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Bioactive Compositions of Cinnamon (Cinnamomum verum J. Presl)

Extracts and Their Capacities in Suppressing SARS-CoV‑2 Spike
Protein Binding to ACE2, Inhibiting ACE2, and Scavenging Free
Radicals
Published as part of the Journal of Agricultural and Food Chemistry virtual special issue “The Future of
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Zhuohong Xie,▽ Yanfang Li,▽ Zhihao Liu, Melody Zeng, Jeffrey C. Moore, Boyan Gao,* Xianli Wu,
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sı Supporting Information

ABSTRACT: Cinnamon (Cinnamomum verum J. Presl) bark and its extracts are popular ingredients added to food and supplement
products. It has various health effects, including potentially reducing the risk of coronavirus disease-2019 (COVID-19). In our study,
the bioactives in cinnamon water and ethanol extracts were chemically identified, and their potential in suppressing SARS-CoV-2
spike protein−angiotensin-converting enzyme 2 (ACE2) binding, reducing ACE2 availability, and scavenging free radicals was
investigated. Twenty-seven and twenty-three compounds were tentatively identified in cinnamon water and ethanol extracts,
respectively. Seven compounds, including saccharumoside C, two emodin−glucuronide isomers, two physcion−glucuronide isomers,
and two type-A proanthocyanidin hexamers, were first reported in cinnamon. Cinnamon water and ethanol extracts suppressed the
binding of SARS-CoV-2 spike protein to ACE2 and inhibited ACE2 activity in a dose-dependent manner. Cinnamon ethanol extract
had total phenolic content of 36.67 mg gallic acid equivalents (GAE)/g and free radical scavenging activities against HO• and 2,2′-
azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation (ABTS•+) of 1688.85 and 882.88 μmol Trolox equivalents (TE)/g,
which were significantly higher than those of the water extract at 24.12 mg GAE/g and 583.12 and 210.36 μmol TE/g. The free
radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl radical (DPPH•) of cinnamon ethanol extract was lower than that of
the water extract. The present study provides new evidence that cinnamon reduces the risk of SARS-CoV-2 infection and COVID-19
development.
KEYWORDS: Cinnamomum verum J. Presl, cinnamon water extract, cinnamon ethanol extract, COVID-19, SARS-CoV-2 spike protein,
ACE2

■ INTRODUCTION
Coronavirus disease-2019 (COVID-19) is a disease caused by
the coronavirus SARS-CoV-2. COVID-19 is highly contagious
and causes severe illness to some, resulting in a pandemic with
more than 600 million cases and 6.8 million deaths (https://
www.worldometers.info/). 1 The infected patients with
COVID-19 present with fever, cough, shortness of breath,
fatigue, loss of smell, sore throat, nasal congestion, or diarrhea,
with more severe symptoms including acute respiratory distress
(ARDS), pneumonia, renal failure, and death.
There are two phases in SARS-CoV-2 infections, including
(1) increased virus infection and transmission and (2)
uncontrolled inflammatory immune responses.2 The virus
infection can be mediated through spike protein−angiotensin-
converting enzyme 2 (ACE2) binding. SARS-CoV-2 can
rapidly replicate in cells with high membrane expression of
ACE2.1 Upon entry into cells, SARS-CoV-2 viruses attract
inflammatory cytokines, amplifying the tissue damage, further
recruiting immune cells, and bringing in additional cytokines,
noted as a “cytokine storm”.3 With cytokine storm, literature
also demonstrated concomitant accumulation of reactive
oxygen species, also noted as a “radical storm” in a pro-
inflammatory status.3 Vaccines can prevent serious illnesses
from COVID-19. Due to the supply−demand imbalance, many
developing countries’ populations do not have access to
vaccines. Moreover, the efficacy of vaccines against new
variants of the coronavirus is decreasing. Current drug
candidates for COVID-19 have been reported to have
undesirable side effects. Alternative approaches to prevent
and treat COVID-19 are hot research topics.
Cinnamon is a popular spice that comes from the bark of
different varieties (Cinnamomum verum, Cinnamomum zeylani-
Received: January 14, 2023
Revised: March 7, 2023
Accepted: March 10, 2023
Published: March 20, 2023

© 2023 American Chemical Society https://doi.org/10.1021/acs.jafc.3c00285

4890 J. Agric. Food Chem. 2023, 71, 4890−4900
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cum, Cinnamomum cassia, and others). Most people refer to C.
verum for nutraceutical and functional purposes because it
contains much lower levels of hepatotoxic coumarin compared
to other varieties. For the rest of the text, cinnamon is a
synonym of C. verum J. Presl bark unless indicated otherwise.
