Design, synthesis, and structure–activity relationship study of O-prenylated 3-acetylcoumarins as potent inhibitors of soybean 15-lipoxygenase

Article abstract of DOI:10.1002/ddr.21787

In this work, the design, synthesis, and structure–activity relationships of a novel array of geranyloxy and farnesyloxy 3-acetylcoumarins were reported as potent soybean 15-lipoxygenase inhibitors. Among the prepared coumarins, 7-farnesyloxy-3-acetylcoumarin (12b) was found to be the most potent inhibitor by IC₅₀?= 0.68 μM while O-geranyl substituents at positions 5 and 6 of 3-acetylcoumarin (10a and 11a) were not inhibitors. Using docking studies, the binding affinity and the preferred pose of synthetic compounds were considered. It was found that lipoxygenase inhibitory activity and prenyl length chain were directly related. The hydrophobic cavity of the enzyme was more effectively occupied by the farnesyl moiety of the potent inhibitor 12b rather than other derivatives. Also, with this pose of farnesyl chain in 7-farnesyloxy-3-acetylcoumarins, the acetyl group could be directed to the hydrophilic pocket in the active site.

Full text of DOI:10.1002/ddr.21787

Received: 27 November 2020
DOI: 10.1002/ddr.21787
Revised: 21 December 2020
Accepted: 22 December 2020
R E S E A R C H A R T I C L E
Design, synthesis, and structure–activity relationship study of
O-prenylated 3-acetylcoumarins as potent inhibitors of
soybean 15-lipoxygenase
Sara Zerangnasrabad1 | Atena Jabbari1
| Elahe Khavari Moghadam1
|
Hamid Sadeghian2
| Seyed Mohammad Seyedi1
1Department of Chemistry, Faculty of Science,
Ferdowsi University of Mashhad,
Mashhad, Iran
Abstract
In this work, the design, synthesis, and structure–activity relationships of a novel
array of geranyloxy and farnesyloxy 3-acetylcoumarins were reported as potent soy-
bean 15-lipoxygenase inhibitors. Among the prepared coumarins, 7-farnesyloxy-
3-acetylcoumarin (12b) was found to be the most potent inhibitor by IC50 = 0.68 μM
while O-geranyl substituents at positions 5 and 6 of 3-acetylcoumarin (10a and 11a)
were not inhibitors. Using docking studies, the binding affinity and the preferred pose
of synthetic compounds were considered. It was found that lipoxygenase inhibitory
activity and prenyl length chain were directly related. The hydrophobic cavity of the
enzyme was more effectively occupied by the farnesyl moiety of the potent inhibitor
12b rather than other derivatives. Also, with this pose of farnesyl chain in
7-farnesyloxy-3-acetylcoumarins, the acetyl group could be directed to the hydro-
philic pocket in the active site.
2Department of Laboratory Sciences, School
of Paramedical Sciences, Mashhad University
of Medical Sciences, Mashhad, Iran
Correspondence
Atena Jabbari and Seyed Mohamad Seyedi,
Department of Chemistry, Faculty of Science,
Ferdowsi University of Mashhad, Mashhad
91775-1436, Iran.
Email: atena.jabbari@gmail.com (A. J.) and
smseyedi@um.ac.ir (S. M. S.)
Funding information
Ferdowsi University of Mashhad
K E Y W O R D S
15-lipoxygenase inhibitor, acetyl-moiety, prenyloxycoumarins, SAR studies
1
|
INTRODUCTION
chemical structure, including heterocyclic, phenolic, allyl, and allyloxy
benzene derivatives (Sadeghian & Jabbari, 2016).
Lipoxygenases are nonheme iron-containing proteins that contribute
to a new successful eicosanoid pathway by acting as biocatalysts in
arachidonic acid's peroxidation at positions 5, 8, 12, and 15 to the
corresponding hydroperoxide derivatives (Segraves et al., 2004).
