Synthesis of amide and ester derivatives of cinnamic acid and its analogs: Evaluation of their free radical scavenging and monoamine oxidase and cholinesterase inhibitory activities

Article abstract of DOI:10.1248/cpb.c17-00416

A series of cinnamic acid derivatives, amides (1–12) and esters (13–22), were synthesized, and structure–activity relationships for antioxidant activity, and monoamine oxidases (MAO) A and B, acetylcholinesterase, and butyrylcholinesterase (BChE) inhibitory activities were analyzed. Among the synthesized compounds, compounds 1–10, 12–18, and rosmarinic acid (23), which contained catechol, o-methoxyphenol or 5-hydroxy-indole moieties, showed potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity. Compounds 9–11, 15, 17–22 showed potent and selective MAO-B inhibitory activity. Compound 20 was the most potent inhibitor of MAO-B. Compounds 18 and 21 showed moderate BChE inhibitory activity. In addition, compound 18 showed potent antioxidant activity and MAO-B inhibitory activity. In a comparison of the cinnamic acid amides and esters, the amides exhibited more potent DPPH free radical scavenging activity, while the esters showed stronger inhibitory activities against MAO-B and BChE. These results suggested that cinnamic acid derivatives such as compound 18, p-coumaric acid 3,4-dihydroxyphenethyl ester, and compound 20, p-coumaric acid phenethyl ester, may serve as lead compounds for the development of novel MAO-B inhibitors and candidate lead compounds for the prevention or treatment of Alzheimer’s disease.

Full text of DOI:10.1248/cpb.c17-00416

1020
Chem. Pharm. Bull. 65, 1020–1027 (2017)
Vol. 65, No. 11
Regular Article
Synthesis of Amide and Ester Derivatives of Cinnamic Acid and Its
Analogs: Evaluation of Their Free Radical Scavenging and Monoamine
Oxidase and Cholinesterase Inhibitory Activities
Koichi Takao,* Kazuhiro Toda, Takayuki Saito, and Yoshiaki Sugita
Laboratory of Bioorganic Chemistry, Department of Pharmaceutical Sciences, Faculty of Pharmacy and
Pharmaceutical Sciences, Josai University; 1–1 Keyaki-dai, Sakado, Saitama 350–0295, Japan.
Received May 19, 2017; accepted August 8, 2017
A series of cinnamic acid derivatives, amides (1–12) and esters (13–22), were synthesized, and structure–
activity relationships for antioxidant activity, and monoamine oxidases (MAO) A and B, acetylcholinesterase,
and butyrylcholinesterase (BChE) inhibitory activities were analyzed. Among the synthesized compounds,
compounds 1–10, 12–18, and rosmarinic acid (23), which contained catechol, o-methoxyphenol or 5-hydroxy-
indole moieties, showed potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity. Com-
pounds 9–11, 15, 17–22 showed potent and selective MAO-B inhibitory activity. Compound 20 was the most
potent inhibitor of MAO-B. Compounds 18 and 21 showed moderate BChE inhibitory activity. In addition,
compound 18 showed potent antioxidant activity and MAO-B inhibitory activity. In a comparison of the cin-
namic acid amides and esters, the amides exhibited more potent DPPH free radical scavenging activity, while
the esters showed stronger inhibitory activities against MAO-B and BChE. These results suggested that cin-
namic acid derivatives such as compound 18, p-coumaric acid 3,4-dihydroxyphenethyl ester, and compound
20, p-coumaric acid phenethyl ester, may serve as lead compounds for the development of novel MAO-B in-
hibitors and candidate lead compounds for the prevention or treatment of Alzheimer’s disease.
Key words cinnamic acid amide; cinnamic acid ester; monoamine oxidase; cholinesterase; antioxidant;
Alzheimer’s disease
Plant secondary metabolites are important sources of bioac- of various mammalian cell types. MAO-A and MAO-B share
tive constituents that promote health. Natural products have approximately 70% sequence identity at the amino acid level,
longꢀplayedꢀaꢀsignificantꢀroleꢀinꢀtheꢀdevelopmentꢀofꢀnewꢀthera- andꢀwereꢀidentifiedꢀbasedꢀonꢀsubstrateꢀselectivityꢀandꢀinhibitorꢀ
peutic leads. For example, phenolic compounds have been sensitivity. MAO-A preferentially deaminates serotonin, nor-
shownꢀtoꢀpreventꢀoxidativeꢀstress,ꢀaꢀconditionꢀknownꢀtoꢀcauseꢀ epinephrine, and epinephrine and is irreversibly inhibited by
cell injury and death and to exacerbate the development of clorgyline,ꢀ whereasꢀ MAO-Bꢀ preferentiallyꢀ deaminatesꢀ dopa-
several age-related chronic pathologies like cancer, and neu- mine, β-phenethylamine, and benzylamine and is irreversibly
rodegenerative diseases such as Alzheimer’s and Parkinson’s inhibited by R-(−)-deprenyl. MAO inhibitors are important in
diseases.1–3)
the treatment of several neurodegenerative diseases. Selective
Alzheimer’s disease is the most common fatal neurode- MAO-A inhibitors are used as anti-depressant and anti-anx-
generative disorder, and the number of affected people is ietyꢀ drugs,ꢀ whereasꢀ selectiveꢀ MAO-Bꢀ inhibitorsꢀ areꢀ usedꢀ inꢀ
expectedꢀ toꢀ reachꢀ 106.8ꢀ millionꢀ byꢀ 2050ꢀ withꢀ theꢀ worldwideꢀ the treatment of Parkinson’s disease. Because of their potential
increases in the aging population.4)
neuroprotective effects, MAO-B inhibitors may be useful for
Although more than 100 years have passed since its dis- the treatment of Alzheimer’s disease.6–8)
covery, effective treatments for Alzheimer’s disease are
Several natural and synthetic cinnamic acid amides and
lacking.ꢀ Currentꢀ therapeuticꢀ options,ꢀ whichꢀ includeꢀ acetyl- theirꢀ estersꢀ wereꢀ foundꢀ toꢀ possessꢀ variousꢀ biologicalꢀ proper-
cholinesterase and butyrylcholinesterase (AChE and BChE) ties such as antioxidant,9,10)ꢀanti-inflammatory,11) anti-tumor,12)
inhibitors (donepezil, rivastigmine, and galantamine) and an cytoprotective,13,14) protection of β-amyloid protein aggrega-
N-methyl-D-aspartate (NMDA) receptor antagonist (meman- tion,15) tyrosinase inhibitory,16,17) α-glucosidase inhibitory,18,19)
tine), have resulted in modest improvement in memory and cholinesterase inhibitory,20) and MAO inhibitory21–23) activi-
cognitive function, but they do not prevent progressive neuro- ties.ꢀ However,ꢀ noꢀ systematicallyꢀ evaluatedꢀ dataꢀ areꢀ availableꢀ
degeneration. The free radical and oxidative stress theory of on the antioxidant and MAO and ChE inhibitory activities of
aging also suggests that oxidative damage is an important fac- cinnamic acid derivatives.
tor in neuronal degeneration. Therefore, the successful protec-
tion of neuronal cells from oxidative damage could potentially family of compounds, a series of cinnamic acid amide and
prevent Alzheimer’s disease.5)
esterꢀderivativesꢀwereꢀsynthesizedꢀ(Fig.ꢀ1),ꢀandꢀtheꢀstructure–
In order to further explore the biological activities of this
In the treatment of Parkinson’s disease, monoamine oxidase activity relationships (SARs) of the cinnamic acid derivatives
is regarded as a key target enzyme. Monoamine oxidases A withꢀ respectꢀ toꢀ antioxidantꢀ capacityꢀ andꢀ MAOꢀ andꢀ ChEꢀ in-
andꢀ Bꢀ (ECꢀ 1.4.3.4;ꢀ MAO-Aꢀ andꢀ MAO-B)ꢀ areꢀ flavoenzymes,ꢀ hibitoryꢀactivitiesꢀwereꢀinvestigated.
whichꢀ playꢀ anꢀ importantꢀ roleꢀ inꢀ theꢀ oxidativeꢀ degradationꢀ ofꢀ
neurotransmitters such as dopamine, serotonin and epineph-
rine. MAOs are found in the outer mitochondrial membrane
Results and Discussion
Chemistry Cinnamic acid and its analogs such as caf-
*ꢀToꢀwhomꢀcorrespondenceꢀshouldꢀbeꢀaddressed.ꢀ e-mail:ꢀktakao@josai.ac.jp
© 2017 The Pharmaceutical Society of Japan

Vol. 65, No. 11 (2017)
Chem. Pharm. Bull.