Bioactives currently identified include trans-cinnamaldehyde,
cinnamic acid, cinnamyl alcohol, cinnamyl methyl ether, p-
cymene, methyl salicylate, 1-tetradecanol (myristyl alcohol),
benzoic acid, and proanthocyanidins.4,5 Extracts and bioactives
from cinnamon have shown potential biological effects against
COVID-19. In molecular docking analysis, tenufolin, pave-
tannin C1, cinnamyl acetate, and cinnamaldehyde in cinnamon
may inhibit SARS-CoV-2 main protease or spike protein, thus
blocking cell entry and virus replication.6,7 Proanthocyanidins
from cinnamon act as a trypsin inhibitor and may prevent the
activation of the spike protein of SARS-CoV-1 and its binding
to ACE-2.5,8,9 Cinnamaldehyde and p-cymene from cinnamon
antagonize toll-like receptors TLR-2 and TLR-4 in the pro-
inflammatory pathway in vitro.10 Further, cinnamaldehyde has
shown antioxidant properties, including activation of Nrf2, a
regulator that mitigates excessive ROS (reactive oxygen
species)/RNS (reactive nitrogen species).11 Extracts from C.
cassia showed the potential to inhibit angiogenesis in vitro and
vascular endothelialitis in Wistar rats.12,13 Synergies in
components were identified in cinnamon extracts.10 The
potential inhibition of viral cell entry, anti-inflammatory and
antioxidant effects, and mitigation of angiogenesis and vascular
endothelialitis suggest cinnamon could be a prophylactic agent
against COVID-19.
Our previous study indicated that clove (Syzygium
aromaticum (L.) Merr. and L.) extracts suppressed the
SARS-CoV-2 spike protein−ACE2 binding and reduced the
ACE2 availability through ACE2 inhibition.14 Building on
knowledge from literature and our previous work, we are
interested in investigating cinnamon’s anti-COVID-19 poten-
tial through investigating the composition of cinnamon water
and ethanol extracts and their effects on suppressing SARS-
CoV-2 spike protein binding to ACE2 and inhibiting ACE2
activity, along with the antioxidant activities of scavenging free
radicals against HO•, DPPH• and ABTS•+. Water extraction
resembles traditional food and herbal medicine preparation,
whereas ethanol is a common solvent used on a large
commercial scale with high purity and fewer safety concerns.
The results from this study may support cinnamon extracts as
candidates for new approaches to managing COVID-19
infection in the future.
■ MATERIALS AND METHODS
Chemicals. Gallic acid, Folin & Ciocalteu’s phenol reagent, 2,2-
diphenyl-1-picrylhydrazyl radical (DPPH•), (±)-6-hydroxy-2,5,7,8-
tetramethylchromane-2-carboxylic acid (Trolox), fluorescein (FL),
2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium
salt (ABTS), ferric chloride (FeCl3) and hydrogen peroxide (H2O2)
were purchased from Sigma-Aldrich (St. Louis, MO). Acetonitrile and
formic acid were LC-MS grade and obtained from Merck (Darmstadt,
Germany). Screening Assay Kits for SARS-CoV-2 spike−ACE2
interaction inhibitor (No. 502050) and ACE2 Inhibitor (No.
502100) were obtained from Cayman (Ann Arbor, Michigan USA).
All other chemicals at analytical grade were obtained from Fisher
Scientific (Hampton, NH, USA) and used in the present study
without further purification.
Sample Preparation. Commercial dry cinnamon (C. verum)
sticks were gifted from Frontier Co-op (Norway, IA, USA). Before
extraction, cinnamon sticks were ground with a micromill (Bel Art
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Products, Pequannock, NJ, USA) and passed through a 40-mesh
sieve. Milled botanical material (1.0000 g) was extracted with 10 mL
of ultrapure water or 100% ethanol for 24 h in closed-cap testing
tubes. For water extraction, the first 2 h of extraction was set in an 85
°C water bath and then back to ambient temperature. The ethanol
extraction was conducted at ambient temperature for 24 h. After
centrifugation (2310g, 5 min), the supernatant was taken and stored
at −20 °C until analysis.
