazone or thiosemi-
carbazone was synthesized under refluxing conditions. The
target product was purified by recrystallization from 95 %
123

4234
Med Chem Res (2013) 22:4228–4238
Table 1 In vitro antibacterial
activities of para-alkoxy
phenyl-b-ketoaldehyde
derivatives
Compounds
MIC (lg/mL)
Staphylococcus
aureus
(ATCC-25923)
Escherichia
coli
(ATCC-25922)
Pseudomonas
aeruginosa
(ATCC-27853)
1
[64
[64
4
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
32
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
64
2
3
4
2
5
4
6
[64
[64
[64
[64
32
7
8
9
10
11
64
12
[64
[64
[64
[64
[64
[64
[64
[64
[64
0.12
0.25
32
13
14
15
16
17
18
19
[64
[64
[64
0.5
20
Clarithromycin
Levofloxacin
Houttuynin
0.025
–
–
ethanol. The other Schiff base derivatives of 3-hydroxy-1-
(4-alkoxy phenyl)prop-2-en-1-one could be synthesized
according to second method shown in Scheme 1. Hydrox-
ylamine hydrochloride or alkoxyamine hydrochloride was
added to the mixture of enolic sodium of 3-hydroxy-1-
(4-alkoxy phenyl)prop-2-en-1-one in anhydrous ethanol, the
reaction mixture was stirred at room temperature. The pro-
gress of the reaction was monitored by TLC (EtOAc:petro-
leun ether = 1:10). Solvent was evaporated and the obtained
residue was purified by chromatography on silica gel to give
the corresponding target compound. The structures of the
synthesized compounds were characterized by IR, 1HNMR,
and 13C NMR and mass spectrometric analyses.
compounds 1–4, 8–9 were tested in vitro against 17 Hp
resistant strains which were HpATCC11637, Hp05-1, Hp05-
2, Hp05-3, Hp05-4, Hp05-5, Hp05-9, Hp05-12, Hp05-14,
Hp06-1, Hp06-2, Hp06-3, Hp06-4, Hp06-5, Hp06-6, Hp06-
7, and Hp06-8. The obtained MIC values, together with the
data of the reference antibacterial agents clarithromycin and
metronidazole for comparison are summarized in Table 2.
As shown in Table 1, compounds 3–5, 10–11 exhibited
certain antibacterial activities against Gram-positive bacte-
ria S. aureus (ATTC-25923); however, all the synthesized
compounds showed no antibacterial activities against Gram-
negative bacteria E. coli (ATTC-25922) and P. aeruginosa
(ATTC-27853). Particularly, compound 4 was found to be
the most potent compound with MIC of 2.0 mg/mL against
S. aureus. These results indicated that Gram-positive bac-
teria might be more susceptible to the newly synthesized
compounds than Gram-negative bacteria. It also showed that
all the compounds tested did not have broad spectrum
antimicrobial activity. From Table 1, when another
O-methyl or O-ethyl oxime moiety was introduced to the
active compounds 4–5 and 10–11, the corresponding diox-
ime-methyl ether or dioxime-ethyl ether derivatives were
nearly inactive at the concentration of 64 lg/mL. The
All the synthesized compounds were tested for their
in vitro antibacterial activities against both Gram-positive
bacteria S. aureus (ATTC-25923) and Gram-negative bac-
teria E. coli (ATTC-25922) and P. aeruginosa (ATTC-
27853). The antibacterial activities were reported as the
MIC in mg/mL that was determined by the agar dilution
method as recommended by the NCCLS (National Com-
mittee for Clinical Laboratory Standards). The MICs are
summarized in Table 1 along with the data of levofloxacin,
clarithromycin, and Houttuynin for comparison. In addition,
123

Med Chem Res (2013) 22:4228–4238
4235
Table 2 Minimal inhibitory concentration (MIC) of the compounds 1–4, 8–9, metronidazole, and clarithromycin against 17 Hp resistant strains
Strains
MIC (lg/ml)
1
2
3
4
8
9
Metronidazole
Clarithromycin
HpATCC11637
Hp05-1
Hp05-2
Hp05-4
Hp05-5
Hp05-9
Hp05-12
Hp05-14
Hp05-3
Hp06-1
Hp06-2
Hp06-3
Hp06-4
Hp06-5
Hp06-6
Hp06-7
Hp06-8
MIC50
128
[128
64
32
[128
[128
[128
[128
[128
[128
[128
[128
[128
[128
[128
[128
[128
[128
128
[128
[128
[128
[128
[128
[128
[128
[128
[128
[128
[128
[128
[128
[128
128
32
32
[128
[128
[128
[128
[128
[128
[128