Plants, fungi, and animals are the primary sources of
lipoxygenases. The large family of these isoenzymes has broad biolog-
ical implications, meaning that in mammalians, lipoxygenases are
involved in the early formation of pro-inflammatory mediators (Jeon
et al., 2009), asthma, immune disorders (Segraves et al., 2004), various
cancer promoters, especially prostate and breast cancers (Das
et al., 2007), atherosclerosis (Bocan et al., 1998), neurodegeneration
(van Leyen et al., 2006), obesity, and diabetes (Mentes¸e et al., 2016).
Today, the use of lipoxygenase inhibitors for therapeutic pur-
poses has received increasing attention. So far, a variety of 15 LOX
inhibitors have been synthesized and categorized based on their
Coumarin is among the widely acclaimed heterocyclic structures
that have been recorded as lipoxygenase inhibitors. Coumarins are
classified as lactones with a benzopyrone scaffold, consisting of ben-
zene joined to a pyrone ring. They were mainly synthesized through
Pechmann (Panetta & Rapoport, 1982), Perkin (Matos et al., 2009),
Knoevenagel (Kumar et al., 2011), Wittig (Upadhyay & Kumar, 2009),
Baylis–Hillman (Kaye & Robinson, 1996), Michael addition (Rao &
Sivakumar, 2006), and Palladium-catalyzed (Trost et al., 2003)
reactions.
Based on its structure, coumarin can be parted into
(a) substituted coumarins, (b) ring-fused coumarins, and (c) C-, and
O-prenylcoumarins (Curini et al., 2006). Prenyloxycoumarins
(isopentenyloxy, geranyloxy, farnesyloxy, and other biosynthetic
derivatives) are secondary metabolites commonly extracted from
plants that belong to Rutaceae and Umbelliferae families. Until
Drug Dev Res. 2021;1–9.
wileyonlinelibrary.com/journal/ddr
© 2021 Wiley Periodicals, LLC.
1

2
ZERANGNASRABAD ET AL.
recently, oxyprenylated compounds were regarded as biosynthetic
intermediates of C-prenylated coumarins. Thus, scant attention has
been paid to the biological activities of prenyloxycoumarins, which
were either isolated or synthesized. Maleki et al. analyzed the
structure–activity relationship (SAR) study of 18 O-prenylated couma-
rin derivatives. They revealed they were not toxic in normal cells, and
oxyprenylation in position 6 of the coumarin ring largely inhibited
HeLa cell (cervical cancer) growth (Maleki et al., 2020). Geovese and
coworkers introduced oxyprenylated coumarins with electron-
withdrawing groups as whitening agents in melanogenesis (Genovese
et al., 2019). They reported that 7-geranyloxycoumarin exerted
remarkable effects in various inflammatory diseases associated with
the activation of the acquired immune system, such as asthma and
multiple sclerosis (Askari et al., 2020). Also, recent studies have dem-
onstrated that prenyloxycoumarins are potent inhibitors of different
types of LOX isoenzymes (Fiorito et al., 2018; Iranshahi et al., 2012;
Jabbari et al., 2017; Kavetsou et al., 2017; Kavetsou et al., 2020).
In recent years, a growing number of studies have explored a vari-
ety of 3-acetyl coumarin scaffolds, which are completely synthesized
through the Knoevenagel condensation of 2-hydroxybenzaldehyde
derivatives with ethyl acetoacetate. Some of the 3-acetyl coumarin
derivatives have been recognized to possess plentiful remedial func-
tions, including cytotoxic activity (Molaverdi et al., 2013), the inhibi-
tion of human monoamine oxidase enzymes
A and B (Secci
et al., 2011), antibacterial properties, radical scavenging effects, and
antiretroviral activity against HIV-1 infection (Srivastav et al., 2018).
SCHEME 1 General procedure for the synthesis of O-prenylated-3-acetylcoumarins

ZERANGNASRABAD ET AL.