Bioactive Compositions. Chemical identification of cinnamon
water and ethanol extracts was achieved using a Vanquish UHPLC
system combined with an Orbitrap Fusion ID-X Tribrid mass
spectrometer.15 Briefly, chromatographic separations were performed
on an Agilent Eclipse Plus-C18 UHPLC column (150 mm × 2.1 mm
i.d., 1.8 μm) combined with an UltraShield precolumn (Agilent, Santa
Clara, CA, USA). Gradient elution was conducted using binary
mobile phases: 0.1% formic acid in water (v/v) as mobile phase A and
0.1% formic acid in acetonitrile (v/v) as mobile phase B. The linear
gradient was applied as 2% B for 5 min as initial; 2% to 10% B at 15
min, 10% B to 40% B at 35 min, 40% B to 95% B at 55 min,
maintained at 95% B until 60 min, and then back to initial condition
for 10 min. The injection volume was 1 μL, and the flow rate was 0.3
mL/min. The mass scan continued for 59 min and ranged from m/z
120 to m/z 1200 with a resolution of 60,000. The spray voltage was
3900 and 2500 V in positive and negative modes, respectively. The
vaporizer temperature and ion transfer tube temperature were set as
275 and 300 °C, respectively.
Inhibition on the Binding Interaction between SARS-CoV-2
Spike Protein and ACE2. The inhibitory effects of cinnamon water
and ethanol extracts on the binding interaction between SARS-CoV-2
spike protein and ACE2 were investigated using a commercial assay
kit (No. 502050, Cayman, Ann Arbor, Michigan USA).14 The assay
was conducted based on the manufacturer’s instructions. The
cinnamon water extract was tested at 33.3 mg dry cinnamon
equivalents/mL, but the cinnamon ethanol extract was tested using
a 10-fold diluted solution (diluted with assay buffer to 3.3 mg dry
cinnamon equivalents/mL) due to the manufacturer’s instructions
regarding the limitation of organic solvent concentration. The results
were reported as the percent (%) inhibition.
Inhibitory Effects on ACE2. The inhibitory effects of cinnamon
extracts on ACE2 were investigated with a commercial assay kit (No.
502100, Cayman, Ann Arbor, Michigan USA) following the
manufacturer’s instructions.14 The concentrations of the cinnamon
extracts in the testing mixture were 5.0 and 0.5 mg dry cinnamon
equivalents/mL based on preliminary study results. The results were
reported as the percent (%) inhibition.
Total Phenolic Content (TPC). The TPC of cinnamon water and
ethanol extract (100 mg dry cinnamon equivalents/mL) was
determined using a laboratory protocol published before.16 Briefly,
3 mL of ultrapure water was added into a test tube, followed by 50 μL
of either solvent, standard, or sample, and 250 μL of Folin−Ciocalteu
reagent, and the mixture was vortexed for 1 min to mix all the regents.
Then, a 2 h reaction at room temperature in the dark was initiated by
adding 750 μL of 20% (w/v) sodium carbonate. When the reaction
was completed, the absorbance of each tested sample was recorded at
765 nm using a multifunction microplate reader (Tecan M200 Pro,
Tecan Group Ltd., Mannedorf, Switzerland). The TPC value was
expressed as milligram gallic acid equivalents/g dry cinnamon (mg
GAE/g).
Relative HO• Scavenging Capacities (HOSC). The HOSC
assay was conducted using a published laboratory protocol.17 First,
fluorescein (92.8 nM) and H2O2 (199 mM) working solutions were
freshly prepared when starting the assay. 170 μL of fluorescein
working solution was added to the wells, followed by 30 μL of either
solvent, standard, or sample (100 mg dry cinnamon equivalents/mL).
To start the reaction, 40 μL of H2O2 and 60 μL of FeCl3 (3.43 mM)
working solution were added to the mixture. Their fluorescence
intensities (excitation 485 nm, emission 535 nm) were measured for 8
h with an interval of 6 min using a Tecan M200 Pro microplate reader
(Tecan Group Ltd., Mannedorf, Switzerland). Area under the curve
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Table 1. Compound Composition of Cinnamon (C. verum J. Presl) Water (WE) and Ethanol Extracts (EE)a

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Table 1. continued

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Table 1. continued
a
Exptl. [M − H]− standards for experimental m/z of molecular ion in negative mode; Exptl. [M + H]+ standards for experimental m/z of molecular
ion in positive mode; #m/z of [M − H]2−; &m/z of [M + 2H]2+; *compounds that are reported for the first time in cinnamon (C. verum J. Presl);
ref stands for references; WE stands for cinnamon water extract; EE stands for cinnamon ethanol extract.
was used for the calculation of the results. The results were reported
as μmol Trolox equivalents/g dry cinnamon (μmol TE/g).