1021
Fig. 1. Structures of Cinnamic Acid Derivatives
feic acid, ferulic acid and p-coumaricꢀacidꢀwereꢀreactedꢀwithꢀ protection step. Chemical structures of these compounds used
biogenic amines (i.e., serotonin, dopamine, tyramine, vanillyl- inꢀthisꢀstudyꢀareꢀshownꢀinꢀFig.ꢀ1.
amine) to get amide compounds (1–12),ꢀ andꢀ withꢀ alcoholsꢀ
Biological Activityꢀ ꢀAllꢀ theꢀ compoundsꢀ synthesizedꢀ wereꢀ
(i.e., 3,4-dihydroxyphenethylalcohol, 4-hydroxyphenethylalco- evaluated for their 1,1-diphenyl-2-picrylhydrazyl (DPPH) free
hol, phenethylalcohol) to get ester compounds (13, 14, 16–22) radical scavenging, and MAO and ChE inhibitory activities.
(Chartꢀ 1).ꢀ Theirꢀ yieldsꢀ wereꢀ satisfactory.ꢀ Caffeicꢀ acidꢀ amidesꢀ The results are summarized in Table 1.
(2–4)ꢀ wereꢀ synthesizedꢀ byꢀ condensationꢀ ofꢀ theꢀ ally-protectedꢀ
DPPH Free Radical Scavenging Activity
caffeicꢀacidꢀwithꢀtheꢀcorrespondingꢀaminesꢀfollowedꢀbyꢀaꢀde-
Caffeic acid derivatives (1–4, 13–15) containing catechol

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Chem. Pharm. Bull.
Vol. 65, No. 11 (2017)
Reagentsꢀ andꢀ conditions:ꢀ (a)ꢀ allylbromide,ꢀ K2CO3,ꢀ acetone,ꢀ reflux;ꢀ (b)ꢀ KOH,ꢀ MeOH–H2O; (c) R3-NH2, EDC, HOBt, Et3N, CH2Cl2–DMF; (d) Pd(PPh3)4, morpholine,
THF, 50°C; (e) R4-OH, DIAD, TPP, THF.
Chart 1. Synthetic Protocol of Cinnamic Acid Derivatives
moietyꢀ showedꢀ aꢀsignificantꢀactivity,ꢀ followedꢀ byꢀ ferulicꢀ acidꢀ be probably due to a stabilization of resonance structure by
derivatives (5–8, 16, 17) containing o-methoxyphenol moiety. amide bond.
p-Coumaric acid derivatives (9, 10) containing 5-hydroxyin-
MAO-A or MAO-B Inhibitory Activity
doleꢀorꢀcatecholꢀmoiety,ꢀrespectively,ꢀalsoꢀshowedꢀaꢀsignificantꢀ
As can be seen in Table 1, all compounds had no inhibitory
activity, but the other p-coumaric acid derivatives (11, 19, 20) activity to MAO-A at 10µM.ꢀ However,ꢀ compoundsꢀ 9–11, 15,
except for compound 12ꢀshowedꢀalmostꢀnoꢀactivityꢀsimilarꢀtoꢀ and 17–22ꢀ showedꢀ aꢀ widelyꢀ differentꢀ inhibitoryꢀ activityꢀ toꢀ
cinnamic acid derivatives (21, 22).ꢀ Fromꢀ theꢀ viewꢀ ofꢀ aminesꢀ MAO-B. Of them compound 20 inhibited the enzyme most
or alcohols, serotonin amide derivatives (1, 5, 9)ꢀ showedꢀ sig- potently (IC50=13 nM)ꢀandꢀitsꢀinhibitoryꢀactivityꢀwasꢀaboutꢀ17ꢀ
nificantꢀactivities,ꢀfollowedꢀbyꢀdopamineꢀamideꢀderivativesꢀ(2, fold more potent than that of pargylin used as a positive con-
6, 10), 3,4-dihydroxyphenethylalcohol ester derivatives (13, trol. And compounds 15, 19, 21 and 22ꢀshowedꢀaꢀfairlyꢀpotentꢀ
16, 18), vanillylamine amide derivatives (4, 8, 12), tyramine activityꢀwithꢀIC50 values of sub-micro molar, nearly equivalent
amide derivatives (3, 7), and 4-hydroxyphenethylalcohol ester toꢀpargylin.ꢀBasedꢀonꢀtheꢀlowꢀIC50 values of these compounds,
derivatives (14, 17). Of those, compounds 1 and 2ꢀshowedꢀtheꢀ theꢀ followingꢀ SARsꢀ couldꢀ beꢀ recognized.ꢀ Theꢀ esterꢀ deriva-
mostꢀ significantꢀ activityꢀ (EC50=8.1 and 8.7µM, respectively), tives of p-coumaric acid inhibited MAO-B more potently than
whichꢀwasꢀaboutꢀ3ꢀfoldꢀmoreꢀactiveꢀthanꢀascorbicꢀacidꢀusedꢀasꢀ those of caffeic acid (20 vs. 15), ferulic acid (19 vs. 17), and
a positive control. EC50 values of each corresponding pair of cinnamic acid (19 vs. 21, 20 vs. 22). This indicated that the
the amide derivatives (2, 3, 6, 7, 10) and the ester derivatives introduction of one hydroxyl group on cinnamic acid moiety
(13, 14, 16–18)ꢀwereꢀcomparedꢀandꢀshowedꢀaꢀlowerꢀvalueꢀforꢀ wasꢀ effectiveꢀ forꢀ theirꢀ inhibitoryꢀ activity,ꢀ andꢀ aꢀ furtherꢀ ad-
theꢀ amideꢀ derivativeꢀ thanꢀ theꢀ esterꢀ derivativeꢀ withoutꢀ excep- dition of hydroxyl group on either cinnamic acid or phenety-
tion,ꢀ beingꢀ consistentꢀ withꢀ theꢀ previousꢀ report.9)ꢀ Thisꢀ wouldꢀ lalcohol moiety reduced the activity (20 vs. 19, 18). From the

Vol. 65, No. 11 (2017)
Chem. Pharm. Bull.
1023
Table 1. DPPH Free Radical Scavenging, MAOs-A, -B, AChE, BChE Inhibitory Activities of Cinnamic Acid Derivatives
DPPH radical scavenging MAO-A inhibition IC50 MAO-B inhibition IC50
AChE inhibition IC50
BChE inhibition IC50
Compound
activity EC50 (µM)
(µM)
(µM)
(µM)
(µM)
1
2
8.1
8.7
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
3
16
4
16
5
14
6
15
7
41
8
28
9
13
1.2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
16
1.9
2.0
>250
70
>10
>10
>10
0.10
>10
1.6
11
20
18
18
87
21
1.3
4.9
>250
>250
>250
>250
20
0.35
0.013
0.67
0.65
>10
>10
6.8
>10
>10
>10
Positive control
Ascorbic acid
23
Pargylin
4.6
Pargylin
0.22
Neostigmine
0.20
Neostigmine
7.1
viewꢀofꢀesterꢀorꢀamide,ꢀtheꢀesterꢀderivativeꢀ(18 or 19) inhibited higher concentration (IC50=122 µM).24)ꢀ Onlyꢀ twoꢀ compoundsꢀ
the enzyme more effectively than the corresponding amide de- (18, 21)ꢀ inhibitedꢀ BChEꢀ activityꢀ withꢀ similarꢀ IC50 values to
rivative (10 or 11), respectively. Choi et al.22) also reported that that of neostigmine used as a positive control. Compound 18
MAO-B inhibitory activities of the ester derivatives, (E)-3- exhibited not only BChE inhibitory activity but also DPPH
(2-(trifluoromethyl)ꢀphenyl)-N-phenyl-2-propenester, (E)-3-(2- free radical scavenging or MAO-B inhibitory activity, sug-
(trifluoromethyl)ꢀphenyl)-N-(4-methoxyphenyl)-2-propenester, gesting the possibility of a multi-target-directed drug lead.
