Synthesis and biological activity of hydroxycinnamoylcontaining antiviral drugs

Article abstract of DOI:10.2298/JSC130222103C

Seven N-hydroxycinnamoyl amides were synthesized by 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide/1-hydroxybenzotriazole (EDC/HOBt) coupling of the corresponding substituted cinnamic acids (p-coumaric-, ferulic-, sinapic- and caffeic acids) with influenza antivirals (amantadine, rimantadine and oseltamivir). The DPPH (1,1-diphenyl-2-picrylhydrazyl) scavenging abilities and the inhibitory effect on mushroom tyrosinase activity (using L-tyrosine as the substrate) were investigated in vitro. Amongst the synthesized compounds, N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]oseltamivir (1) and N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]rimantadine (4), containing a catechol moiety, exhibited the most potent DPPH radical-scavenging activity. Amide (1) also displayed tyrosinase inhibitory effect toward L-tyrosine as the substrate (=50 %). The synthesized compounds were also investigated for their in vitro inhibitory activity against the replication of influenza virus A (H3N2).

Full text of DOI:10.2298/JSC130222103C

J. Serb. Chem. Soc. 79 (5) 517–526 (2014)
JSCS–4603
UDC 547.568.1–36+542.813:57–188:615.281:
615.281:615.276:615.27
Original scientific paper
Synthesis and biological activity of hydroxycinnamoyl-
containing antiviral drugs
1
1
2
*
MAYA G. CHOCHKOVA , ASSYA P. GEORGIEVA , GALYA I. IVANOVA ,
NADYA NIKOLOVA3, LUCHIA MUKOVA3, LUBOMIRA NIKOLAEVA-GLOMB3
and TSENKA S. MILKOVA1
1South-West University ‘‘Neofit Rilski”, Blagoevgrad, Bulgaria, 2Departamento de Química,
Faculdade de Ciências, Universidade do Porto, Porto, Portugal and 3The Stephan Angeloff
Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria
(Received 22 February, revised 24 June, accepted 1 October 2013)
Abstract: Seven N-hydroxycinnamoyl amides were synthesized by 1-[3-(dime-
thylamino)propyl]-3-ethylcarbodiimide/1-hydroxybenzotriazole (EDC/HOBt)
coupling of the corresponding substituted cinnamic acids (p-coumaric-, ferulic-,
sinapic- and caffeic acids) with influenza antivirals (amantadine, rimantadine
and oseltamivir). The DPPH (1,1-diphenyl-2-picrylhydrazyl) scavenging abi-
lities and the inhibitory effect on mushroom tyrosinase activity (using L-tyro-
sine as the substrate) were investigated in vitro. Amongst the synthesized com-
pounds, N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]oseltamivir (1) and
N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]rimantadine (4), containing
a
catechol moiety, exhibited the most potent DPPH radical-scavenging activity.
Amide (1) also displayed tyrosinase inhibitory effect toward L-tyrosine as the
substrate (≈50 %). The synthesized compounds were also investigated for their
in vitro inhibitory activity against the replication of influenza virus A (H3N2).
Keywords: N-hydroxycinnamoylamides; influenza antivirals; mushroom tyro-
sinase; monophenolase activity; antioxidant activity; anti-influenza activity.
INTRODUCTION
Phenolics are secondary plant metabolites, important not only for the func-
tional aspects of plant life, but also they have a potential impact on public health.
Amongst the main families of phenolic compounds, hydroxycinnamic acids (e.g.,
ferulic, p-coumaric, caffeic acids, etc.) and their derivatives (esters, amides and
glycosides) have become an emergent topic of many research groups and hence
1–4
the subject of our interest.
*Corresponding author. E-mail: mayabg2002@yahoo.com
doi: 10.2298/JSC130222103C
517
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518
CHOCHKOVA et al.
Hydroxycinnamic acid amides, both natural and synthetic, possess diverse
5–12
physiological activities, such as being potent antioxidants,
antimicrob-
acting as
and tyrosi-
3,4,6,13,14
15–18
ials,
inhibitors of hepatotoxic and proliferative activity,
19–22
23,24
inhibitors of HIV integrase,
inhibitors of ߙ-glucosidase,
1,25,26
nase,
etc.