Relative DPPH• Scavenging Capacities (RDSC). The RDSC
assay was determined using a previously published protocol.18 Briefly,
100 μL of either solvent, standards (7 to 36 μmol/L Trolox), or
sample (100 mg dry cinnamon equivalents/mL) was added to the
wells with 100 μL of freshly prepared 0.2 mM DPPH in the 96-well
plate. Then the absorbance was read at 515 nm every minute for 40
min using a microplate reader (Tecan M200 Pro, Tecan Group Ltd.,
Mannedorf, Switzerland). Area under the curve was used for the
calculation of the results. The data was reported as μmol Trolox
equivalents/g dry cinnamon (μmol TE/g).
Relative ABTS•+ Scavenging Capacities (ABTS). The ABTS
assay was conducted based on a laboratory protocol.18 Briefly, 2 mL
of ABTS•+ working solution was added to the test tubes. Then 160 μL
of either solvent, standard solution (5 to 300 μmol/L Trolox), or
sample (100 mg dry cinnamon equivalents/mL) was added and
vortexed for 30 s. After another 60 s reaction, the absorbance at 734
nm was read using a Genesys 20 spectrophotometer (ThermoFisher
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Scientific, Norristown, PA, USA). The results were expressed as μmol
Trolox equivalents/g dry cinnamon (μmol TE/g).
Statistical Analysis. The results were expressed as mean ±
standard deviation (SD) of triplicate experiments. Statistically
significant difference was determined by t-test (P < 0.05) with
SPSS Statistics 25 (SPSS, Inc., Chicago, IL, USA). All the figures were
prepared with Microsoft Excel (Redmond, WA, USA). The mass
spectra were obtained from Xcalibur 4.2 (ThermoFisher Scientific,
Norristown, PA, USA).
■ RESULTS AND DISCUSSION
Bioactive Compositions. Bioactive identification of
cinnamon water and ethanol extracts was based on high-
resolution full MS scan data and MS2 data and the published
literature (Table 1 and Figure S1). Twenty-seven and twenty-
three compounds were tentatively identified in cinnamon
water and ethanol extracts, respectively (Table 1). Nineteen
compounds were found in both extracts. Seven compounds
were found in cinnamon extracts for the first time:
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Figure 1. Identification of emodin−glucuronide (C21H18O11): (A) Full scan MS in negative ionization mode; (B) MS2 in negative ionization mode;
(C) Full scan MS in positive ionization mode; (D) MS2 in positive ionization mode.

Figure 2. Identification of physcion−glucuronide (C22H20O11): (A) Full scan MS in negative ionization mode; (B) MS2 in negative ionization
mode; (C) Full scan MS in positive ionization mode; (D) MS2 in positive ionization mode.

saccharumoside C (compound 2), two emodin−glucuronide
isomers (compounds 26, 27), and two physcion−glucuronide
isomers (compounds 28, 29) in the water extract and two
type-A proanthocyanidin hexamers (compounds 15, 19) in
both water and ethanol extracts (Table 1).
Taking the identification of compound 26 as an example, the
detected molecular ions in the negative ([M − H]−) and
positive ([M + H]+) modes were m/z 445.0768 and m/z
447.0917, respectively (Figure 1 and Table 1). The two ions
were matched with the elemental composition of C21H17O11
(mass accuracy, −0.83 mmu) and C21H19O11 (mass accuracy,
−0.45 mmu), respectively (Figure 1 and Table 1). The results
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indicated that the molecular formula of compound 26 was
C21H18O11. The major fragment ions detected in the negative
and positive modes were at m/z 269.0449 and 271.0598,
respectively (Figure 1). The fragment ions coincide with the
loss of a glucuronide group. The aglycone of compound 26 is
C15H10O5, which might be emodin19 or apigenin20 reported in
cinnamon before. Interestingly, the MS spectrum of the major
fragment ion of compound 26 was the same as the MS
spectrum of compound 30 (Figure S2). Compared with the
published literature, compound 30 was tentatively identified as
emodin.19 Therefore, compound 26 was tentatively identified
as emodin−glucuronide. Compound 27, an isomer of
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Figure 3. Inhibitory effects of cinnamon (A) water and (B) ethanol extracts at different concentrations on the binding interaction between SARS-
CoV-2 spike protein and ACE2. WE33.3 and WE1.7 stand for the water extracts with concentrations of 33.3 and 1.7 mg dry cinnamon equivalents/
mL in the testing mixture, respectively; EE3.3 and EE0.3 stand for the ethanol extracts with concentrations of 3.3 and 0.3 mg dry cinnamon
equivalents/mL in the testing mixture, respectively. Values are mean ± standard deviation (SD) of triplicate experiments. * indicates significant
differences (P < 0.05).
compound 26, was also tentatively identified as an emodin−
glucuronide isomer because the same MS data was observed
(Table 1).