(E)-3-(2-chlorophenyl)-N-(4-methoxyphenyl)-2-propenester), Recent approaches in the development of drug leads for Al-
wereꢀ moreꢀ potentꢀ thanꢀ theꢀ correspondingꢀ amideꢀ derivatives,ꢀ zheimer’s disease have been multi-target-directed.25,26)
(E)-3-(2-(trifluoromethyl)phenyl)-N-phenyl-2-propenamide,
Thisꢀisꢀtheꢀfirstꢀreportꢀtoꢀidentifyꢀp-coumaric acid phenethyl
(E)-3-(2-(trifluoromethyl)phenyl)-N-(4-methoxyphenyl)-2- ester derivatives as potent and selective MAO-B inhibitors
propenamide, (E)-3-(2-chlorophenyl)-N-(4-methoxyphenyl)-2- and multi-target-directed drug leads.
propenamide). Badavath et al.21) recently reported feruloyl-
phenetylamide as a selective MAO-B inhibitor, and found that
Conclusion
N-phenethyl-3-(3-hydroxy-4-methoxyphenyl)ꢀacrylamideꢀwasꢀtheꢀ
A series of cinnamic acid derivatives (1–22)ꢀ wereꢀ synthe-
most potent MAO-B inhibitor. Also, their molecular dock- sizedꢀandꢀtheirꢀSARsꢀ wereꢀ evaluatedꢀwithꢀrespectꢀ toꢀantioxi-
ing study using N-phenethyl-3-(3-hydroxy-4-methoxyphenyl)- dant activity, MAO-A, MAO-B, AChE, and BChE inhibitory
acrylamide and feruloylphenetylamide, demonstrated that the activities. Among the synthesized compounds, compounds 1–
twoꢀ compoundsꢀ showedꢀ theꢀ sameꢀ orientationꢀ atꢀ theꢀ MAO-Bꢀ 10, 12–18, and 23,ꢀwhichꢀcontainedꢀcatechol,ꢀo-methoxyphenol
activeꢀ site,ꢀ however,ꢀ theꢀ formerꢀ inhibitedꢀ MAO-Bꢀ activityꢀ orꢀ5-hydroxyindoleꢀmoieties,ꢀshowedꢀpotentꢀDPPHꢀfreeꢀradicalꢀ
more potent than the latter. This suggested that the hydroxyl scavenging activities. Compounds 9–11, 15, 17–22ꢀ showedꢀ
groupꢀ onꢀ cinnamicꢀ acidꢀ moietyꢀ bestꢀ fitꢀ atꢀ 3ꢀ positionꢀ andꢀ theꢀ potent and selective MAO-B inhibitory activities. Compound
methoxy group at 4 position for the inhibition. From their re- 20ꢀ wasꢀ theꢀ mostꢀ potentꢀ inhibitorꢀ forꢀ MAO-Bꢀ (IC50=13 nM).
sults and ours, the synthesis of 3-hydroxy-4-methoxycinnamic Compound 18ꢀshowedꢀmoderateꢀBChEꢀinhibitoryꢀactivityꢀandꢀ
acid phenethylester and its inhibitory activity to MAO-B potent antioxidant and MAO-B inhibitory activities. In com-
shouldꢀbeꢀtestedꢀinꢀfuture.ꢀMAO-Bꢀinhibitorꢀhasꢀbeenꢀshownꢀ paring cinnamic acid amides and esters, the amides had more
to be an important drug lead for several diseases.8) Thus com- potentꢀ DPPHꢀ freeꢀ radicalꢀ scavengingꢀ activities,ꢀ whileꢀ theꢀ es-
pound 20 may serve as such a drug lead.
tersꢀshowedꢀstrongerꢀinhibitoryꢀactivitiesꢀagainstꢀMAO-Bꢀandꢀ
AChE and BChE Inhibitory Activity
BChE. These results suggest that cinnamic acid derivatives,
As can be seen in Table 1, no inhibitory activity to AChE such as compound 18, p-coumaric acid 3,4-dihydroxypheneth-
wasꢀ observedꢀ forꢀ allꢀ compoundsꢀ atꢀ 10ꢀµM. Kim and Lee re- yl ester, and compound 20, p-coumaric acid phenethyl ester,
ported AChE inhibitory activity of compound 11 using much may be applicable as lead compounds for the development of

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Chem. Pharm. Bull.
Vol. 65, No. 11 (2017)
novel MAO-B inhibitors and as candidate lead compounds for 7.24 (1H, d, J=15.7Hz, H-β), 7.12 (1H, d, J=8.6Hz, H-7′),
the prevention or treatment of Alzheimer’s disease.
7.05 (1H, s, H-2′), 6.94 (1H, d, J=2.1Hz, H-2), 6.84 (1H,
d, J=2.3Hz, H-4′), 6.83 (1H, dd, J=8.1, 2.1Hz, H-6), 6.74
(1H, d, J=8.1Hz, H-5), 6.59 (1H, dd, J=8.6, 2.3Hz, H-6′),
Experimental
Chemistryꢀ ꢀAllꢀ reagentsꢀ andꢀ solventsꢀ wereꢀ purchasedꢀ 6.33 (1H, d, J=15.7Hz, H-α), 3.45–3.35 (2H, m, NCH2), 2.77
from commercial sources. Compounds 15 and 22ꢀ wereꢀ pur- (2H, t, J=7.5Hz, CH2). MS (electron ionization (EI)) m/z 338
1
chased from Tokyo Chemical Industry Co., Tokyo, Japan. [M]+. The H-NMRꢀ spectrumꢀ wasꢀ similarꢀ toꢀ thatꢀ aꢀ previousꢀ
Compound 23ꢀ wasꢀ purchasedꢀ fromꢀ Wakoꢀ Pureꢀ Chemicalꢀ In- report.16)
dustries,ꢀ Ltd.,ꢀ Tokyo,ꢀ Japan.ꢀ Analyticalꢀ TLCꢀ wasꢀ performedꢀ
(2E)-3-(3,4-Dihydroxyphenyl)-N-[2-(3,4-dihydroxyphenyl)-
on silica-coated plates (silica gel 60F-254; Merck Ltd., Tokyo, ethyl]-2-propenamide (2)
Japan) and visualized under UV light. Column chromatogra-
Yield 70%. Ocher solid. mp 183–185°C (hexane–AcOEt) (lit.
1
phyꢀ wasꢀ carriedꢀ outꢀ usingꢀ silicaꢀ gelꢀ (Wakogelꢀ C-200;ꢀ Wakoꢀ 180–182°C29)). H-NMR (DMSO-d6, 400MHz) δ:ꢀ 9.05ꢀ (1H,ꢀ
Pure Chemical Industries, Ltd., Tokyo, Japan). All melting brs, OH), 8.80 (1H, brs, OH), 8.02 (1H, brt, J=5.7Hz, NH),
pointsꢀ wereꢀ determinedꢀ usingꢀ aꢀ Yanagimotoꢀ micro-hotꢀ stageꢀ 7.22 (1H, d, J=15.7Hz, H-β), 6.93 (1H, d, J=2.0Hz, H-2), 6.83
1
and are uncorrected. H- and 13C-NMRꢀspectraꢀwereꢀrecordedꢀ (1H, dd, J=8.1, 2.0Hz, H-6), 6.73 (1H, d, J=8.1Hz, H-5), 6.64
on a Varian 400-MR spectrometer using tetramethylsilane (1H, d, J=8.0Hz, H-5′), 6.59 (1H, d, J=2.1Hz, H-2′), 6.45
asꢀ theꢀ internalꢀ standard.ꢀ MSꢀ spectraꢀ wereꢀ measuredꢀ usingꢀ aꢀ (1H, dd, J=8.0, 2.1Hz, H-6′), 6.31 (1H, d, J=15.7Hz, H-α),
JEOLꢀJMS-700ꢀspectrometer.ꢀElementalꢀanalysesꢀwereꢀcarriedꢀ 3.35–3.25 (2H, m, NCH2), 2.56 (1H, t, J=7.4Hz, CH2). MS
1
out on a Yanaco CHN MT-6 elemental analyzer.
