Synthesis, Inhibitory Activity, and in Silico Modeling of Selective COX-1 Inhibitors with a Quinazoline Core

COX ‑1 Inhibitors with a Quinazoline Core

Letter

Synthesis, Inhibitory Activity, and In Silico Modeling of Selective

Marcela Dvorakova,* Lenka Langhansova, Veronika Temml, Antonio Pavicic, Tomas Vanek,

and Premysl Landa

Cite This: ACS Med. Chem. Lett. 2021, 12, 610 −616

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ABSTRACT: Selective cyclooxygenase-1 (COX-1) inhibition has got

into the spotlight with the discovery of COX-1 upregulation in various

cancers and the cardioprotective role of COX-1 in control of thrombocyte

aggregation. Yet, COX-1-selective inhibitors are poorly explored. Thus,

three series of quinazoline derivatives were prepared and tested for their

potential inhibitory activity toward COX-1 and COX-2. Of the prepared

compounds, 11 exhibited interesting COX-1 selectivity, with 8

compounds being totally COX-1-selective. The IC₅₀value of the best

quinazoline inhibitor was 64 nM. The structural features ensuring COX-1

selectivity were elucidated using in silico modeling.

KEYWORDS: Cyclooxygenase, inhibitor, quinazoline, selectivity, docking

yclooxygenase (COX) is a bifunctional, membrane-

bound homodimer with fatty acid oxygenase and

and modulates platelet function. This oversimpliﬁed view

−9

has been lately challenged by a number of studies. Today, it

is believed that COX-1 is responsible for the primary

prostanoid response to inﬂammatory stimuli, especially in

these cells and tissues, where it is constitutively expressed,

whereas COX-2 contributes to prostanoid synthesis later in the

Moreover, COX-1 upregulation

was found in various cancers, such as skin, breast, colorectal, or

peroxidase function. It is a key enzyme of the inﬂammation

process and the main target of nonsteroidal anti-inﬂammatory

drugs (NSAIDs). Two catalytically functional COX isoforms

are present in mammals, COX-1 and COX-2. These isoforms

share a considerable protein sequence, and their catalytic

mechanism is very similar. Both are activated by peroxides;

however, COX-1 requires much higher concentrations for

−6,10−12

inﬂammation process.

10,11

epithelial ovarian cancer

as well as during atherosclerosis,

12,15,16

tocolysis, or neuroinﬂammation.

Consequently, selec-

activation than COX-2. Both also consist of three domains,

tive COX-1 inhibition is a promising target for the treatment of

cancers and neurodegenerative disorders. Furthermore, the

cardioprotective role of COX-1 in control of thrombocyte

one of which is the catalytic domain that contains both the

fatty acid oxygenase and peroxidase active sites. The oxygenase

site is buried deep in the catalytic domain, and its entrance is

governed by Arg120, Tyr355, and Glu524 amino acids. The

volume of the COX-1 oxygenase site is about 20% smaller than

that of COX-2. In addition, the COX-2 oxygenase site contains

an additional hydrophilic side-pocket in the proximity of

Phe518. In COX-1, an access to this pocket is hindered by

bulky amino acids, Ile523 and Ile434, which in COX-2 are

7,18

aggregation has been reported.

On the top of that, COX-1

has been identiﬁed as one of two main enzymes involved in the

synthesis of chemoprotective factors derived from mesen-

chymal stem cells, which are able to modulate the response to

chemotherapy, suggesting that the inhibition of COX-1 may

reverse drug resistance. Therefore, selective COX-1 inhib-

itors may provide a new direction in the development of anti-

inﬂammatory compounds with potential activity toward

diseases other than those treated with NSAIDs.

replaced by smaller valines.

The oxygenase site catalyzes the synthesis of prostaglandins

from arachidonic acid (AA). COX-1 is a primary contributor to

the synthesis of thromboxane A2 (TXA2), while COX-2

furnishes predominantly prostaglandin E2 (PGE2) and

Relatively few selective COX-1 inhibitors have been

developed so far, such as SC-560, mofezolac, or FR122047

prostacyclin (PGI2). Thus, deletion of the COX-1 gene

Received: January 3, 2021

Accepted: March 5, 2021

Published: March 12, 2021

causes predominantly impaired platelet aggregation, whereas

COX-2 gene deletion seems to be detrimental to an organism.