3
TABLE 1 Inhibitory assessment data of O-prenylated-
3-acetylcoumarins in comparison with 4-MMPB against soybean
15-lipoxygenase. The data are shown as SD
In this project, in line with our previous studies on O-prenylated
coumarin and O-prenylated 3-carboxycoumarin derivatives, which
were highly effective 15-LOX inhibitors (Iranshahi et al., 2012; Jabbari
et al., 2017), we give an introduction of the synthesis, structural char-
acterization and, in vitro inhibitory potency of 15-soybean
lipoxygenase, along with SAR studies on new derivatives of oxy-
prenylated coumarins. This research aimed to design and synthesis of
new O-prenylated-3-acetylcoumarin analogs to investigate the role of
acetyl groups in the soybean LOX inhibitory activity of prenyloxy
coumarins.
Compound
10a
IC50
Compound
13b
IC50
<100
1.46 0.02
0.8 0.1
2.1 0.1
3.1 0.1
5.8 0.2
18 0.8
10b
34.16 0.2
<100
10b0
11a
11b0
11b
13.5 0.2
3.3 0.18
0.68 0.2
4.1 0.2
12b0
12a
13b0
12b
4-MMPB
13a
Abbreviation: 4-MMPB, 4-methyl-2-(4-methylpiperazinyl)pyrimido[4,5-b]
benzothiazine.
2
|
RESULTS AND DISCUSSION
The synthesis of novel O-prenylated-3-acetylcoumarin derivatives is
depicted in Scheme 1. All eight analogs including geranyloxy and
farnesyloxy moiety at positions 5, 6, 7, and 8 of 3-acetyl coumarin
(10a-b, 11a-b, 12a-b, and 13a-b) were synthesized through the
prenylation of desired 3-acetyl hydroxycoumarin compounds (5, 6, 7,
and 9) with prenyl bromide and sodium hydride as a base in dry DMF
(Jabbari et al., 2017). All O-prenylated-3-acetylcoumarins were puri-
fied by column chromatography and were also structurally determined
by 1H and 13C NMR spectroscopy. Compounds 5, 6, as well as 7, were
prepared by Knoevenagel reaction of dihydroxybenzaldehyde (1, 2,
and 3) with ethyl acetoacetate (KhanYusufzai et al., 2017), while
8-hydroxy-3-acetyl coumarin (9) was obtained from Knoevenagel con-
densation of 2-hydroxy- 3-methoxy benzaldehyde (4) with ethyl
acetoacetate. It was then followed by the demethylation of the
resulted methoxy-3-acetyl coumarins (8) via refluxing with anhydrous
aluminum chloride in dry toluene (Kalaiarasi et al., 2018) (Scheme 1).
The inhibitory potency of synthetic compounds toward soybean
15-lipoxygenase (SLO) was measured using the rectified catalytic oxi-
dative coupling of 3-methyl-2-benzothiazolinone (MBTH) with
3-(dimethylamino)benzoic acid (DMAB), just as announced in an initial
survey.(Jabbari et al., 2012). In this procedure, the 15-SLO enzyme
assay is conducted to determine fatty acid peroxide concentration.
The analyses were performed in the presence of a widely known
lipoxygenase inhibitor, 4-methyl-2-(4-methylpiperazinyl)pyrimido
[4,5-b]benzothiazine (4-MMPB; CAS 928853-86-5) as the standard.