A huge amount of data on various polyhydroxy tyrosinase inhibitors exists in
the literature. Tyrosinase inhibition is an important strategy in many medicinal,
food and agricultural areas. Hyperpigmentation of the human skin and enzymatic
browning in fruits and mushrooms are the results of two distinct reactions of
tyrosinase (EC 1.14.18.1) – the hydroxylation of tyrosine by monophenolase
action to 3,4-dihydroxyphenylalanine (L-DOPA), and further L-DOPA oxidation
to o-dopaquinone (diphenolase activity). This copper-containing enzyme is
widely present in bacteria, fungi and higher plants (mushrooms, bananas, apples,
27,28
pears, potatoes, etc.).
In order to overcome the instability and low degree of percutaneous absorp-
tion of natural polyphenols in cosmetic compositions, synthesized N-hydroxy-
cinnamoyl amantadine amides, which manifested increased antioxidant, melanin
29
inhibitory and procollagen inducing effects, were synthesized.
The incorporation of the lipophilic adamantyl moiety in another class of
small molecules, such as N-benzylbenzamide, appeared to be also an important
30
element for enhanced depigmentation activity.
Since 1960s, the aminoadamantanes (amantadine, rimantadine) have been
representatives of the first class of antivirals, approved for prophylaxis and treat-
ment of influenza. They are known to inhibit virus replication by blocking the
31
proton channel of the M2 structural protein of the virion (M2 blockers). As
only the influenza A viruses possess this structural M2 ion channel protein,
aminoadamantanes are not effective against influenza B viruses, since the latter
32,33
do not encode for M2 protein.
In the quest for therapeutic agents with a broader spectrum that are active
against both types (A and B) of influenza viruses, neuraminidase inhibitors
(oseltamivir and zanamivir) were discovered as the second class of anti-influenza
34,35
antivirals.
They interfere with viral neuraminidase, which is essential for the
release of newly synthesized infective virus progeny.
A set of polyphenol compounds (e.g., resveratrol; curcumin and isoquer-
36
cetin) was reported to inhibit both influenza viruses type A and B in vitro.
However one of the latest investigations on the matter revealed that the men-
tioned polyphenols possess an antiviral activity only against influenza A virus
37
replication.
It was found that the reception of a combination of antioxidants (e.g., poly-
phenolics) with influenza drugs synergized on the reduction of viral repli-
38,39
cation.
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N-HYDROXYCINNAMOYL ANALOGUES OF ANTIVIRAL DRUGS
519
The above findings encouraged us to link chemically antioxidant-functioning
hydroxycinnamic acids with anti-influenza drugs (amantadine, rimantadine and
oseltamivir) and to study some of their biological activities.
RESULTS AND DISCUSSION
Seven N-hydroxycinnamoylamides were synthesized from hydroxycinnamic
acids (ferulic, caffeic, sinapic and p-coumaric acids) and influenza antivirals
7
(amantadine, rimantadine and oseltamivir) by a previously described procedure.
Unlike the three-step (reactions of the hydroxycinnamoyl amide synthesis, pro-
29
vided previously, the present synthetic route (Scheme 1) was performed by
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide/1-hydroxybenzotriazole (EDC/
/HOBt) coupling, without preliminary protection and further deprotection steps
of the phenolic hydroxyl groups.
Scheme 1. EDC/HOBt-coupling in preparation of N-hydroxycinnamoylamides.
After purification by column or preparative thin-layer chromatography, the
compounds were obtained in moderate to good yields. The geometry of the
1
double bond in the cinnamoyl residue was confirmed by H-NMR spectroscopy,
where the resonance of olefinic protons in all N-hydroxycinnamoylamides was
observed at 6.19–6.51 ppm and at 7.19–7.55 ppm as two doublets with J ≈ 15.5
Hz. These signals are evidence that all of the synthesized amides present were
E-diasteroisomers.
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CHOCHKOVA et al.