[128
[128
[128
[128
128
[128 [128
[128 [128
[128 [128
[128 [128
[128 [128
[128 [128
[128 [128
[128 [128
32
[128
[128
[128
[128
[128
[128
[128
[128
[128
[128
[128
[128
[128
[128
[128
[128
[128
[128
32 to [128
[128
64
16
16
[128
[128
[128
[128
[128
64
32
64
[128
16
16
[128
[128 [128
[128 64
[128 [128
64
16
64
32
[128
[128
[128
[128
128
32
32
128
[128
[128
[128
64
64
64
32
128
16
128
32
128
128
128
[128
[128
[128
[128 [128
[128 [128
[128 [128
32
[128
[128
[128
128 to [128
[128
[128
[128
128 to [128
[128
[128
[128
32 to [128
32
MIC90
32
MICrange
128 to [128 [128
64 to [128
16 to [128
Table 3 MIC of compound 4, sodium houttuyfonate, and levoflox-
acin against strains clinical separated of Staphylococcus aureus
activities decreased gradually. It could be found that com-
pound 4 (MIC = 2.0 mg/mL) could perform higher activity
against S. aureus (ATTC-25923) than the other similar
compounds. These results suggested that the increase of the
length of alkyl chain might cause stereohindrance for the
synthesized compounds approaching the target. In addition,
comparing the antibacterial activities of compounds
with 4-methoxyphenyl group. Oxime-methyl ether (4) and
oxime-ethyl ether (5) exhibited potent antibacterial activi-
ties with MIC values ranging from 2 to 4 lg/mL. However,
3-(4-methoxyphenyl)-1-hydroxy-3-oxopropane-1-sulfonate
sodium (2), 3-hydroxy-1-(4-methoxyphenyl)prop-2-en-1-
one (1), the semicarbazone derivative (8), and thiosemi-
carbazone derivative (9) failed to exhibit the antibacterial
activities at the concentration of 64 lg/mL. It implicated
that the O-methyl and O-ethyl oxime moiety might play an
important role in improving the antibacterial activities.
The MIC data in Table 2 indicated that some of the
compounds possessed antibacterial activity against some
resistant Hp strains, especially compound 4 could perform
more potent antibacterial activities against some resistant
Hp than clarithromycin and metronidazole at the same
conditions, the MIC50 value of the compound was 32 lg/
mL. These screening results also further supported the
above conclusion that the O-methyl oxime moiety might
Strains
MIC (lg/mL)
Compound 4
Levofloxacin
Houttuynin
S. aureus 1
S. aureus 2
S. aureus 3
S. aureus 4
S. aureus 5
S. aureus 6
S. aureus 7
S. aureus 8
S. aureus 9
S. aureus 10
MIC50
16
16
8
0.25
0.5
64
64
64
64
32
64
64
64
64
32
64
64
0.25
0.25
0.125
0.5
16
8
8
8
0.25
0.25
0.25
0.5
16
16
16
16
16
0.25
0.5
MIC90
results suggested that the presence of ketone carbonyl
moiety might be absolutely necessary for determining the
antibacterial activity of these compounds. In general, the
introduction of methoxyl group into the 4-position of phenyl
ring could enhance the activity of synthesized compounds.
With the increase of the length of chain R, the inhibitory
123

4236
Med Chem Res (2013) 22:4228–4238
Table 4 MBC of compound 4,
sodium houttuyfonate, and
levofloxacin against strains
clinical separated of
Strains
MBC (lg/mL)
Compound 4
Levofloxacin
Houttuynin
Staphylococcus aureus
S. aureus 1
S. aureus 2
S. aureus 3
S. aureus 4
S. aureus 5
S. aureus 6
S. aureus 7
S. aureus 8
S. aureus 9
S. aureus 10
MIC50
128
64
0.25
0.5
64
64
64
0.5
128
128
128
128
64
128
64
0.5
0.25
0.5
64
128
32
0.25
0.25
0.5
128
256
128
128
128
128
[128
64
0.5
0.5
MIC90
128
0.5
Table 5 MIC of compound 4 against strains of methicillin-resistant Staphylococcus aureus (MRSA)
Compounds
MIC (lg/mL)
MIC50
MIC90
MRSA1
MRSA2
MRSA3
MRSA4
MRSA5
4
8
8
8
8
8
16
16
8
16
16
8
[16
16
8
16
16
8
[16
16
Levofloxacin
Houttuynin
16
16
Table 6 MBC of compound 4 against strains of methicillin-resistant Staphylococcus aureus (MRSA)
Compounds
MBC (lg/mL)
MBC50
MBC90
MRSA1
MRSA2
MRSA3
MRSA4
MRSA5
4
128
[16
32
256
[16
128
256
[16
64
256
[16
32
256
[16
64
256
[16
64
256
[16
128
Levofloxacin
Houttuynin
play an important role in improving the antibacterial
activities.