According to our previous studies, given the shallow inhibitory
potential of allyloxy and isopentenyloxy chain in coumarins (Iranshahi
et al., 2012) and coumarin-3-carboxylic acid (Jabbari et al., 2017), in
this project, only O-geranyl and O-farnesyl of 3-acetylcoumarin were
synthesized and studied. Prenylated-3-acetylcoumarins in positions
7, 8 of aromatic ring demonstrated the best inhibitory activity at IC50
value less than 5 μM compared with 4-MMPB (IC50 = 18.00 μM) as a
standard (Table 1). Among the prepared coumarins, farnesyloxy series
exhibited the best inhibitory activity toward soybean15-lipoxygenase
while compounds (10a and 11a) were inactive (Table 1). As shown by
data, 7-farnesyloxy analog (12b) was a potent inhibitor by an IC50
value of 0.68 μM. Compound 10b was a low active inhibitor by an
IC50 value of 34.16 μM among the farnesyloxy derivatives. The most
active LOX inhibitor among O-geranylated series was compound 12a
with IC50 3.3 μM. The result suggested that the soybean LOX inhibi-
tory activity was improved by increasing the prenyl chain. It is remark-
ably enhanced in O-prenylated-3-acetyl coumarins from geranyl to
farnesyl moiety on positions 5 and 6, while in other positions (7, 8), its
effect was less significant (five- and three-fold increase, respectively).
To obtain a profound understanding of the structural parameters
responsible for desired coumarins' inhibitory potency, docking studies
of these molecules into the active site of 15-soybean lipoxygenase
(PDB Code: 1IK3) were performed. To do so, AutoDockTools (ADT)
software was used to analyze 100 conformers of the compounds gen-
erated. In docking, rotatability of the flexible side chain of the active
site pocket remains was authorized (Leu277, Leu515, Leu557,
Leu560, Leu565, Val566, Ile572, Phe576, Leu773, and Ile857). Also,
the Fe core was modified to FeIII–OH based on our previous study
(Iranshahi et al., 2012). The docking analysis showed versatile interac-
tions between these molecules and nonpolar and polar amino acids.
Analysis of the proposed binding of the best inhibitor 12b (Figure 1)
within the active site revealed that the farnesyloxy chain was sur-
rounded by Leu277, Lys278, Leu515, His518, Trp519, His523, Ile557,
Leu560, Leu565, Val566, Leu773, and Ile857. At the same time cou-
marin scaffold was shielded by side chains of Val 372, Ser510,
His513, Gln514, His 518, Thr575, Phe576, Gln716, Thr717, Gly720,
Gln721, Arg726, Thr728, Asp766, Val769, Ile770, Phe848, and
Arg849. Among these amino acids, Ser510, Gly720, Gln721, Arg726,
and Thr728 provided a suitable hydrophilic pocket for the acetyl func-
tional group. Eleven residues from cited amino acids, including Ile557,
Leu560, Leu565, Val566, Ile572, Leu773, Ile857, His513, Gln514,
Gln716, and Asp766 were highly conserved (Sadeghian et al., 2009).
The docking results with compound 12b exhibited π-π interaction
between Phe576 and the aromatic ring of coumarin.
It also was observed that the carbonyl group in the pyranone ring
and acetyl group were able to make a hydrogen bond with the side
chain of His513 and Ser510 amino acids residue, respectively. A
strong relationship was detected between binding energies and the
inhibitory activities of compounds, 12b and 10a and 11a
(ΔGbinding = −11.7 and −10.05 and −9.41 kcal/mol), which were the
most and least active inhibitors, respectively. By considering the

4
ZERANGNASRABAD ET AL.
FIGURE 1 (a) Stick and solvent
surface view of the 15-soybean
15-lipoxygenase (SLO) (PDB code:
1IK3) active site residues interactions
with the conformer with the least Ki
of 12b. (b) The docking pose of the
conformer with the least Ki of 12b in
active site pocket of 15-SLO. (c) 2D
representation of the interaction of
conformer with the least Ki of
compound 12b in 15-soybean
15-lipoxygenase (SLO)
docked conformers of synthetic compounds it was found that the
lipoxygenase inhibition potency and prenyl length chain were directly
related due to the ability of the more extended prenyl moiety (farne-
syl) of prenyloxy-3-acetylcoumarins to occupy the lipophilic cavity,
which is created by Leu277, Leu515, Trp519, Ile557, Leu560, Leu565,
Val566, Ile572, Leu773, and Ile857.