The detected molecular ions in the negative ([M − H]−)
and positive ([M + H]+) modes of compound 28 were m/z
459.0928 and m/z 461.1080, respectively (Figure 2 and Table
1). The two ions were matched with the elemental
composition of C22H19O11 (mass accuracy, −0.51 mmu) and
C22H21O11 (mass accuracy, 0.16 mmu), respectively (Figure 2
and Table 1). The results indicated that the molecular formula
of compound 28 was C22H20O11. The molecular ions of
compound 28 were 14 Da higher than that of compound 26,
indicating that compound 28 may be a methyl ether derivative
of compound 26. Additionally, the major fragment ions of
compound 28 detected in the negative and positive modes
were at m/z 283.0608 and 285.0755, respectively (Figure 2),
suggesting the loss of a glucuronide group. The aglycone of
compound 28 is then C16H12O5, which might be physcion
reported in cinnamon before.19 Physcion is a methyl ether
derivative of emodin. Therefore, compound 28 was tentatively
identified as physcion−glucuronide. Compound 29, an isomer
of compound 28 was also tentatively identified as a physcion−
glucuronide isomer (Table 1). Physcion−glucuronide has been
reported as a metabolite of physcion in vivo.21,22
Among the identified compounds, there are 7 phenolic
glycosides (compounds 1, 2, 6, 11, 13, 22, 23), 1
hydroxybenzaldehyde (compound 24), 1 carboxylic acid
(compound 25), 5 anthraquinones (compounds 26−30), 14
proanthocyanidins (compounds 3−5, 7−10, 14−20), and 2
unidentified compounds (21, 31). For the 14 proanthocyani-
dins, there are 6 type-A proanthocyanidin tetramers (com-
pounds 3, 4, 5, 14, 17, 18), 5 type-A proanthocyanidin
pentamers (compounds 7, 8, 9, 16, 20), 2 type-A
proanthocyanidin hexamers (compounds 15, 19), and 1
type-B proanthocyanidin dimer (compound 10). The type-A
proanthocyanidin hexamers were first reported in cinnamon,
which was found in the leaves of Machilus philippinensis.23
There were five different tetramers reported in cinnamon
before, namely, pavetannin C1,24 parameritannin A1,25
cassiatannin A,26 and two other tetramers without common
names (epicatechin-(4β → 8)epicatechin-(4β → 8, 2β → 7)-
epicatechin-(4α → 8)-epicatechin and epicatechin-(4β → 6)-
epicatechin-(4β → 8, 2β → 7)-epicatechin-(4α → 8)-
epicatechin).27
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The ion counts of the identified compounds are shown in
Table 1. The total ion count of the cinnamon water extract was
much higher than that of the ethanol extract (Table 1). In
cinnamon water extract, type A proanthocyanidin hexamer 1
(15), kelampayoside A (11), type A proanthocyanidin
tetramer 3 (5), 3,4-dimethoxyphenol-apiofuranosyl-glucopyr-
anoside (13), and type A proanthocyanidin hexamer 2 (19)
are the five major compounds. In the ethanol extract, cinnamic
acid (25), type A proanthocyanidin hexamer 1 (15), type A
proanthocyanidin tetramer 5 (17), type A proanthocyanidin
tetramer 3 (5), and type A proanthocyanidin pentamer 3 (9)
are the five compounds with the highest ion intensities (Table
1). Type A proanthocyanidins are the major compounds in
cinnamon water and ethanol extracts.