(EI) m/z 315 [M]+. The H-NMRꢀspectrumꢀwasꢀsimilarꢀtoꢀthatꢀ
Preparation of Cinnamic Acid Amides (5–12) Cin- a previous report.9)
namic acid amides (5–12)ꢀ wereꢀ synthesizedꢀ accordingꢀ toꢀ aꢀ
(2E)-3-(3,4-Dihydroxyphenyl)-N-[2-(4-hydroxyphenyl)-
modifiedꢀ previousꢀ procedure.27) 1-(3-Dimethylaminopropyl)- ethyl]-2-propenamide (3)
3-ethylcarbodiimide hydrochloride (EDC) (2.1mmol) and
Yieldꢀ 46%.ꢀ Paleꢀ brownꢀ solid.ꢀ mpꢀ 208–209°Cꢀ (hexane–
1-hydroxybenzotriazoleꢀ (HOBt)ꢀ (2.1ꢀmmol)ꢀ wereꢀ addedꢀ toꢀ aꢀ AcOEt) (lit. 206–208°C9)). 1H-NMR (DMSO-d6, 400MHz)
solution of cinnamic acid derivatives (Ib or Ic, 2mmol) in δ:ꢀ 8.02ꢀ (1H,ꢀ brꢀt,ꢀ J=5.7Hz, NH), 7.22 (1H, d, J=15.6Hz,
N,N-dimethylformamide (DMF) (2mL) and CH2Cl2 (12mL). H-β), 7.01 (2H, d, J=8.4Hz, H-2′ and H-6′), 6.93 (1H, d,
Theꢀ solutionꢀ wasꢀ stirredꢀ forꢀ 30ꢀminꢀ atꢀ roomꢀ temperature,ꢀ J=2.0Hz, H-2), 6.82 (1H, dd, J=8.1, 2.0Hz, H-6), 6.73 (1H,
and then the selected biogenic amines (2.0mmol) and Et3N d, J=8.1Hz, H-5), 6.68 (2H, d, J=8.4Hz, H-3′ and H-5′), 6.32
(2.0ꢀmmol)ꢀ wereꢀ addedꢀ toꢀ theꢀ reactionꢀ mixture.ꢀ Theꢀ mixtureꢀ (1H, d, J=15.6Hz, H-α), 3.36–3.26 (2H, m, NCH2), 2.64 (1H,
1
wasꢀ thenꢀ stirredꢀ overnightꢀ atꢀ roomꢀ temperatureꢀ underꢀ argonꢀ t, J=7.4Hz, CH2). MS (EI) m/z 299 [M]+. The H-NMR spec-
atmosphere.ꢀ Theꢀ solventꢀ wasꢀ evaporatedꢀ underꢀ reducedꢀ pres- trumꢀwasꢀsimilarꢀtoꢀthatꢀaꢀpreviousꢀreport.9)
sureꢀ andꢀ theꢀ residueꢀ wasꢀ treatedꢀ withꢀ waterꢀ andꢀ extractedꢀ
(2E)-3-(3,4-Dihydroxyphenyl)-N-[(4-hydroxy-3-methoxy-
withꢀ ethylꢀ acetateꢀ (AcOEt).ꢀ Theꢀ organicꢀ extractꢀ wasꢀ washedꢀ phenyl)methyl]-2-propenamide (4)
successivelyꢀwithꢀ10%ꢀcitricꢀacidꢀsolution,ꢀsaturatedꢀNaHCO3
Yieldꢀ 65%.ꢀ Brownꢀ solid.ꢀ mpꢀ 214–217°Cꢀ (hexane–AcOEt).ꢀ
solution,ꢀandꢀbrine.ꢀTheꢀorganicꢀlayerꢀwasꢀdriedꢀoverꢀNa2SO4 1H-NMR (DMSO-d6, 400MHz) δ:ꢀ 8.36ꢀ (1H,ꢀ brꢀt,ꢀ J=5.6Hz,
andꢀ theꢀ solventꢀ wasꢀ evaporatedꢀ underꢀ reducedꢀ pressure.ꢀ Theꢀ NH), 7.27 (1H, d, J=15.7Hz, H-β), 6.94 (1H, d, J=2.0Hz,
residueꢀ wasꢀ purifiedꢀ byꢀ silicaꢀ gelꢀ columnꢀ chromatographyꢀ H-2), 6.86 (1H, d, J=1.8Hz, H-2′), 6.84 (1H, dd, J=8.1,
(hexaneꢀ:ꢀAcOEt=1ꢀ:ꢀ2)ꢀtoꢀgiveꢀtheꢀtitleꢀcompound.
2.0Hz, H-6), 6.75–6.70 (2H, m, H-5 and H-5′), 6.68 (1H, dd,
Preparation of Caffeoyl Amides (1–4) According to J=8.1, 1.8Hz, H-6′), 6.38 (1H, d, J=15.7Hz, H-α), 4.27 (2H,
the general procedure for the preparation of cinnamic acid d, J=5.6Hz, NCH2), 3.74 (3H, s, OCH3). 13C-NMR (DMSO-
amides, 3,4-diallyloxy cinnamic acid (IIa)28) and the bio- d6, 100MHz) δ:ꢀ165.2,ꢀ147.4,ꢀ147.3,ꢀ145.5,ꢀ145.4,ꢀ139.3,ꢀ130.2,ꢀ
genicꢀ aminesꢀ (2.0ꢀmmol)ꢀ wereꢀ treatedꢀ withꢀ EDCꢀ (2.1ꢀmmol),ꢀ 126.4, 120.5, 120.0, 118.4, 115.7, 115.2, 113.8, 111.9, 55.6, 42.2.
HOBt (2.1mmol) and Et3N (2.0mmol), and then the residue HR-MS m/z:ꢀ Calcdꢀ forꢀ C17H17NO5 (M+):ꢀ 315.1107.ꢀ Found:ꢀ
wasꢀ passedꢀ onceꢀ throughꢀ aꢀ shortꢀ silicaꢀ gelꢀ columnꢀ (hex- 315.1108.
aneꢀ:ꢀAcOEt=1ꢀ:ꢀ2)ꢀ andꢀ theꢀ solventꢀ wasꢀ evaporated.ꢀ Theꢀ ob-
(2E)-N-[2-(5-Hydroxy-1H-indol-3-yl)ethyl]-3-(4-hydroxy-3-
tainedꢀ allylꢀ protectedꢀ compoundꢀ (1.0ꢀmmol)ꢀ wasꢀ dissolvedꢀ inꢀ methoxyphenyl)-2-propenamide (5)
degassed anhydrated tetrahydrofuran (THF) (30mL) and mor-
Yield 57%. Pale violet solid. mp 117–120°C (hexane–
pholine (20mmol), and Pd(PPh3)4ꢀ (5ꢀmol%)ꢀ wasꢀ added.ꢀ Theꢀ AcOEt). 1H-NMR (DMSO-d6, 400MHz) δ:ꢀ 10.49ꢀ (1H,ꢀ d,ꢀ
greenꢀ mixtureꢀ wasꢀ stirredꢀ atꢀ 50°Cꢀ (monitoredꢀ byꢀ TLC)ꢀ andꢀ J=2.4Hz, H-1′), 9.41 (1H, brs, OH), 8.62 (1H, brs, OH), 8.06
concentratedꢀunderꢀreducedꢀpressure.ꢀTheꢀresidueꢀwasꢀtreatedꢀ (1H, brt, J=5.7Hz, NH), 7.33 (1H, d, J=15.7Hz, H-β), 7.13
withꢀ NH4Clꢀ solutionꢀ andꢀ extractedꢀ withꢀ AcOEt.ꢀ Theꢀ organicꢀ (1H, d, J=8.6Hz, H-7′), 7.12 (1H, d, J=1.9Hz, H-2), 7.06 (1H,
layerꢀ wasꢀ driedꢀ overꢀ Na2SO4ꢀ andꢀ theꢀ solventꢀ wasꢀ evaporatedꢀ d, J=2.4Hz, H-2′), 6.99 (1H, dd, J=8.1, 1.9Hz, H-6), 6.85
underꢀ reducedꢀ pressure.ꢀ Theꢀ residueꢀ wasꢀ purifiedꢀ byꢀ silicaꢀ (1H, d, J=2.3Hz, H-4′), 6.79 (1H, d, J=8.1Hz, H-5), 6.59
gelꢀcolumnꢀchromatographyꢀ(hexaneꢀ:ꢀAcOEt=1ꢀ:ꢀ5)ꢀtoꢀgiveꢀtheꢀ (1H, dd, J=8.6, 2.3Hz, H-6′), 6.45 (1H, d, J=15.7Hz, H-α),
title compound.