HIS513 and SER510) and prenyl moiety of the docked conformers of
7-farnesyloxy-3-acetylcoumarins (12b) and 7-farnesyloxycoumarins
(12b0) were not identical. The hydrophobic cavity was filled entirely
by the farnesyl chain of 12b. Hence, it was the more desirable inhibi-
tor. Generally, the significant parameter of the inhibitor bonding pro-
pensity to SLO is the hydrophobic nature of the active site pocket,
which is formed by the lipophilic side-chain of Leu277, Leu515,
Trp519, Ile557, Leu560, Leu565, Val566, Ile572, Leu773, and Ile857.
It can contribute to a lead for designing brand-new inhibitors. Despite
the same remarkable inhibitory constant for 12b and 10b0
(IC50 = 0.68 μM), 7-O-farnesyl-3-acetylcoumarin seems to be a better
candidate for further development and studies. The synthesis proce-
dure of these analogs was more convenient than that of 5-O-
farnesylcoumarin (10b0). Several studies have led to synthesizing
brand-new coumarins' derivatives to disclose desirable functional
groups at various positions (from C-3 to C-8) of coumarin nucleus to
come by a higher biological activity. The analysis of related SAR stud-
ies revealed that a coumarin ring bearing a polar substitution ( OR,
OH, NH) at position 7 further improved the biological activity.
Regarding the results of this research and our previous study
(Iranshahi et al., 2012), it could be concluded that the acetyl as a mild
electron-withdrawing group at position 3, led to positive effect on
To examine the effect of acetyl functional group on inhibitory
activity, a comparison was made between the lipoxygenase inhibition
of synthetic compounds and analogs without acetyl substituents. For
this aim, soybean 15-LOX inhibitory potency of all farnesyloxy deriva-
tives at position 5-, 6-, 7-, and 8-coumarin (10b0, 11b0, 12b0, and 13b0,
respectively), reported in our previous study (Iranshahi et al., 2012)
were compared to the O-farnesyl derivatives of 3-acetylcoumarins
(10a-b, 11a-b, 12a-b, 13a-b) (Figure 2). It was worth noting that 12b
and 13b with the farnesyloxy moiety at positions 7 and 8 demon-
strated
a
higher lipoxygenase inhibitory activity than the
corresponding analogs with no acetyl group (4.5–1.4 folds higher,
respectively). However, 10a and 11a inhibitors were 43–7 times wea-
ker than similar coumarin derivatives, respectively. The preferred
docking pose of 12b and 12b'in soybean 15-LOX was shown in
Figure 3. The superimposition of two compounds demonstrated that
the status of coumarin scaffold (due to two hydrogen bond with

ZERANGNASRABAD ET AL.
5
FIGURE 2 Structure of compounds 10b0, 11b0, 12b0, and 13b0
coumarin nucleus with His513, and SER510 as well as hydrophobic-
hydrophobic interaction of prenyl chain with the lipophilic side chain
of amino acids in the active site.
4
|
MATERIALS AND METHODS
| Structure optimization
4.1
ChemDraw Ultra 12.0 used to sketch the required structures trans-
ported to the HyperChem 8.07 software and geometrical form opti-
mized by classic MM+ (RMS gradient = 0.05 kcal mol−1) to simulating
of the 3D scaffolds. Crystal skeleton of SLO in combination with
13(S) - hydroproxy-9(Z)-2,11(E)-octadecadienoic acid was repossessed
from RCSB Protein Data Bank (PDB entry: 1IK3).