The yields of the compounds, and the analytic and complete spectral data for
the synthesized compounds are given in the Supplementary material to this paper.
Scavenging effect on DPPH radicals
40
Since it is well known that the DPPH test gives a rough, primary index of
antioxidant activity, by measuring the ability of DPPH to scavenge an electron or
hydrogen radical of the tested compounds (scavengers) in vitro, a myriad of
articles have been published.
DPPH scavenging activity of the synthesized N-hydroxycinnamoylamides,
as well as the used standards caffeic, ferulic, sinapic and p-coumaric acids, dis-
played an activity at 12, 24 and 48 μM in a concentration dependent manner
(Table I). As shown in Table I (data for 12 and 24 μM concentration are not
presented), the evaluated scavenging activity of the compounds decreased in the
following order: CafA ≈ CafA-Os (1) > CafA-Rim (4) > SA > SA-Os (2) > FA >
FA-Os (3) ≈ SA-Am (5) > FA-Am (6) > p-CoumA > p-CoumA-Am (7) ≈ Os >
> Rim > Am.
TABLE I. DPPH radical scavenging activity of N-hydroxycinnamoylamides, antivirals and
the tested references at a concentration of 48 μM. The given values are the means ± con-
fidence interval, calculated at the level of significance 0.05 (n = 3)
Compound
DPPH radical scavenging activity, %
1
2
3
4
5
6
7
91.83±5.08
48.10±1.23
31.75±3.77
72.58±8.26
30.37±2.58
20.28±1.04
3.00±0.60
92.65±2.90
60.73±0.62
44.30±0.10
6.10±0.04
3.51±0.90
1.75±0.21
2.48±0.30
Caffeic acid
Sinapic acid
Ferulic acid
р-Coumaric acid
Oseltamivir
Amantadinе hydrochloride
Rimantadinе hydrochloride
Amongst the tested newly synthesized amides, N-caffeoylamides (1 and 4)
revealed the best activity, commensurable with that of the free caffeic acid at 3.6
mM concentration. It is not surprising that the latter compounds are the most
active ones. The presence of a catechol moiety is the structural feature, res-
41
ponsible for their better radical quenching abilities. All the newly synthesized
compounds demonstrated a higher radical scavenging activity than amantadine,
rimantadine and oseltamivir, which do not possess DPPH scavenging ability at
all. The reported results are in agreement with earlier findings for the disability of
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N-HYDROXYCINNAMOYL ANALOGUES OF ANTIVIRAL DRUGS
521
42
rimantadine to scavenge superoxide radicals, although its antioxidant effect has
been observed in vivo. Moreover, the existence of the more polar substituted nuc-
leus of ethyl cyclohex-1-ene-1-carboxylate (i.e., the skeleton of oseltamivir) in
the N-hydroxycinnamoylamides seems to be more efficient in radical scavenging
than the corresponding amides of the hydrophobic aminoadamantanes.
Effect of N-hydroxycinnamoylamides on mushroom tyrosinase
Considering substituted cinnamic acids and their derivatives as potential
25,43–46
tyrosinase inhibitors,
the effects of the obtained N-hydroxycinnamoyl-
amides on the monophenolase activity of mushroom tyrosinase (using L-tyrosine
as substrate) at 23 μM concentration was studied herein.
The results of the evaluated activity of the amides, presented as percentage
(%) of mushroom tyrosinase inhibition, are outlined in Table II. Hydroquinone
was used as a reference compound.
TABLE II. Tyrosinase inhibitory activity of N-hydroxycinnamoylamides at a concentration of
23 μM. The given values are the means ± confidence interval, calculated at the level of
significance 0.05 (n = 3); NA –not analyzed; N.I. – no inhibition
Compound
Tyrosinase inhibition, %
Hydroquinone
CafA-Os (1)
SA-Os (2)
98.61±3.45
49.32±9.37
N.I.
FA-Os (3)
N.I.
CafA-Rim (4)
SA-Am (5)
N.I.
N.I.