Inhibition of the SARS-CoV-2 Spike Protein and ACE2
Interaction. Among the ways to suppress COVID-19
infection, blocking the entry of the virus via interaction
between spike protein and ACE2 has recently been considered
a promising approach.14 Cinnamon water and ethanol extracts
dose-dependently inhibited the binding interaction between
SARS-CoV-2 spike protein and ACE2 (Figure 3). Cinnamon
water extract WE33.3 (33.3 mg dry cinnamon equivalents/mL
in the testing mixture) completely inhibited the binding
interaction between SARS-CoV-2 spike protein and ACE2,
significantly higher than the 33.51% inhibition of the water
extract WE1.7 (1.7 mg dry cinnamon equivalents/mL in the
testing mixture) (Figure 3A). These results are comparable to
that of clove water extracts (99% for WE33.3 and 46% for
WE1.7).14 As for the ethanol extract (Figure 3B), the ethanol
extract EE3.3 (3.3 mg dry cinnamon equivalents/mL in the
testing mixture) significantly inhibited 98.73% of the
interaction between SARS-CoV-2 spike protein and ACE2
(Figure 3B). No inhibition was observed with the ethanol
extract EE0.3 (0.3 mg dry cinnamon equivalents/mL in the
testing mixture, EE0.3) (Figure 3B).
Compounds in cinnamon such as kaempferol, quercetin,
rutin, cinnamaldehyde, cinnamyl acetate, tenufolin, and
pavetannin C1 might be able to bind with receptor binding
spike protein of COVID-19 from in silico analysis.12,28,19
Proanthocyanidins, the major components found in cinnamon
water and ethanol extracts, were reported to have antiviral
effects. Pavetannin C1, a type-A proanthocyanidin tetramer,
exhibited good binding efficacy with the main protease
(6LUZ) and spike proteins of SARS-CoV2.24 Proanthocyani-
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Figure 4. Inhibitory effects of cinnamon (A) water and (B) ethanol extracts at different concentrations on ACE2 activity. WE5.0 and WE0.5 stand
for the water extracts with concentrations of 5.0 and 0.5 mg dry cinnamon equivalents/mL in the testing mixture, respectively; EE5.0 and EE0.5
stand for the ethanol extracts with concentrations of 5.0 and 0.5 mg dry cinnamon equivalents/mL in the testing mixture, respectively. Values are
mean ± standard deviation (SD) of triplicate experiments. * indicates significant differences (P < 0.05).

Figure 5. (A) Total phenolic content and relative free radical scavenging activities of cinnamon water (WE) and ethanol extracts (EE) against (B)
HO•, (C) DPPH•, and (D) ABTS•+. Results are expressed as mean ± SD of experiments performed in triplicate, and values are based on a per dry
cinnamon weight.

din A2 (type-A proanthocyanidin dimer) and proanthocyani-
din B1 (type-B proanthocyanidin dimer) extracted from
cinnamomi cortex inhibited the activity of wild-type severe
acute respiratory syndrome coronavirus (wtSARS-CoV).29
Connell et al. found that type-A proanthocyanidin trimers
and pentamers extracted from Cinnamomum zeylanicum
exhibited entry inhibition against CXCR4 and CCR5 viruses
through binding to the viral envelope glycoprotein.30 Other
compounds binding to the ACE2 protein based on in silico
analysis include kaempferol, quercetin, rutin, cinnamaldehyde,
cinnamyl acetate, and tenufolin,12,18,19 which belong to the
phenolics category. Our identified compounds in the water and
ethanol extracts are mainly within the proanthocyanidin and
phenolics groups, in agreement with the literature. These
compounds may contribute to the binding inhibition here. To
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our knowledge, this is the first to report on the inhibition of
the SARS-CoV-2 spike protein and ACE2 interaction by
cinnamon extracts in vitro. These results indicated the potential
anti-COVID-19 effects of cinnamon extracts.
Inhibition of ACE2. Cinnamon water and ethanol extracts
dose-dependently inhibited ACE2 (Figure 4). The water
extract WE5.0 (5.0 mg dry cinnamon equivalents/mL in the
testing mixture) inhibited 98.83% of the ACE2 activity,
significantly higher than the 10.51% of the water extract
WE0.5 (0.5 mg dry cinnamon equivalents/mL in the testing
mixture) (Figure 4A). Similarly, 97.24% and 18.03% of the
ACE2 activity were inhibited by the ethanol extract with
concentrations of 5.0 (EE5.0) and 0.5 mg dry cinnamon
equivalents/mL in the testing mixture (EE0.5), respectively
(Figure 4B). We previously determined the inhibition of ACE2
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activity by clove water and ethanol extract. The clove water
extract inhibited 100% (WE5.0) and 82% (WE0.5), which was
more potent than the cinnamon water extract (98.83% for
WE5.0 and 10.51% for WE0.5). Interestingly, the clove ethanol
extract possessed strong potency (91% for EE5.0) but had no
inhibition for the lower concentration (0% for EE0.5), while
the cinnamon ethanol extract possessed 97.24% for EE5.0 and
18.03% for EE0.5.14 This is the first report of cinnamon
extracts’ inhibition of ACE2 activity. As an important mediator
for SARS-CoV-2 cell entry, the availability of ACE2 can impact
the viral infection and progression. Reducing the availability of
ACE2 through inference with flavonoids or phenolics in
natural products is a potentially effective approach,31,32 which
may provide explanations for the cinnamon extract’s inhibition
on ACE2. The dose- and extract-dependent results indicated
that suitable solvents and concentrations of bioactives are
required to achieve optimal potency. As noted previously,14
while ACE2 inhibition may help interrupt SARS-CoV-2’s cell
entry, specific population groups with comorbidities may need
to take caution. Further studies on the in vivo effects of
cinnamon extracts are warranted.