FIGURE 3 Superimposition of conformer with the least Ki of
compounds 12b (orang stick) and 12b0 (green stick) in soybean
15-LOX active site
4.2
|
Molecular docking
The ligand of the SLO 3D structure was eliminated. Then, the Fe was
altered to FeIII-OH, in terms of geometrical form optimized using
MM+ approach in HyperChem12.0 and embedded in pdb format for
docking procedure (Iranshahi et al., 2012). Docking of the minimized
structures into the active site of 1IK3 was carried out using AutoDock
4.2 (Morris et al., 2009). The torsion angles of the ligands were deter-
mined, bond lengths were edited out, hydrogens and solvent parame-
ters were added to the enzyme 3D structure. Partial atomic charges
were then dedicated to the macromolecule and ligands (Gasteiger for
the ligands and Kollman for the protein). The docking areas of the
enzyme were determined by supposing a Cartesian chart 18.3, 4.8,
and 19.2 as the center of a grid size with 44, 56, and 62 points in X, Y,
and Z axes. The docking parameter files were generated utilizing
Lamarckian genetic algorithm Parameters while the number of genera-
tions and the maximum number of energy assessments was set to
100 and 2,500,000, successively. The 100 docked complexes were
clustered with a root-mean-square deviation tolerance of 2.5 Å.
15-LOX inhibitory activity of O-prenyl chain as polar moiety at posi-
tions 7, and 8 rather than 5,6 positions.
3
|
CONCLUSION
In conclusion, new geranyloxy and farnesyloxy derivatives in all posi-
tions of the aromatic ring of 3-acetylcoumarin were synthesized, char-
acterized, and assessed in vitro as soybean 15-LOX inhibitors. Among
eight newly synthesized coumarins, 12a, 12b, 13a, and 13b showed
excellent inhibitory activities against 15-LOX and were more potent
than 4-MMPB as the standard (IC50 = 18.00 μM). In this work,
3-acetylcoumarin with farnesyloxy chain at position 7 was found to
be the best inhibitor (IC50 = 0.68 μM). According to the SAR, the
inhibitory activity of 12b is possibly due to the H-bond interaction of

6
ZERANGNASRABAD ET AL.
Docking outcomes were submitted to Accelrys Discovery Studio v4.5
for further simulation.
5.1.2
|
3-Acetyl-5-hydroxy-2H-chromen-2-one (5)
Yellow solid, yield 45%, m.p. 238–240ꢀC; IR (KBr disc) ν 3484, 3178,
3080, 3047, 2920, 2735, 1735, 1640 cm−1; MS (m/z) 204 (M+), 187,
161; Anal. calcd for C11H8O4: C 64.71, H 3.95, found: C 64.02,
H 4.00%.
4.3
|
Lipoxygenase inhibitory assessment
Linoleic acid and two assay solutions (A and B) were arranged before-
hand. Solution A was 50 mM DMAB in an l00 mM phosphate buffer
(pH 7.0). Solution B was a mixture of 10 mM MBTH (3 ml), hemoglo-
bin (5 mg/ml, 3 ml) in 50 mM phosphate buffer at pH 5.0 (25 ml). A
linoleic acid solution was arranged using mixing 5.6 mg of linoleic acid
(Sigma Aldrich, L1376) with 0.5 ml methanol and then diluted with
KOH 100 mM to a final volume 5 ml (4 mM). In the standard assay,
the sample in ethanol (25 μl), SLO (4000 units/ml in 50 mM phos-
phate buffer pH 7.0; 25 μl) and phosphate buffer pH 7.0 (50 mM;
900 μl) were mixed in a test tube, and preincubation was done for
5 min at ambient temperature. A control test was carried out by an
equal volume of ethanol. After the preincubation, linoleic acid solution
(50 μl) was added to start the peroxidation reaction at 30ꢀC, and,
7 min later, solution A (270 μl) and afterward solution B (130 μl) was
added to commence the color formation. Moreover, in 3 min then
200 μl of a 2% SDS solution was added to conclude the reaction. The
absorbance at 598 nm was compared with the control test. These
experiments were carried out in triplicate. The data evaluation was
accomplished utilizing GraphPad Prism 5.01.