and MRSA, and the results were summarized in Tables 5
and 6. Compound 4 displayed moderate antibacterial
activity against MRSA, which is slightly superior to the
Houttuynin and levofloxacin. But the compound showed
lower fungicidal activity against MRSA than Houttuynin.
These results preliminarily indicated that clinical isolates of
S. aureus and MRSA might be susceptible to the newly
synthesized compounds.
With the purpose of preliminary corroborating the
prominent antibacterial activities and antibacterial features,
compound 4 was selected to investigate the antibacterial
activities and fungicidal activities against 10 strains of
clinical isolates of S. aureus and the results are summarized
in Tables 3 and 4. As shown in Table 3, compound 4
exhibited certain antibacterial activity against clinical iso-
lates of S. aureus. Compound 4 showed less antimicrobial
activity than levofloxacin; however, it showed more potent
antibacterial activity than Houttuynin. The results showed
that structure modification of Houttuynin could enhance the
antibacterial activities. As shown in Table 4, compound 4
exhibited lower fungicidal activity against clinical isolates
of S. aureus than levofloxacin. Furthermore, compound 4
was selected to test the antibacterial activity and fungicidal
activity against the clinically important pathogenic bacteria
Effect of different pH on antibacterial activity was also
investigated and the results were showed in Table 7. From
the date of Table 7, we can see that compound 4 exhibited
more potent antibacterial activity against 24 strains of
clinical isolates of S. aureus in slight alkaline conditions
than in slight acid conditions or neutral conditions. The
result further showed that oxime-methyl ether was an
important active group of this kind of compound; oxime-
methyl ether was unstable in acid conditions, while it was
stable in alkaline conditions.
123

Med Chem Res (2013) 22:4228–4238
4237
4 is 32 lg/mL. Interestingly, compound 4 exhibited more
potent antibacterial activities against clinically important
pathogenic bacteria MRSA than Houttuynin and levoflox-
acin. Compound 4 was selected to investigate the antibac-
terial activities and fungicidal activities against 10 strains
of clinical isolates of S. aureus, and it exhibited potent
antibacterial activity and certain fungicidal activity. The
preliminary structure–activity relationship (SAR) analysis
suggested that (1) the presence of O-alkyl oxime moiety
might play an important role in improving antibacterial
activities of these compounds; (2) the increase of the length
of ether chain might cause stereohindrance for the com-
pounds approaching the target; (3) the presence of ketone
carbonyl moiety might play a vital role in determining sig-
nificant antibacterial activities of these compounds. In
addition, compound 4 exhibited more potent antibacterial
activity against 24 strains of clinical isolates of S. aureus in
slight alkaline conditions than in slight acid environment
and neutral environment. The acute toxicity of compound 4
was evaluated; MTD value of the compound was 5,000 mg/
kg. It indicated that compound 4 should be safe in clinical
treatment.
Table 7 Effect of different pH values on MIC of compound 4 against
strains clinical separated of Staphylococcus aureus (lg/mL)
Strains
pH
5.0
7.0
9.0
S. aureus 1
S. aureus 2
S. aureus 3
S. aureus 4
S. aureus 5
S. aureus 6
S. aureus 7
S. aureus 8
S. aureus 9
S. aureus 10
S. aureus 11
S. aureus 12
S. aureus 13
S. aureus 14
S. aureus 15
S. aureus 16
S. aureus 17
S. aureus 18
S. aureus 19
S. aureus 20
S. aureus 21
S. aureus 22
S. aureus 23
S. aureus 24
MIC50
64
32
32
64
16
64
16
32
32
16
32
16
32
32
16
32
16
32
16
64
32
16
16
64
32
64
32
16
16
16
16
32
8
16
8
8
8
8
8
8
16
32
32
16
32
8
8
8
8
8
8
8
16
8
8
8
8
8
16
16
16
16
16
16
16
8
16
16
16
8
Acknowledgments This work was financially supported by the
Foundation of Education Department of Hunan Province, China
(09B091), and the Key Subject Foundation of Shaoyang University
(2008XK201).
8
8
8
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