3.80 (3H, s, OCH3), 3.46–3.33 (2H, m, NCH2), 2.78 (2H, t,
1
(2E)-3-(3,4-Dihydroxyphenyl)-N-[2-(5-hydroxy-1H-indol-3- J=7.5Hz, CH2). MS (EI) m/z 352 [M]+. The H-NMR spec-
yl)ethyl]-2-propenamide (1)
trumꢀwasꢀsimilarꢀtoꢀthatꢀaꢀpreviousꢀreport.16)
Yield 42%. Pale gray solid. mp 105–108°C (hexane–
(2E)-N-[2-(3,4-Dihydroxyphenyl)ethyl]-3-(4-hydroxy-3-
AcOEt). H-NMR (dimethylsulfoxide (DMSO)-d6, 400MHz) methoxyphenyl)-2-propenamide (6)
1
δ:ꢀ 10.49ꢀ (1H,ꢀ brꢀs,ꢀ H-1′), 9.21 (1H, brs, OH), 8.60 (1H, brs,
Yieldꢀ 56%.ꢀ Paleꢀ yellowꢀ solid.ꢀ mpꢀ 145–147°Cꢀ (hexane–
OH), 8.61 (1H, brs, OH), 8.06 (1H, brt, J=5.6Hz, NH), AcOEt) (lit. 144–146°C29)). 1H-NMR (DMSO-d6, 400MHz)

Vol. 65, No. 11 (2017)
Chem. Pharm. Bull.
1025
δ:ꢀ 9.42ꢀ (1H,ꢀ brꢀs,ꢀ OH),ꢀ 8.72ꢀ (2H,ꢀ brꢀs,ꢀ OH),ꢀ 7.97ꢀ (1H,ꢀ brꢀt,ꢀ d, J=15.7Hz, H-β), 6.78 (2H, d, J=8.6Hz, H-3 and H-5), 6.64
J=5.7Hz, NH), 7.30 (1H, d, J=15.7Hz, H-β), 7.11 (1H, d, (1H, d, J=8.0Hz, H-5′), 6.59 (1H, d, J=2.0Hz, H-2′), 6.45
J=1.9Hz, H-2), 6.98 (1H, dd, J=8.2, 1.9Hz, H-6), 6.78 (1H, (1H, dd, J=8.0, 2.0Hz, H-5′), 6.39 (1H, d, J=15.7Hz, H-α),
d, J=8.2Hz, H-5), 6.64 (1H, d, J=7.9Hz, H-5′), 6.59 (1H, d, 3.29 (2H, m, NCH2), 2.57 (1H, t, J=7.4Hz, CH2). 13C-NMR
J=2.1Hz, H-2′), 6.46 (1H, dd, J=7.9, 2.1Hz, H-5′), 6.43 (1H, (DMSO-d6, 100MHz) δ:ꢀ 165.2,ꢀ 158.7,ꢀ 145.0,ꢀ 143.5,ꢀ 138.5,ꢀ
d, J=15.7Hz, H-α), 3.80 (3H, s, OCH3), 3.35–3.26 (2H, m, 130.2, 129.1, 125.9, 119.2, 118.7, 115.9, 115.7, 115.4, 40.7, 34.7.
NCH2), 2.57 (1H, t, J=7.4Hz, CH2). 13C-NMR (DMSO-d6, HR-MS m/z:ꢀ Calcdꢀ forꢀ C17H17NO4 (M+):ꢀ 299.1158,ꢀ Found:ꢀ
1
100 MHz) δ:ꢀ 165.4,ꢀ 148.4,ꢀ 148.0,ꢀ 145.3,ꢀ 143.7,ꢀ 139.0,ꢀ 130.4,ꢀ 299.1174. The H-NMRꢀspectrumꢀwasꢀsimilarꢀtoꢀthatꢀaꢀprevi-
126.6, 121.7, 119.4, 119.2, 116.1, 115.8, 115.7, 110.9, 55.7, 40.8, ous report.11)
34.9. HR-MS m/z:ꢀCalcdꢀforꢀC18H19NO5 (M+):ꢀ329.1263.ꢀFound:ꢀ
(2E)-3-(4-Hydroxyphenyl)-N-[2-(4-hydroxyphenyl)ethyl]-2-
1
329.1254. The H-NMRꢀspectrumꢀwasꢀsimilarꢀtoꢀthatꢀaꢀprevi- propenamide (11)
ous report.11)
Yieldꢀ 63%.ꢀ Whiteꢀ solid.ꢀ mpꢀ 245–248°Cꢀ (hexane–AcOEt)ꢀ
(2E)-3-(4-Hydroxy-3-methoxyphenyl)-N-[2-(4-hydroxy- (lit. 247–248°C30)). 1H-NMR (DMSO-d6, 400MHz) δ:ꢀ 9.84ꢀ
phenyl)ethyl]-2-propenamide (7)
(1H, brs, OH), 9.18 (1H, brs, OH), 8.01 (1H, brt, J=5.6Hz,
Yieldꢀ 58%.ꢀ Whiteꢀ solid.ꢀ mpꢀ 143–145°Cꢀ (hexane–AcOEt)ꢀ NH), 7.38 (2H, d, J=8.6Hz, H-2 and H-6), 7.31 (1H, d,
(lit. 144–145°C29)). 1H-NMR (DMSO-d6, 400MHz) δ:ꢀ 9.38ꢀ J=15.7Hz, H-β), 7.01 (2H, d, J=8.5Hz, H-2′ and H-6′), 6.78
(1H, brs, OH), 9.24 (1H, brs, OH), 7.98 (1H, brt, J=5.6Hz, (2H, d, J=8.6Hz, H-3 and H-5), 6.67 (2H, d, J=8.5Hz, H-3′
NH), 7.31 (1H, d, J=15.7Hz, H-β), 7.11 (1H, d, J=2.0Hz, and H-5′), 6.39 (1H, d, J=15.6Hz, H-α), 3.35–3.27 (2H, m,
H-2), 7.02 (2H, d, J=8.4Hz, H-2′ and H-6′), 6.98 (1H, dd, NCH2), 2.63 (1H, t, J=7.4Hz, CH2). MS (EI) m/z 283 [M]+.