Total Phenolic Content (TPC) and Free Radical
Scavenging Activities. The TPC values of cinnamon water
and ethanol extracts were investigated since the phenolics in
botanicals may significantly contribute to their overall
antioxidant activity.33,34 The TPC values of cinnamon water
and ethanol extracts were 24.12 and 36.67 mg GAE/g,
respectively (Figure 5A). Our extracts were from barks, and the
results were lower than those reported in 50% acetone (186
mg GAE/g) and 80% methanol extracts (148 mg GAE/g) but
higher than leaf extracts (ranging from 0.68 to 22.35 mg GAE/
g).35,36 Free radical scavenging activities of cinnamon extracts
against HO•, DPPH•, and ABTS•+ were determined. The
cinnamon ethanol extract had a higher HOSC value (1688.85
μmol TE/g) than that of the water extract (583.12 μmol TE/
g) (Figure 5B). The RDSC values of cinnamon water and
ethanol extracts were 97.47 μmol TE/g and 65.08 μmol TE/g,
respectively. The cinnamon water and ethanol extracts
possessed ABTS•+ scavenging activities of 210.36 and 882.88
μmol TE/g, respectively. These ABTS values were comparable
to those previously reported in cinnamon 50% acetone and
80% methanol extracts and higher than the leaf extracts.35,36
The results supported previous findings that barks had higher
TPC levels and free radical scavenging activities than leaves,
and different solvent extractions may yield different TPC and
antioxidants.
Free radicals such as hydroxyl and superoxide (O2−) radicals
are highly active substances that can damage DNA, proteins,
carbohydrates and lipids in vivo, which have been implicated as
possible pathogenic molecules in different viral disease
pathogenesis.37 During COVID-19 infection, the excess
formation of free radicals may lead to oxidative stress in the
host (“radical storm”), which may aggravate the severity of the
infection.38 Therefore, it is important to investigate the free
radical scavenging activities of natural botanical products. As
noted previously,14 HOSC, RDSC, and ABTS assays were
conducted due to their reaction mechanism and properties.
HOSC is a hydrogen atom-transfer-based assay, whereas
DPPH and ABTS are electron-transfer-based assays. Based
on a similar mechanism, it is interesting to see the different
trends in RDSC and ABTS results (Figure 5C,D). The
divergence between the RDSC and ABTS results may be
because DPPH• is more stable and can be reduced by those
4898
pubs.acs.org/JAFC Article
components with more reactive reducing activities.39 When
future in vivo study is conducted, careful consideration should
be taken for the subtle differences in the bioactive behaviors of
the cinnamon extracts. Overall, we demonstrated that
cinnamon water and ethanol extracts possessed high levels of
TPC and potent free radical scavenging capacities. The results
supported using cinnamon as a potential candidate against
elevated oxidative stress during COVID-19 infection.
In conclusion, the bioactive compositions of cinnamon water
and ethanol extracts were identified, and their potential anti-
COVID-19 activities were demonstrated in the present study.
Seven compounds were found in cinnamon for the first time:
saccharumoside C, two emodin−glucuronide isomers, and two
physcion−glucuronide isomers in the water extract and two
type-A proanthocyanidin hexamers in both water and ethanol
extracts. The current study was the first to report the inhibitory
effect of cinnamon extracts on the binding between SARS-
CoV-2 spike protein and ACE2 and the ACE2 activity through
reducing availability. The TPC and antioxidant activities are
high in the water and ethanol extracts. The TPC and radical
scavenging activities are dependent on extracts. While the
ethanol extract showed higher values in TPC, HOSC, and
ABTS, the water extract showed a higher value in RDSC. The
study demonstrated the overall promising role of cinnamon as
a candidate for the prevention of COVID-19. Given the
different chemical and biological behavior differences, careful
consideration should be taken to select cinnamon extraction
solvents and fractions. To further verify the benefit of
cinnamon and elucidate the mechanism, additional in vivo
study is warranted.