Moreover, because COX-2 cannot be usually detected under

normal conditions and is rapidly induced during inﬂammation,

it was long believed that COX-2 is the main proinﬂammatory

isoform and COX-1 provides gastrointestinal tract protection

2021 American Chemical Society

ACS Medicinal Chemistry Letters

ACS Med. Chem. Lett. 2021, 12, 610−616

Figure 1. Examples of selective COX-1 inhibitors.

Letter

Scheme 2. Synthesis of Quinazoline Intermediates 5a,b via

Quinazoline 4

Figure 2. Quinazoline anti-inﬂammatory drugs on market.

Reagents and conditions: (a) urea, 200 °C, 3 h; (b) POCl , N,N-

dimethylaniline, 120 °C, 4 h; (c) 4-methoxybenzylamine or 3,4-

diﬂuorobenzylamine, sodium acetate, THF, 65 °C, 3 h.

Scheme 1. Synthesis of Quinazolines 2a and 2b

selectivity is due to their tighter ﬁt within the COX-1 binding

site caused by the nature of substituents on heterocycle core,

while carboxylic acid and chlorine in mofezolac and P6,

respectively, made inevitable contact with Arg120 and Tyr355

at the entrance to the catalytic domain.

Reagents and conditions: (a) acetic anhydride, 120 °C, 3 h; (b)

Quinazolines are heterocyclic compounds with numerous

therapeutic applications such as anti-inﬂammatory, analgesic,

anticonvulsant, or anticancer applications. There are a few

quinazoline compounds on the market used as anti-

inﬂammatory drugs, for example, tryptanthrin, proquazone,

or ﬂuproquazone (Figure 2). Proquazone and ﬂuproquazone

were developed as third-generation NSAIDs with outstanding

aqueous ammonia, reﬂux, 3 h; (c) benzaldehyde, acetic acid, reﬂux, 12

h; (d) POCl , 4-(dimethylamino)pyridine (DMAP), toluene, reﬂux, 5

(Figure 1). From these, only mofezolac is used clinically as an

4,5

analgesic drug and only in Japan. Other compounds, often

abundantly used as reference compounds in in vitro and in vivo

studies, have poor pharmacodynamic or pharmacokinetic

safety and eﬃcacy. Still, the potential of other quinazolines to

inhibit COXs is weakly explored. Only several quinazolinones

21−26

proﬁles to enter clinical trials. Cingolani et al. studied the

were identiﬁed as selective COX-2 inhibitors.

structural basis for COX-1 selectivity of two inhibitors, P6 and

mofezolac (Figure 1). They concluded that the COX-1

Therefore, three series of 2,4,7-substituted quinazolines as

potential COX-1 inhibitors were designed and synthesized.

Table 1. First Series of Quinazoline Derivatives

entry

reagent: RNH₂

product (yield %)

entry

reagent: RNH₂

product (yield %)

3,4-dimethylaniline

p-toluidine

4-methoxyaniline

piperazine

ethyl 4-aminobenzoate

3,4-diﬂuoroaniline

4-nitroaniline

8-aminoquinoline

2-aminopyridine

3-amino-5-methylpyrazole

3,4-diﬂuorobenzylamine

3a (73.5)

3b (53.0)

3c (53.8)

3d (82.1)

3e (60.4)

3f (86.3)

3g (28.5)

3h (84.9)

3i (88.8)

3j (44.0)

3k (61.6)

methyl 3-aminopropanoate

4-tert-butylaniline

4-butylaniline

3l (78.0)

3m (62.0)

3n (72.3)

3o (63.8)

3p (79.7)

3q (75.1)

3r (67.4)

3s (68.2)

3t (37.7)

3u (54.1)

3v (70.7)

4-propoxyaniline

2,4,6-trimethylaniline

2,4,6-triﬂuoroaniline

2-bromo-4-ﬂuoro-6-methylaniline

3,5-dimethoxyaniline

3,5-bis(triﬂuoromethyl)aniline

4-(triﬂuoromethyl)aniline

4-aminophenol

Reagents and conditions: (a) corresponding amine or aniline, DMAP, triethylamine, THF, or toluene, reﬂux, 20 h.