FA-Am (6)
N.I.
p-CoumA-Am(7)
NA
Amongst the tested compounds, the amide CafA-Os (1) was found to inhibit
the enzyme with half the activity of the used standard tyrosinase inhibitor hydro-
quinone.
Despite the fact that both amides (CafA-Os (1) and CafA-Rim (4)) contain
the same caffeoyl moiety (catechol entity) in their structure, the inhibitory acti-
vity in vitro toward mushroom tyrosinase was lost in amide 4, which could be
attributed to the sterically hindered adamantane rest.
The obtained results confirmed the finding that the inhibitory activity of
p-coumaric acid varies from weaker to stronger in comparison with kojic acid
47
and arbutin, depending on the tyrosinase source (mushroom, human or murine).
The data of the present investigation do not correspond to the developmental
work on a study of tyrosinase inhibition by N-feruloylamantadine amide and
related analogues, which possessed similar or greater melanin inhibitory effect
than the positive controls – kojic acid and hydroquinone, in cell-based environ-
29
ments.
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522
CHOCHKOVA et al.
Effect of the chemically connected hydroxycinnamic acids with rimantadine,
amantadine and oseltamivir against the influenza virus A/Aichi/2/68 (H3N2)
Earlier studies showed that antioxidant therapy could be successfully used as
39,48–50
a potential approach to influenza-associated complications.
The existence
of these findings is connected with the synergistic combination of antioxidants
with approved influenza antivirals, but antioxdiants and antivirals have never
been combined chemically until now.
Therefore, the newly synthesized N-hydroxycinnamoylamides, were eva-
luated for their antiviral activity against influenza virus A/Aichi/2/68 (H3N2).
The newly synthesized compounds did not reveal a significant inhibitory effect
against the in vitro replication of influenza A virus H3N2.
EXPERIMENTAL
Materials and methods
1-Adamantylamine hydrochloride (amantadine hydrochloride), 1-(1-adamantyl)ethyl-
amine hydrochloride (rimantadine hydrochloride), (E)-4-hydroxy-3-methoxycinnamic (feru-
lic, FA), (E)-3,4-dihydroxycinnamic (caffeic, CafA), (E)-4-hydroxy-3,5-dimethoxycinnamic
(sinapic, SA), (E)-4-hydroxycinnamic (p-coumaric, p-CoumA) acids, 1-[3-(dimethylamino)-
propyl]-3-ethylcarbodiimide hydrochloride (EDC), N-methylmorpholine (NMM), mushroom
tyrosinase (EC 1.14.18.1) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical were from
Sigma-Aldrich. Hydroquinone was obtained from Ferak (Germany) and L-tyrosine was
obtained from Merck (Germany). Ethyl (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-
-1-cyclohexene-1-carboxylate (оseltamivir) was purchased from Aopharm (China). All sol-
vents were of reagent grade and used without further purification and the water used was
deionized.
Apparatus
The structures and purity of all newly synthesized amides were confirmed by spectral
1
1
methods, i.e., UV, H- and 13C-NMR spectroscopy and ESI-MS. The H- and 13C-NMR
spectra were acquired on a Bruker Avance III 400 spectrometer, operating at 400.15 MHz for
protons and 100.62 MHz for carbons. The UV spectra of the amides were measured with an
Agilent 8453 UV–Vis spectrophotometer. Elemental analyses for C, H and N were realized on
a Perkin Elmer 2400 analyzer. The ESI mass spectra were obtained on an Esquire3000 plus
instrument.
General procedure for the preparation of N-hydroxycinnamoylamides
In a typical preparation, to a solution of substituted cinnamic acid (3.2 mmol), EDC
(0.61 g, 3.2 mmol) and 1-hydroxybenzotriazole (0.43 g, 3.2 mmol) in 10 mL THF, after 10
min stirring at 0 °C, the antiviral compound (3.2 mmol) and NMM (0.35 mL, 3.2 mmol),
dissolved in 7 mL THF were added. The resultant reaction mixture was stirred for 1 h at 0 °C
and then for 24 h at room temperature, under a nitrogen atmosphere. After completion of the
reaction (TLC control – CH2Cl2/CH3OH (3:0.2; 3:0.3); CH2Cl2/EtOAc/CH3OH (3:0.1:0.1)),
the THF was evaporated in vacuo, and the residue was diluted with EtOAc and then was suc-
cessively washed with 5 % NaHSO4, NaHCO3 and brine, dried over anhydrous Na2SO4 and
evaporated in vacuo. The residue was purified by column chromatography or preparative TLC
on silica gel (CH2Cl2/CH3OH) to give the desired compound.