■ ASSOCIATED CONTENT
* Supporting Information
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.jafc.3c00285.
Base peak ion (BPI) chromatogram of cinnamon
(Cinnamomum verum J. Presl) water and ethanol extracts
and identification of C15H10O5 by full scan MS and MS2
in negative and positive ionization modes (PDF)
■ AUTHOR INFORMATION
Corresponding Authors
Boyan Gao − Institute of Food and Nutraceutical Science,
School of Agriculture and Biology, Shanghai Jiao Tong
University, Shanghai 200240, China; orcid.org/0000-
0003-4866-9988; Phone: +86 021 34204538;
Email: gaoboyan@sjtu.edu.cn
Xiaohua He − Western Regional Research Center, Agricultural
Research Service, United States Department of Agriculture,
Albany, California 94710, United States; Phone: +1-(510)
559-5823; Email: xiaohua.he@usda.gov
Authors
Zhuohong Xie − Department of Nutrition and Food Science,
University of Maryland, College Park, Maryland 20742,
United States; orcid.org/0000-0001-8009-3523
Yanfang Li − Department of Nutrition and Food Science,
University of Maryland, College Park, Maryland 20742,
United States; Methods and Application of Food
Composition Laboratory, Beltsville Human Nutrition
Research Center, Agricultural Research Service, United States
https://doi.org/10.1021/acs.jafc.3c00285
J. Agric. Food Chem. 2023, 71, 4890−4900
Journal of Agricultural and Food Chemistry
Department of Agriculture, Beltsville, Maryland 20705,
United States; orcid.org/0000-0003-2761-0282
Zhihao Liu − Department of Nutrition and Food Science,
University of Maryland, College Park, Maryland 20742,
United States; Methods and Application of Food
Composition Laboratory, Beltsville Human Nutrition
Research Center, Agricultural Research Service, United States
Department of Agriculture, Beltsville, Maryland 20705,
United States; orcid.org/0000-0003-1644-0679
Melody Zeng − Department of Nutrition and Food Science,
University of Maryland, College Park, Maryland 20742,
United States
Jeffrey C. Moore − Moore FoodTech, LLC, Silver Spring,
Maryland 20910, United States
Xianli Wu − Methods and Application of Food Composition
Laboratory, Beltsville Human Nutrition Research Center,
Agricultural Research Service, United States Department of
Agriculture, Beltsville, Maryland 20705, United States
Jianghao Sun − Methods and Application of Food
Composition Laboratory, Beltsville Human Nutrition
Research Center, Agricultural Research Service, United States
Department of Agriculture, Beltsville, Maryland 20705,
United States; orcid.org/0000-0003-2823-4012
Thomas T. Y. Wang − Diet, Genomics and Immunology
Laboratory, Beltsville Human Nutrition Research Center,
Agricultural Research Service, United States Department of
Agriculture, Beltsville, Maryland 20705, United States;
orcid.org/0000-0003-2299-9452
Pamela Pehrsson − Methods and Application of Food
Composition Laboratory, Beltsville Human Nutrition
Research Center, Agricultural Research Service, United States
Department of Agriculture, Beltsville, Maryland 20705,
United States
Liangli Lucy Yu − Department of Nutrition and Food Science,
University of Maryland, College Park, Maryland 20742,
United States; orcid.org/0000-0001-6497-0864
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.jafc.3c00285
Author Contributions
▽ cinnamaldehyde is mediated by decreasing HIF-1α protein synthesis
Z.X. and Y.L. contributed equally to this work.
Funding
This work was funded by a grant from a cooperative agreement
with USDA-ARS.
Notes
The authors declare no competing financial interest.
■ ABBREVIATIONS
SARS-CoV-2, severe acute respiratory syndrome coronavirus
2; RBD, receptor binding domain; ACE2, angiotensin-
converting enzyme 2; COVID-19, coronavirus disease 2019;
UHPLC-HRMS, ultrahigh-performance liquid chromatogra-
phy−high resolution mass spectrometry; TPC, total phenolic
content; GAE, gallic acid equivalent; HOSC, relative HO•
scavenging capacity; RDSC, relative DPPH• scavenging
capacity; ABTS, relative ABTS•+ scavenging capacity; TE,
Trolox equivalent
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