ACS Med. Chem. Lett. 2021, 12, 610−616

ACS Medicinal Chemistry Letters

Letter

Table 2. Second Series of Quinazoline Derivatives

Table 4. IC₅₀Values for COX-1 and COX-2 Enzymes

IC₅₀COX-1

IC₅₀COX-2

selectivity index (COX-2/

COX-1)

compound

(μM)

1.57 ± 0.54

1.89 ± 0.63

1.90 ± 0.69

3.14 ± 0.99

0.376 ± 0.189

0.142 ± 0.014

1.39 ± 0.72

0.78 ± 0.64

1.58 ± 0.89

0.141 ± 0.045

0.064 ± 0.044

2.19 ± 0.78

0.006 ± 0.003

43.0 ± 10.3

37.3 ± 9.36

10.1 ± 1.38

>50

27.4

19.7

5.32

COX-1-selective

1.51

product (yield

>50

entry reactant

R₃(intermediate)

R₄

4-methoxyphenyl (6a) morpholin-1-yl

4-methoxyphenyl (6a) pyrrolidin-1-yl

4-methoxyphenyl (6a) piperazin-1-yl

4-methoxyphenyl (6a) diethylamino

4-ﬂuorophenyl (6b)

thiophen-2-yl (6c)

7a (89.8)

7b (80.2)

7c (79.6)

7d (40.7)

7e (94.9)

7f (96.6)

7g (90.8)

7h (34.7)

7i (82.6)

7j (87.6)

7k (90.1)

7l (91.8)

7m (84.9)

7n (54.4)

7o (90.5)

morpholin-1-yl

pyrrolidin-1-yl

piperazin-1-yl

diethylamino

morpholin-1-yl

pyrrolidin-1-yl

ibuprofen

SC-560

3.30 ± 0.96

1.03 ± 0.40

179.5

phosphoryl chloride (POCl ) aﬀorded (E)-4-chloro-2-styryl-

4-methoxyphenyl (6d) morpholin-1-yl

4-methoxyphenyl (6d) pyrrolidin-1-yl

4-methoxyphenyl (6d) piperazin-1-yl

4-methoxyphenyl (6d) diethylamino

quinazoline (2a) (Scheme 1). Final compounds (3a−v) were

prepared via amination of quinazoline 2a with variously

substituted anilines or amines (Table 1).

The synthesis of the second series began with the

preparation of 7-bromo-2,4-dichloroquinazoline (4) from the

commercially available 2-amino-4-bromobenzoic acid (1b), by

thiophen-2-yl (6e)

morpholin-1-yl

Reagents and conditions: (a) corresponding boronic acid or ester,

K CO , PdCl (PPh ) , toluene/dioxane/water (10:5:8, v/v/v), 90 °C,

the reaction with urea followed by a treatment with POCl ,

overnight; (b) corresponding secondary amine, KI, K CO , N,N-

according to published procedure (Scheme 2). The step-by-

step modiﬁcation of three functional groups in quinazoline 4

aﬀorded the desired ﬁnal quinazolines. Shortly, the 4-chloro

position was aminated using two diﬀerent benzylamines to give

the intermediates 5a,b (Scheme 2), which underwent a Suzuki

diisopropylethylamine, dimethylformamide, 110 °C, overnight.

The derivatization of the quinazoline core in positions 2, 4, and

was chosen in order to resemble the shape of a letter “V”,

which is typical for numerous diarylheterocyclic COX-1

inhibitors. Although several of the selective COX-2 inhibitors

coxibs) also possess the diarylheterocyclic moiety, they always

cross-coupling reaction of the 7-bromo position with three

aromatic boronic acids to aﬀord intermediates 6a−e. Finally,

the 2-chloro position was aminated using four diﬀerent

secondary amines to give the ﬁnal quinazoline derivatives

7a−o (Table 2).

(

contain either a sulfonamide or methylsulfamoyl group.

Instead, we decided to bet on the substitution with a styryl

group to partly resemble the structure of stilbenes, a class of

selective COX-1 inhibitors. Other substituents were chosen

with the aim to oﬀer distinct electronic and steric properties of

the ﬁnal compounds as well as potential variability in H-

bonding with the amino acids within the COX-1 binding site.

The synthesized compounds were evaluated in vitro for their

ability to inhibit COX-1 and COX-2 isoenzymes. The results

were also supported by in silico modeling.