J=8.1, 2.0Hz, H-6), 6.78 (1H, d, J=8.1Hz, H-5), 6.68 (2H, The 1H-NMRꢀ spectrumꢀ wasꢀ similarꢀ toꢀ thatꢀ aꢀ previousꢀ re-
d, J=8.4Hz, H-3′ and H-5′), 6.43 (1H, d, J=15.6Hz, H-α), port.26)
3.80 (3H, s, OCH3), 3.35–3.26 (2H, m, NCH2), 2.64 (1H, t,
(2E)-N-[(4-Hydroxy-3-methoxyphenyl)methyl]-3-(4-
J=7.4Hz, CH2). 13C-NMR (DMSO-d6, 100MHz) δ:ꢀ 165.3,ꢀ hydroxyphenyl)-2-propenamide (12)
155.6, 148.2, 147.8, 138.8, 129.5, 129.5, 126.4, 121.5, 119.0,
Yieldꢀ 75%.ꢀ Whiteꢀ solid.ꢀ mpꢀ 173–175°Cꢀ (hexane–AcOEt).ꢀ
115.6, 115.1, 110.7, 55.5, 40.7, 34.4. MS (EI) m/z 313 [M]+. 1H-NMR (DMSO-d6, 400MHz) δ:ꢀ 9.84ꢀ (1H,ꢀ brꢀs,ꢀ OH),ꢀ 8.86ꢀ
Anal. Calcd for C18H19NO4:ꢀC,ꢀ68.99;ꢀH,ꢀ6.11;ꢀN,ꢀ4.47.ꢀFound:ꢀ (1H, brs, OH), 8.34 (1H, brt, J=5.8Hz, NH), 7.38 (2H, d,
1
C, 68.78; H, 5.96; N, 4.48. The H-NMRꢀspectrumꢀwasꢀsimilarꢀ J=8.6Hz, H-2 and H-6), 7.35 (1H, d, J=15.7Hz, H-β), 6.86
to that a previous report.10)
(1H, d, J=1.8Hz, H-2′), 6.78 (2H, d, J=8.6Hz, H-3 and H-5),
(2E)-3-(4-Hydroxy-3-methoxyphenyl)-N-[(4-hydroxy-3- 6.72 (1H, d, J=8.0Hz, H-5′), 6.68 (1H, dd, J=8.0, 1.8Hz,
methoxyphenyl)methyl]-2-propenamide (8)
H-6′), 6.46 (1H, d, J=15.7Hz, H-α), 4.27 (2H, d, J=5.8Hz,
Yieldꢀ 44%.ꢀ Paleꢀ brownꢀ solid.ꢀ mpꢀ 142–144°Cꢀ (hexane– NCH2), 3.74 (3H, s, OCH3). 13C-NMR (DMSO-d6, 100MHz)
AcOEt). 1H-NMR (DMSO-d6, 400MHz) δ:ꢀ 9.44ꢀ (1H,ꢀ brꢀs,ꢀ δ:ꢀ 165.2,ꢀ 158.8,ꢀ 147.4,ꢀ 145.5,ꢀ 138.9,ꢀ 130.2,ꢀ 129.2,ꢀ 125.9,ꢀ 119.9,ꢀ
OH), 8.85 (1H, brs, OH), 8.32 (1H, brt, J=5.7Hz, NH), 7.35 118.6, 115.7, 115.2, 111.9, 55.6, 42.1. HR-MS m/z:ꢀ Calcdꢀ forꢀ
(1H, d, J=15.7Hz, H-β), 7.12 (1H, d, J=1.9Hz, H-2), 6.99 (1H, C17H17NO4 (M+):ꢀ 299.1158.ꢀ Found:ꢀ 299.1166.ꢀ Anal. Calcd for
dd, J=8.1, 1.9Hz, H-6), 6.86 (1H, d, J=1.8Hz, H-2′), 6.78 (1H, C17H17NO4:ꢀ C,ꢀ 68.23;ꢀ H,ꢀ 5.69;ꢀ N,ꢀ 4.68.ꢀ Found:ꢀ C,ꢀ 67.98;ꢀ H,ꢀ
d, J=8.1Hz, H-5), 6.72 (1H, d, J=8.0Hz, H-5′), 6.68 (1H, dd, 5.73; N, 4.69.
J=8.0, 1.8Hz, H-6′), 6.50 (1H, d, J=15.7Hz, H-α), 4.27 (2H,
Preparation of Cinnamic Acid Esters (13–22) Cinnamic
d, J=5.7Hz, NCH2), 3.80 (3H, s, OCH3), 3.75 (3H, s, OCH3). acid esters (13–22)ꢀwereꢀsynthesizedꢀaccordingꢀtoꢀaꢀmodifiedꢀ
13C-NMR (DMSO-d6, 100MHz) δ:ꢀ 165.2,ꢀ 148.3,ꢀ 147.8,ꢀ 147.5,ꢀ previous procedure.31) To a mixture of cinnamic acid deriva-
145.5, 139.2, 130.2, 126.4, 121.5, 120.0, 118.9, 115.7, 115.2, tives (Ia–d, 3.0mmol) and the appropriate alcohol (2.0mmol)
111.9, 110.8, 55.6, 55.5, 42.2. HR-MS m/z:ꢀCalcdꢀforꢀC18H19NO5 inꢀ dryꢀ tetrahydrofuranꢀ (6ꢀmL)ꢀ wereꢀ addedꢀ triphenylphos-
(M+):ꢀ 329.1263.ꢀ Found:ꢀ 329.1247.ꢀ Anal. Calcd for C18H19NO5:ꢀ phine (3.0mmol) and diisopropyl azodicarboxylate (DIAD)
C,ꢀ65.65;ꢀH,ꢀ5.78;ꢀN,ꢀ4.26.ꢀFound:ꢀC,ꢀ65.43;ꢀH,ꢀ5.72;ꢀN,ꢀ4.23.
(2E)-N-[2-(5-Hydroxy-1H-indol-3-yl)ethyl]-3-(4-hydroxy- temperatureꢀandꢀtheꢀwholeꢀmixtureꢀwasꢀextractedꢀwithꢀAcOEtꢀ
phenyl)-2-propenamide (9) and saturated NaHCO3ꢀ solution,ꢀ andꢀ theꢀ organicꢀ extractꢀ wasꢀ
(3.0ꢀmmol).ꢀTheꢀreactionꢀmixtureꢀwasꢀstirredꢀforꢀ48ꢀhꢀatꢀroomꢀ
Yield 82%. Pale gray solid. mp 200–203°C (hexane–AcOEt). washedꢀwithꢀbrine.ꢀTheꢀorganicꢀlayerꢀwasꢀdriedꢀoverꢀNa2SO4
1H-NMR (DMSO-d6, 400MHz) δ:ꢀ 10.47ꢀ (1H,ꢀ d,ꢀ J=2.4Hz, andꢀ theꢀ solventꢀ wasꢀ evaporatedꢀ underꢀ reducedꢀ pressure.ꢀ Theꢀ
H-1′), 8.60 (2H, brs, OH), 8.06 (1H, brt, J=5.6Hz, NH), 7.37 residueꢀwasꢀthenꢀpurifiedꢀbyꢀsilicaꢀgelꢀcolumnꢀchromatographyꢀ
(2H, d, J=8.6Hz, H-2 and H-6), 7.31 (1H, d, J=15.7Hz, H-β), (hexaneꢀ:ꢀAcOEt=2ꢀ:ꢀ1)ꢀtoꢀgiveꢀtheꢀtitleꢀcompound.
7.10 (1H, d, J=8.6Hz, H-7′), 7.03 (1H, d, J=2.4Hz, H-2′), 6.83
(2E)-3-(3,4-Dihydroxyphenyl)-2-propenoic Acid 2-(3,4-dihy-
(1H, d, J=2.3Hz, H-4′), 6.77 (2H, d, J=8.6Hz, H-3 and H-5), droxyphenyl)ethyl Ester (13)
6.57 (1H, dd, J=8.6, 2.3Hz, H-6′), 6.39 (1H, d, J=15.7Hz,
Yieldꢀ 73%.ꢀ Paleꢀ yellowꢀ solid.ꢀ mpꢀ 137–139°Cꢀ (hexane–
H-α), 3.43–3.32 (2H, m, NCH2), 2.75 (2H, t, J=7.5Hz, CH2). AcOEt). 1H-NMR (DMSO-d6, 400MHz) δ:ꢀ8.90ꢀ(4H,ꢀbrꢀs,ꢀOH),ꢀ
1
MS (EI) m/z 322 [M]+. The H-NMRꢀspectrumꢀwasꢀsimilarꢀtoꢀ 7.44 (1H, d, J=15.9Hz, H-β), 7.02 (1H, d, J=2.0Hz, H-2), 6.98
that a previous report.16)
(1H, dd, J=8.2, 2.0Hz, H-6), 6.74 (1H, d, J=8.2Hz, H-5), 6.64
(2E)-N-[2-(3,4-Dihydroxyphenyl)ethyl]-3-(4-hydroxy- (1H, d, J=8.0Hz, H-5′), 6.63 (1H, d, J=2.1Hz, H-2′), 6.48
phenyl)-2-propenamide (10)
(1H, dd, J=8.0, 2.1Hz, H-6′), 6.20 (1H, d, J=15.9Hz, H-α)
Yieldꢀ 72%.ꢀ Paleꢀ yellowꢀ solid.ꢀ mpꢀ 200–202°Cꢀ (hexane– 4.20 (2H, t, J=7.0Hz, OCH2), 2.74 (2H, t, J=7.0Hz, CH2). MS
AcOEt) (lit. 204–206°C29)). 1H-NMR (DMSO-d6, 400MHz) (FAB) m/z 316 [M]+. The H-NMRꢀ spectrumꢀ wasꢀ similarꢀ toꢀ
1
δ:ꢀ 9.82ꢀ (1H,ꢀ brꢀs,ꢀ OH),ꢀ 8.72ꢀ (2H,ꢀ brꢀs,ꢀ OH),ꢀ 8.00ꢀ (1H,ꢀ brꢀt,ꢀ that a previous report.32)
J=5.7Hz, NH), 7.38 (2H, d, J=8.6Hz, H-2 and H-6), 7.30 (1H,

1026
Chem. Pharm. Bull.