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N-HYDROXYCINNAMOYL ANALOGUES OF ANTIVIRAL DRUGS
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DPPH radical scavenging assay
The free DPPH scavenging assay was performed according to the Nenadis method.51
The vanishing of the deep violet color of the DPPH radical was accomplished by mixing
2.96 mL 0.1 mM ethanolic DPPH solution with 40 µL of a free radical scavenger (antioxi-
dant) at the reaction mixture concentrations: 12, 24 and 48 μM. The decrease in absorbance at
516 nm was measured after 20 min incubation in the dark at room temperature.
The measurements were performed in triplicate and results are presented as the percent-
tage of radical scavenging activity, calculated as follows:
Free radical scavenging activity (%) = 100(ADPPH – Asample)/ADPPH
Mushroom tyrosinase inhibition assay
Inhibition of tyrosinase activity was determined spectrophotometrically by a modified
dopachrome method25 using L-tyrosine as the substrate.
The reaction media (3 mL) contained: phosphate buffer (1.0 mL, 0.1 M, pH 6.8);
L-tyrosine (1.0 mL, 1.5 mM) dissolved in deionized water; inhibitor (0.350 mL, 0.2 mM)
dissolved in DMSO; deionized water (0.350 mL); an aqueous mushroom tyrosinase solution
(0.300 mL, 192 U mL-1). After adding the mushroom tyrosinase solution, the reaction mixture
was incubated at 37 °C for 20 min, and thereafter, the UV absorbance of the reaction mixture
was measured at 475 nm. Results were compared with a reference solution consisting of 0.350
mL of DMSO instead of a sample (inhibitor).
The percentage of mushroom tyrosinase inhibitory activity was calculated using the
following equation:
Inhibition (%) = 100(Arefs – Asample)/Arefs
where, Arefs is the absorbance of the reference solution and Asample is the absorbance of the test
sample solution).
Each experiment was performed in triplicate and averaged. Results were evaluated at a
level of significance 0.05. Hydroquinone was used as the positive control.
Antiviral activity assay
Cells and viruses. MDCK cells for the propagation of influenza virus A originated from
the collection of the Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sci-
ences, Sofia, Bulgaria, and were grown in a growth medium containing Dulbecco modified
Eagles’ medium (DMEM) (Gibko BRL, USA), supplemented with 10 % fetal bovine serum,
10 mM HEPES buffer (Меrck, Germany) and antibiotics (penicillin 100 IU mL-1 and strepto-
mycin 100 μg mL-1). The cells were cultured as confluent monolayers in a humidified atmo-
sphere containing 5 % CO2 at 37 °C.
Influenza virus A/Aichi/2/68 (H3N2) from the collection of the Stephan Angeloff Insti-
tute of Microbiology, Bulgarian Academy of Sciences, was grown in MDCK cells in a maint-
enance medium of Dulbecco modified Eagles’ medium (DMEM) (Gibko BRL, USA), con-
taining 0.5 % fetal bovine serum, 10 mM HEPES buffer and antibiotics, as well as 3 mg mL-1
trypsin (Gibco BRL).