The synthesis of the ﬁrst series started with the preparation

of (E)-4-chloro-2-styrylquinazoline (2a) from the commer-

cially available anthranilic acid (1a), following a literature

procedure. Shortly, the treatment of 1a with acetic

anhydride, followed by the reaction with benzaldehyde in

acetic acid gave an intermediate, which upon exposure to

Out of the synthesized compounds, seven exerted potent

activity toward COX-1. For these, IC values were determined

on both COX isoforms, while compounds exhibiting less than

50% inhibition on both COX isoforms were considered

inactive (for percent inhibition, see Table 1S in the Supporting

Information B ). From the ﬁrst series, three compounds (3b,

3c, 3k) exerted single-digit micromolar inhibitory activity

toward COX-1, which was comparable with the inhibitory

activity of the reference inhibitor ibuprofen, while their

inhibitory activity toward COX-2 was rather moderate

(Table 4). Their selectivity index was between 5 and 27. On

the other hand, one compound from the ﬁrst series (3v) and

three compounds from the second series (6c, 6e, and 7o) were

totally COX-1-selective, as they did not inhibit COX-2 even at

Table 3. Third Series of Quinazoline Derivatives

entry

reagent 1: RNH₂

product (yield %)

reagent 2: R B(OH)₂

product (yield %)

4-methylaniline

3,4-diﬂuorobenzylamine

8a (53.4)

8b (93.2)

thiophene-2-boronic acid pinacol ester

9a (77.0)

9b (85.3)

Reagents and conditions: (a) Corresponding aniline or benzylamine, DMAP, Et N, toluene, reﬂux, 3 h; (b) thiophene-2-boronic acid pinacol

ester, K CO , PdCl (PPh ) , toluene/dioxane/water (10:5:8, v/v/v), 90 °C, overnight.

3 2

ACS Medicinal Chemistry Letters

ACS Med. Chem. Lett. 2021, 12, 610−616

Letter

Figure 3. (A,C) 9b in the binding site of COX-1. The amine functionality acts as a hydrogen bond donor (green arrow) to Tyr355. The yellow

spheres represent hydrophobic contacts within the binding pocket. Within COX-1, 9b assumes an orientation, where the ﬂuorinated benzyl ﬁlls a

pocket leading up to Met113 and the styryl moiety rests in a pocket leading up to Tyr385. The thiophene moiety adds additional stability by ﬁlling

a channel leading to Phe518. (B,D) The key hydrogen bond interaction is lost in COX-2, where 9b assumes a ﬂipped orientation.

0 μM. It should be noted that two of these COX-1-selective

position 2, a thiophene ring was placed in position 7, and

position 4 was substituted with 3,4-diﬂuorobenzylamine or 4-

methylaniline (Table 3). The synthesis followed the procedure

compounds, 6c and 6e, were just intermediates, and only one

compound, 7o, belonged to the ﬁnal derivatives. In addition,

these two intermediates exhibited IC values in the nanomolar

range (1 order of magnitude better than ibuprofen), while the

IC value of the ﬁnal compound 7o was in micromolar range,

and two other corresponding ﬁnal derivatives, 7i and 7j, were

found inactive. From these results, it is obvious that the

presence of an amine moiety in position 2 decreases

substantially the inhibitory activity toward COX-1.

Structurally, all active compounds possessed either a

chlorine or styryl group in position 2 and in position 4 was

a phenyl or benzyl ring substituted in the para-position with an

electron-donating group (F, CH , NH , OCH ). Except for

for the ﬁrst series, while the starting material from the second

series, 2-amino-4-bromobenzoic acid (1b), was used. Thus,

(E)-7-bromo-4-chloro-2-styrylquinazoline 2b was formed

(Scheme 1). The reaction of 2b with 3,4-diﬂuorobenzylamine

or 4-methylaniline, respectively, aﬀorded intermediates 8a,b,

which upon Suzuki cross-coupling with thiophene-2-boronic

acid pinacol ester gave the ﬁnal quinazolines 9a,b (Table 3).