Vol. 65, No. 11 (2017)
1
(2E)-3-(3,4-Dihydroxyphenyl)-2-propenoic Acid 2-(4-Hydro- J=7.1Hz, CH2). MS (EI) m/z 284 [M]+. The H-NMR spec-
xyphenyl)ethyl Ester (14)
trumꢀwasꢀsimilarꢀtoꢀthatꢀaꢀpreviousꢀreport.34)
Yieldꢀ 33%.ꢀ Paleꢀ brownꢀ solid.ꢀ mpꢀ 186–189°Cꢀ (hexane–
(2E)-3-(4-Hydroxyphenyl)-2-propenoic Acid 2-Phenylethyl
1
AcOEt) (lit. 184–186°C33)). H-NMR (DMSO-d6, 400MHz) δ:ꢀ Ester (20)
9.25 (1H, brs, OH), 7.46 (1H, d, J=15.9Hz, H-β), 7.07 (2H, d,
Yieldꢀ40%.ꢀWhiteꢀsolid.ꢀmpꢀ86–88°Cꢀ(hexane–AcOEt)ꢀ(lit.ꢀ
J=8.4Hz, H-2′ and H-6′), 7.05 (1H, d, J=2.1Hz, H-2), 7.00 90–92°C14)). 1H-NMR (DMSO-d6, 400MHz) δ:ꢀ 10.01ꢀ (1H,ꢀ
(1H, dd, J=8.2, 2.1Hz, H-6), 6.76 (1H, d, J=8.1Hz, H-5), brs, OH), 7.55 (2H, d, J=8.6Hz, H-2 and H-6), 7.54 (1H,
6.69 (2H, d, J=8.4Hz, H-3′ and H-5′), 6.24 (1H, d, J=15.9Hz, d, J=16.0Hz, H-β), 7.34–7.20 (5H, m, H-2′, H-3′, H-4′, H-5′
H-α), 4.24 (2H, t, J=7.0Hz, OCH2), 2.83 (2H, t, J=7.0Hz, and H-6′), 6.79 (2H, d, J=8.6Hz, H-3 and H-5), 6.37 (1H, d,
1
CH2). MS (EI) m/z 300 [M]+. The H-NMRꢀ spectrumꢀ wasꢀ J=16.0Hz, H-α), 4.33 (2H, t, J=6.9Hz, OCH2), 2.96 (2H, t,
similar to that a previous report.33)
J=6.9Hz, CH2). MS (EI) m/z 268 [M]+. The H-NMR spec-
1
(2E)-3-(4-Hydroxy-3-methoxyphenyl)-2-propenoic Acid 2-(3,4- trumꢀwasꢀsimilarꢀtoꢀthatꢀaꢀpreviousꢀreport.14)
Dihydroxyphenyl)ethyl Ester (16)
(2E)-3-Phenyl-2-propenoic Acid 2-(4-Hydroxyphenyl)ethyl
Yieldꢀ 70%.ꢀ Whiteꢀ solid.ꢀ mpꢀ 135–137°Cꢀ (hexane–AcOEt).ꢀ Ester (21)
1H-NMR (DMSO-d6, 400MHz) δ:ꢀ 9.56ꢀ (1H,ꢀ brꢀs,ꢀ OH),ꢀ 8.75ꢀ
Yieldꢀ 76%.ꢀ Whiteꢀ solid.ꢀ mpꢀ 138–140°Cꢀ (hexane–AcOEt).ꢀ
(2H, brs, OH), 7.50 (1H, d, J=15.9Hz, H-β), 7.30 (1H, d, 1H-NMR (DMSO-d6, 400MHz) δ:ꢀ7.73–7.66ꢀ(2H,ꢀm,ꢀPh),ꢀ7.62ꢀ
J=2.0Hz, H-2), 7.09 (1H, dd, J=8.1, 1.9Hz, H-6), 6.77 (1H, (1H, d, J=16.0Hz, H-β), 7.43–7.38 (3H, m, Ph), 7.06 (2H, d,
d, J=8.1Hz, H-5), 6.64 (1H, d, J=8.0Hz, H-5′), 6.64 (1H, d, J=8.3Hz, H-2′ and H-6′), 6.68 (2H, d, J=8.3Hz, H-3′ and
J=2.0Hz, H-2′), 6.49 (1H, dd, J=8.0, 2.0Hz, H-6′), 6.42 (1H, H-5′), 6.60 (1H, d, J=16.0Hz, H-α), 4.27 (2H, t, J=7.0Hz,
d, J=15.9Hz, H-α), 4.22 (2H, t, J=7.0Hz, OCH2), 3.80 (3H, OCH2), 2.82 (2H, t, J=7.0Hz, CH2). 13C-NMR (DMSO-d6,
s, OCH3), 2.75 (2H, t, J=7.0Hz, CH2). 13C-NMR (DMSO-d6, 100 MHz) δ:ꢀ 166.2,ꢀ 155.9,ꢀ 144.6,ꢀ 1340,ꢀ 130.5,ꢀ 129.8,ꢀ 128.9,ꢀ
100 MHz) δ:ꢀ 166.6,ꢀ 149.4,ꢀ 147.9,ꢀ 145.1,ꢀ 145.0,ꢀ 143.7,ꢀ 128.6,ꢀ 128.4, 127.9, 118.0, 115.2, 65.0, 33.6. HR-MS m/z:ꢀ Calcdꢀ forꢀ
125.5, 123.2, 119.5, 116.2, 115.5, 115.4, 114.4, 111.1, 64.7, 55.7, C17H16O3 (M+):ꢀ 268.1099.ꢀ Found:ꢀ 268.1096.ꢀ Anal. Calcd for
33.9. HR-MS m/z:ꢀ Calcdꢀ forꢀ C18H19O6 (M+):ꢀ 331.1182.ꢀ Found:ꢀ C17H16O3:ꢀC,ꢀ76.10;ꢀH,ꢀ6.01.ꢀFound:ꢀC,ꢀ75.84;ꢀH,ꢀ5.82.
1
331.1190. The H-NMRꢀspectrumꢀwasꢀsimilarꢀtoꢀthatꢀaꢀprevi-
Biological Assays Recombinant human monoamine oxi-
dase A (MAO-A), MAO-B, acetylcholinesterase, horse serum
ous report.34)
(2E)-3-(4-Hydroxy-3-methoxyphenyl)-2-propenoic Acid 2-(4- butyrylcholinesterase,ꢀ pargylineꢀ andꢀ kynuramineꢀ wereꢀ pur-
Hydroxyphenyl)ethyl Ester (17) chased from Sigma-Aldrich Japan Co., Tokyo, Japan. DPPH
1
Yieldꢀ 14%.ꢀ Paleꢀ yellowꢀ semisolid.ꢀ H-NMR (DMSO-d6, free radical, neostigmine and 5,5′-dithiobis(2-nitrobenzoic
400MHz) δ:ꢀ9.28ꢀ(1H,ꢀbrꢀs,ꢀOH),ꢀ7.50ꢀ(1H,ꢀd,ꢀJ=15.7Hz, H-β), acid)ꢀ(DTNB)ꢀwereꢀpurchasedꢀfromꢀTokyoꢀChemicalꢀIndustryꢀ
7.30 (1H, d, J=2.0Hz, H-2), 7.10 (1H, dd, J=8.0, 2.0Hz, H-6), Co., Tokyo, Japan.