Cytopathic effect (CPE) inhibition test. Monolayer MDCK cells in 96-well microplates
(Costar, USA) were inoculated, following the removal of the growth medium, with 0.1 mL virus
suspension containing 100 CCID50 (cell culture infectious dose 50 %). After 1 h at 37 °C for
virus adsorption, the innoculum was washed out and replaced by 0.1 mL of non-cytotoxic 0.5
log10 dilutions in the maintenance medium of the newly synthesized compounds. Each
dilution was applied in quadruplicate. Cells that were not inoculated with virus were left for
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524
CHOCHKOVA et al.
cell controls (with only maintenance medium) and toxicity controls (with respective dilution
of the compound in the maintenance medium). Cells inoculated with virus but not treated with
a compound were left for virus controls. Then cells were incubated for 48 h in a humidified
atmosphere with 5 % CO2 at 37 °C or until the virus specific cytopathic effect had destroyed
100 % of the cells in the virus control wells. Then cells were stained according to the neutral red
uptake procedure and the percentage of CPE inhibition, if present, was calculated using the
following formula: % CPE = (ODtest sample – ODvirus control)/(ODtoxicity control – ODvirus control) – 100.
CONCLUSIONS
Seven N-(hydroxycinnamoyl)amides were synthesized and identified, six of
which were new. The compounds were evaluated for their anti-influenza, DPPH
scavenging and mushroom tyrosinase inhibitory activities. The results indicated
that amides 1 and 4, containing the catechol moiety, were the most active as
DPPH radical-scavengers. In addition, CafA-Os (1) was found to be the most
active as a tyrosinase inhibitor (≈50 %) in vitro.
SUPPLEMENTARY MATERIAL
Analytic and spectral data for the synthesised compounds are available electronically
from http://www.shd.org.rs/JSCS/, or from the corresponding author on request.
Acknowledgment. This work was supported by the Bulgarian Science Fund (contract
DMU 03/2).
ABBREVIATIONS
DPPH – 1,1-diphenyl-2-picrylhydrazyl radical;
ROS – reactive oxygen species;
DMSO – dimethyl sulfoxide;
EDC – 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide;
HOBt – 1-hydroxybenzotriazole;
p-CoumA – p-coumaric acid;
FA – ferulic acid;
SA – sinapic acid;
CafA – caffeic acid;
Os – oseltamivir;
Rim – rimantadine;
Am – amantadine;
% RSA – percentage of radical scavenging activity.
И З В О Д
СИНТЕЗА И БИОЛОШКА АКТИВНОСТ ХИДРОКСИЦИНАМОИЛ
АНТИВИРУСНИХ ЛЕКОВА
MAYA G. CHOCHKOVA1, ASSYA P. GEORGIEVA1, GALYA I. IVANOVA2, NADYA NIKOLOVA3, LUCHIA MUKOVA3,
LUBOMIRA NIKOLAEVA-GLOMB3 И TSENKA S. MILKOVA1
1
2
South-West University ‘‘Neofit Rilski”, Blagoevgrad, Bulgaria, Departamento de Química, Faculdade de
3
Ciências, Universidade do Porto, Porto, Portugal and The Stephan Angeloff Institute of Microbiology,
Bulgarian Academy of Sciences, Sofia, Bulgaria
Синтетисано је седам N-хидроксицинамоил-амида EDC/HOBt катализованим куп-
ловањем одговарајућих супституисаних циметних киселина (p-кумаринска, ферулинска,
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N-HYDROXYCINNAMOYL ANALOGUES OF ANTIVIRAL DRUGS
525
синапинска и кафена киселина) са једињењима која показују антивиралну активност
(амантадин, римантидин и оселтамивир). Испитивана је in vitro способност пресретања
1,1-дифенил-2-пикрилхидразил (DPPH) радикала и инхибиција активности тирозиназе
гљива (употребом L-тирозина као супстрата). Од синтетисаних једињења, деривати N-
[(E)-3-(3,4-дихидроксифенил)-2-пропеноил]оселтамивир (1) и N-[(E)-3-(3,4-дихидрок-
сифенил)-2-пропеноил]римантидин (4), који садрже катехолски фрагмент, показују нај-
бољу способност пресретања DPPH радикала. Такође, амид 1 показује инхибиторни
ефекат према тирозинази (око 50 %). Испитивана је in vitro инхибиторна активност
синтетисаних једињења према вирусу грипа А (H3N2).
(Примљено 22. фебруара, ревидирано 24. јуна, прихваћено 1. октобра 2013)
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