Both intermediates 8a,b as well as both ﬁnal compounds

9a,b exerted selective COX-1 inhibitory activity. As expected,

the IC₅₀values of intermediates 8a,b were comparable with

ibuprofen, as their structure resembled that of the ﬁnal

compounds of the ﬁrst series, 3b and 3k (Table 4). Moreover,

the comparison of the IC values of the ﬁnal compounds 9a,b

ﬂuorine, which was tolerated also in the meta-position, the

presence of other substituents, either an electron-donating

(

EDG) or electron-withdrawing (EWG), in the meta- or ortho-

(141/64 nM, respectively) with 6c and 6e (376 and 142 nM,

respectively) demonstrated the importance of the 2-styryl

group for the inhibitory activity toward COX-1. Furthermore,

similarly to compounds of the second series, the presence of

the thiophene ring in compounds 9a,b signiﬁcantly augmented

the COX-1 inhibitory activity, causing a decrease in IC values

by 1 to 2 orders of magnitude, with the best value observed for

compound 9b (IC₅₀= 64 nM). Even though this value was 1

order of magnitude higher than the IC₅₀value determined for

the reference COX-1-selective inhibitor, SC-560, such activity

together with total COX-1 selectivity renders quinazoline 9b as

position caused inactivity in COX assays. Similarly, with

aliphatic or heterocyclic substitution in position 4, the

inhibitory activity vanished. Thiophene ring in position 7

signiﬁcantly enhanced COX-1-selective inhibitory activity and

was even indispensable for this activity when the styryl group

in position 2 was missing.

Based on these results, two other quinazoline derivatives

were prepared as examples of a third series. A combination of

the substituents from the active compounds of both previous

series was employed. Thus, the styryl group was placed in

ACS Medicinal Chemistry Letters

ACS Med. Chem. Lett. 2021, 12, 610−616

Letter

Figure 4. (A,C) 3k also forms the key hydrogen bond with Tyr355 in COX-1. The ﬂuorinated benzyl group is oriented toward Met113, while the

styryl moiety ﬁlls the channel leading up to Tyr385. (B,D) In COX-2, the molecule is ﬂipped, but the pyrimidine ring can act as a hydrogen bond

acceptor to Tyr355, explaining the residual COX-2 activity in the smaller molecules of the ﬁrst series. Here, the ﬂuorinated benzyl group ﬁlls the

channel leading up to Tyr385, while the styryl is oriented toward Phe518. The yellow spheres represent hydrophobic contacts with the binding

pocket.

a promising compound for further evaluation of its biological

activity and pharmacological proﬁle.

most active quinazoline derivative 9b is placed in the COX-1

binding site so that the amine functionality is located within

binding vicinity of Tyr355. The three ring substituents ﬁll

diﬀerent hydrophobic parts of the pocket. The ﬂuorinated

benzyl ﬁlls a pocket leading up to Met113, and the styryl

moiety rests in a pocket leading up to Tyr385. The thiophene

moiety is oriented toward Phe518 (Figure 3). In the binding

site of COX-2, compound 9b is ﬂipped and can no longer

interact with Tyr355 (Figure 3). The loss of this key

interaction could explain the loss of in vitro activity.

To determine whether the synthesized compounds compete

with the substrate (AA) in binding to the binding site of the

COX-1 enzyme, 9b was selected as a representative compound

and tested in COX-1 assays with diﬀerent concentrations of

AA. The ability of compound 9b to inhibit COX-1 was

reduced when the concentration of AA increased in the

reaction. IC values increased from 21.1 nM in the presence of

250 nM AA, through 72.8 nM in the presence of 1250 nM AA,

to 254 nM in the presence of 6250 nM AA. It suggests that

A similar eﬀect, but less pronounced, occurs for the smaller

molecules from the ﬁrst series, which still display dual activity.

Compound 3k binds to COX-1 in the same orientation as 9b,

also forming the hydrogen bond with Tyr355, but as it lacks

the thiophene ring, the channel leading to Phe518 is empty

causing a reduced activity. In COX-2, the molecule is again

ﬂipped, but due to the smaller size, the pyrimidine ring can act

as an interaction partner for Tyr355 (Figure 4).

In summary, three series of quinazoline derivatives were

synthesized, and their inhibitory activity toward COX-1 and

COX-2 isoenzymes was evaluated in vitro. From the

synthesized compounds, 11 quinazoline derivatives exhibited

compound 9b competed with AA in binding to COX-1.

Ibuprofen, which is a known competitive COX-1 inhibitor,

also exhibited such a tendency, as its IC₅₀values increased

from 4.00 μ M with 250 nM AA to 70.1 μ M with 6250 nM AA

Table 2S in the Supporting Information B).