7.06 (2H, d, J=8.3Hz, H-2′ and H-6′), 6.78 (1H, d, J=8.0Hz,
DPPH Free Radical Scavenging Assay DPPH free
H-5), 6.68 (2H, d, J=8.3Hz, H-3′ and H-5′), 6.44 (1H, d, radicalꢀ scavengingꢀ activityꢀ wasꢀ measuredꢀ accordingꢀ toꢀ theꢀ
J=15.7Hz, H-α), 4.25 (2H, t, J=7.0Hz, OCH2), 3.80 (3H, s, method of Nile et al.35)ꢀ withꢀ minorꢀ modifications.ꢀ Briefly,ꢀ
OCH3), 2.82 (2H, t, J=7.0Hz, CH2). 13C-NMR (DMSO-d6, 180 µL of 100µMꢀ DPPHꢀ freeꢀ radicalꢀ solutionꢀ inꢀ MeOHꢀ wasꢀ
100 MHz) δ:ꢀ 166.6,ꢀ 155.8,ꢀ 149.3,ꢀ 147.9,ꢀ 145.1,ꢀ 129.8,ꢀ 128.0,ꢀ mixedꢀ withꢀ 20ꢀµL of various concentrations of the sample
125.5, 123.2, 115.4, 115.2, 114.4, 111.1, 64.7, 55.7, 33.7. HR-MS solutionꢀ inꢀ MeOH.ꢀ Theꢀ absorbanceꢀ ofꢀ theꢀ mixtureꢀ wasꢀ mea-
m/z:ꢀCalcdꢀforꢀC18H18O5 (M+):ꢀ314.1154.ꢀFound:ꢀ314.1155.ꢀTheꢀ sured at 517nm using a microplate reader (Molecular Devices
1H-NMRꢀspectrumꢀwasꢀsimilarꢀtoꢀthatꢀaꢀpreviousꢀreport.34)
(2E)-3-(4-Hydroxyphenyl)-2-propenoic Acid 2-(3,4-Dihy- MeOHꢀasꢀaꢀcontrol.ꢀAscorbicꢀacidꢀwasꢀusedꢀasꢀaꢀpositiveꢀcon-
SPECTRAꢀMAXꢀM2).ꢀTheꢀsampleꢀsolutionꢀwasꢀreplacedꢀwithꢀ
droxyphenyl)ethyl Ester (18)
Yieldꢀ 73%.ꢀ Whiteꢀ solid.ꢀ mpꢀ 188–190°Cꢀ (hexane–AcOEt).ꢀ
trol.
MAO Inhibitory Assayꢀ ꢀMAOꢀinhibitoryꢀactivityꢀwasꢀas-
1H-NMR (DMSO-d6, 400MHz) δ:ꢀ 10.00ꢀ (1H,ꢀ brꢀs,ꢀ OH),ꢀ 8.73ꢀ sayed using the method of Novaroli et al.36)ꢀwithꢀminorꢀmodi-
(2H, brs, OH), 7.54 (2H, d, J=8.6Hz, H-2 and H-6), 7.52 (1H, fications.ꢀ Briefly,ꢀ 140ꢀµL of 0.1M potassium phosphate buffer
d, J=15.8Hz, H-β), 6.77 (2H, d, J=8.6Hz, H-3 and H-5), 6.63 (pH 7.4), 8µL of 0.75mM kynuramine, and 2µL of DMSO
(1H, d, J=8.0Hz, H-5′), 6.63 (1H, d, J=2.0Hz, H-2′), 6.48 inhibitorꢀsolutionꢀ(finalꢀDMSOꢀconcentrationꢀofꢀ1%ꢀv/v)ꢀwereꢀ
(1H, dd, J=8.0, 2.0Hz, H-6′), 6.35 (1H, d, J=15.8Hz, H-α), preincubated at 37°C for 10min. Diluted human recombi-
4.21 (2H, t, J=7.0Hz, OCH2), 2.74 (2H, t, J=7.0Hz, CH2). nant enzyme (50µL)ꢀwasꢀthenꢀaddedꢀtoꢀobtainꢀaꢀfinalꢀproteinꢀ
13C-NMR (DMSO-d6, 100MHz) δ:ꢀ 166.6,ꢀ 159.9,ꢀ 145.1,ꢀ 144.8,ꢀ concentration of 0.0075mg/mL (MAO-A) or 0.015mg/mL
143.8, 130.4, 128.7, 125.1, 119.5, 116.2, 115.8, 115.5, 114.1, 64.7, (MAO-B)ꢀ inꢀ theꢀ assayꢀ mixture.ꢀ Furtherꢀ incubationꢀ wasꢀ car-
33.9. MS (FAB) m/z 300 [M]+. Anal. Calcd for C17H16O5:ꢀ C,ꢀ riedꢀ outꢀ atꢀ 37°Cꢀ andꢀ theꢀ reactionꢀ wasꢀ stoppedꢀ afterꢀ 20ꢀminꢀ
67.99;ꢀ H,ꢀ 5.37.ꢀ Found:ꢀ C,ꢀ 67.94;ꢀ H,ꢀ 5.42.ꢀ Theꢀ 1H-NMR spec- by the addition of 75µL of 2Mꢀ NaOH.ꢀ Theꢀ fluorescenceꢀ atꢀ
trumꢀwasꢀsimilarꢀtoꢀthatꢀaꢀpreviousꢀreport.34)
(2E)-3-(4-Hydroxyphenyl)-2-propenoic Acid 2-(4-Hydroxy- byꢀ MAO,ꢀ wasꢀ measuredꢀ withꢀ aꢀ micro-plateꢀ readerꢀ (Molecu-
phenyl)ethyl Ester (19) larꢀ Devicesꢀ SPECTRAꢀ MAXꢀ M2).ꢀ Theꢀ sampleꢀ solutionꢀ wasꢀ
Ex 310 nm/Em 400nm, due to the production of 4-quinolinol
Yieldꢀ 40%.ꢀ Whiteꢀ solid.ꢀ mpꢀ 228–231°Cꢀ (hexane–AcOEt).ꢀ replacedꢀ withꢀ DMSOꢀ asꢀ aꢀ control.ꢀ Pargylineꢀ wasꢀ usedꢀ asꢀ aꢀ
1H-NMR (DMSO-d6, 400MHz) δ:ꢀ 9.28ꢀ (H,ꢀ brꢀs,ꢀ OH),ꢀ 7.54ꢀ positive control.
(2H, d, J=8.3Hz, H-2 and H-6), 7.52 (1H, d, J=16.0Hz, H-β),
AChE and BChE Inhibitory Assays AChE and BChE
7.05 (2H, d, J=8.3Hz, H-2′ and H-6′), 6.77 (2H, d, J=8.3Hz, inhibitoryꢀ activityꢀ wereꢀ assayedꢀ usingꢀ theꢀ methodꢀ ofꢀ Obohꢀ
H-3 and H-5), 6.67 (2H, d, J=8.3Hz, H-3′ and H-5′), 6.35 (1H, et al.37)ꢀBriefly,ꢀ2ꢀµL of cinnamic acid derivatives dissolved in
d, J=16.0Hz, H-α), 4.23 (2H, t, J=7.1Hz, OCH2), 2.81 (2H, t, DMSO, 6µL of 0.06mg/mL acetylthiocholine or 0.12mg/mL

Vol. 65, No. 11 (2017)
Chem. Pharm. Bull.
H., Food Chem., 134, 1128–1131 (2012).
1027
butyrylthiocholine dissolved in 0.1M phosphate buffer (pH
8.0), 180µL of the buffer, 6µL of 0.3mM DTNB dissolved in
the buffer, 6µL of 0.15U/mL AChE or 0.075U/mL BChE dis-
solvedꢀinꢀtheꢀbufferꢀwereꢀaddedꢀandꢀmixedꢀinꢀaꢀ96-wellꢀplate.ꢀ
Theꢀenzymeꢀactivityꢀwasꢀdeterminedꢀasꢀtheꢀchangeꢀinꢀabsor-
banceꢀatꢀ412ꢀnmꢀeveryꢀ5ꢀminꢀduringꢀ30ꢀminꢀwithꢀaꢀmicro-plateꢀ
reader (Molecular Devices SPECTRA MAX M2). The sample
solutionꢀ wasꢀ replacedꢀ withꢀ DMSOꢀ asꢀ aꢀ control.ꢀ Neostigmineꢀ
wasꢀusedꢀasꢀaꢀpositiveꢀcontrol.
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