In order to elucidate the structural causes of the selective

binding mechanism, all compounds (3−9) were docked into

the binding sites of COX-1 using the pdb entry 3n8w,

cocrystallized with ﬂurbiprofen, and COX-2 using the pdb

entry 6COX, cocrystallized with SC-558. An analysis of the

resulting docking poses revealed a hydrogen bridge between

the secondary amine functionality and Tyr355, a key residue

for electron transfer in the COX mechanism of action, as the

primary indicator of activity within the compound class. The

good to excellent inhibitory activity toward COX-1 (IC₅₀

0.064−3.14 μM). Out of these, seven compounds did not

inhibit a COX-2 isoform even at 50 μM, making these

ACS Med. Chem. Lett. 2021, 12, 610−616

ACS Medicinal Chemistry Letters

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Letter

compounds totally COX-1-selective. The IC₅₀values of the

most active compounds were 1 to 2 orders of magnitude lower

than the inhibitory activity of the reference compound,

ibuprofen (IC₅₀= 2.19 μM). According to our results, the

compounds compete with the substrate in the binding to

COX-1 binding site. All the active compounds possessed in the

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0003-0364-2247

https://pubs.acs.org/10.1021/acsmedchemlett.1c00004

Author Contributions

-position of the quinazoline ring either para-EDG-substituted

M.D. synthesized the compounds and wrote the paper, V.T.

did the molecular docking studies, L.L., A.P., and P.L. carried

out the COX inhibition experiments, P.L. did the substrate

competition experiment, and T.V. supervised the work.

aniline or benzylamine and in the 2-position a chlorine or

styryl group. The presence of a thiophene ring in the 7-

position markedly enhanced the inhibitory activity as well as

COX-1 selectivity. In the docking study, it was shown that the

activity hinges on the formation of a hydrogen bond between

the secondary amine and key enzyme residue Tyr355. This

interaction is only formed in the binding site of COX-1 and

thus may be the cause of the selectivity.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

The authors gratefully acknowledge the ﬁnancial support by

the grant LTC17048 from the Ministry of Education, Youth

and Sports of the Czech Republic. V.T. is funded by a FWF

Hertha Firnberg fellowship (T-942).

ASSOCIATED CONTENT

sı Supporting Information

■

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acsmedchemlett.1c00004.

ABBREVIATIONS

■

(

Supporting Information A: Detailed synthetic proce-

dures, complete spectroscopic data of synthesized

compounds, experimental procedure of docking experi-

ments and presentation of docking scores, and

experimental procedure of the determination of COX

inhibition (PDF)

AA, arachidonic acid; COX, cyclooxygenase; DMAP, 4-

dimethylamino)pyridine; EDG, electron-donating group;

EWG, electron-withdrawing group; NSAIDs, nonsteroidal

anti-inﬂammatory drugs; PDB, protein data bank;

PdCl (PPh ) , bis(triphenylphosphine)palladium(II) dichlor-

3 2

ⁱ^d^e^;^P^G^E²^,^p^r^o^s^t^a^g^l^aⁿ^dⁱⁿ^E²^;^P^G^I²^,^p^r^o^s^t^a^c^y^c^lⁱⁿ^;^P^O^C^l3^,

phosphoryl chloride; THF, tetrahydrofuran; TXA2, thrombox-

ane A2

Supporting Information B: H and ¹³C NMR spectra of

all newly synthesized compounds, percentual inhibition

of COX-1 and COX-2 isoenzymes by tested compounds

at 20 μM, COX-1 inhibition by compound 9b and

ibuprofen at diﬀerent substrate concentrations, percen-

tual inhibition of COX-1 by active compounds at

diﬀerent concentrations graphically depicted as %

inhibition vs log(concentration), UPLC/UV−vis chro-

matograms of the active compounds showing their

purity (PDF )

REFERENCES

■

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AUTHOR INFORMATION

■

Corresponding Author

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Marcela Dvorakova − Laboratory of Plant Biotechnologies,

Czech Academy of Sciences, Institute of Experimental Botany,

375.

65 02 Prague 6 - Lysolaje, Czech Republic; orcid.org/

(4) Perrone, M. G.; Scilimati, A.; Simone, L.; Vitale, P. Selective

000-0002-6664-6870 ; Email: dvorakova@ueb.cas.cz

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Authors

Lenka Langhansova − Laboratory of Plant Biotechnologies,

Czech Academy of Sciences, Institute of Experimental Botany,

(5) Perrone, M. G.; Lofrumento, D. D.; Vitale, P.; De Nuccio, F.; La

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Veronika Temml − Department of Pharmaceutical and

Medicinal Chemistry, Paracelsus Medical University of

Salzburg, 5020 Salzburg, Austria; orcid.org/0000-0001-

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