5.1.3
|
3-Acetyl-6-hydroxy-2H-chromen-2-one (6)
Green crystals, yield 65%, m.p. 246–249ꢀC; Lit: 247–248ꢀC
(Martínez-Martínez et al., 2012); IR (KBr disc) ν 3468.79,3168, 3063,
3047, 2945, 2735, 1740, 1644, 1567, 1119 cm−1
204 (M+).
; MS (m/z)
5.1.4
|
3-Acetyl-7-hydroxy-2H-chromen-2-one (7)
White crystals, yield 65%, m.p. 226–228ꢀC; Lit: 236–238ꢀC (Durgapal
et al., 2020); IR (KBr disc) ν 3490, 3065, 2982, 2929, 1716, 1662,
1603, 1451, 1049 cm−1; MS (m/z) 204 (M+).
5.2
|
General procedure for preparation of
3-acetyl-8-hydroxycoumarin (9)
3-Methoxysalicylaldehyde (4) (3 mmol; 0.45 g), ethyl acetoacetate
(4.0 mmol, 0.5 ml), acetic acid (2 drops), piperidine (5 drops) and etha-
nol (8 ml) were refluxed. After 4 h, the reaction mixture was cooled,
and the crude precipitate was formed by adding water. The produced
methoxy-3-acetylcoumarin (8) was recrystallized by ethanol and after
drying, used for the next step.
5
|
EXPERIMENTAL SECTION
| Instruments
5.1
The IR spectra were acquired by a 4300 Shimadzu Spectrometer. 1H
NMR (300 MHz) was acquired by a Bruker Avance DRX-300 Fourier
transformer spectrometer. Chemical shifts are stated in parts per mil-
lion (δ) downfield from tetramethylsilane. The mass spectra were
recorded on a Varian Mat CH-7 instrument at 70 eV. Elemental analy-
sis was performed on a Thermo Finnigan Flash EA microanalyzer. Per-
formance of lipoxygenase was analyzed utilizing BioTek Synergy HTX
Multi-Mode reader. Chemicals were bought from Aldrich and
Merck Co.
5.2.1
|
3-Acetyl-8-methoxy-2H-chromen-2-one (8)
Orange crystals, yield 60%, m.p. 143–144ꢀC; IR (KBr disc) ν 3076,
3015, 2941, 1734, 1685, 1601, 1092 cm−1; MS (m/z) 218 (M+), 175
(M-COMe).
A mixture of 8-methoxy-3-acetylcoumarin (8) (0.3 mmol, 0.07 g)
and AlCl3 (0.9 mmol, 0.12 g) were suspended in dry toluene (25 ml)
and refluxed for 24 h. The precipitate was poured into HCl (10%) solu-
tion and extracted with chloroform. After washing with water,
8-methoxy-3-acetylcoumarin (9) was prepared with good purity and
yield in brick color (Kalaiarasi et al., 2018).
5.1.1
|
General procedure for preparation of
3-acetylhydroxycoumarins (5), (6), and (7)
Desired hydroxysalicylaldehyde (2,6-dihydroxybenzaldehyde (1),
2,5-dihydroxybenzaldehyde (2), and 2,4-dihydroxybenzaldehyde (3))
(3 mmol, 0.411 g), ethyl acetoacetate (4.0 mmol, 0.5 ml), acetic acid
(2 drops), piperidine (5 drops) and ethanol (8 ml) were refluxed for 4 h.
After the reaction was finished (control with TLC), the solvent volume
reduced, and the crude products were crystallized by ethanol
(Martínez-Martínez et al., 2012).
5.2.2
|
3-Acetyl-8-hydroxy-2H-chromen-2-one (9)
Brick crystals, yield 50%, m.p. 249–251ꢀC; Lit: 253ꢀC (la Pietra
et al., 2012) IR (KBr disc):
1600 cm−1; MS (m/z) 204 (M+).
ν 3227, 3039, 2921, 1696, 1679,

ZERANGNASRABAD ET AL.
7
5.3
|
General procedure for preparation of
157.7, 159.4, 195.8, 164.6, 195.6 ppm; IR (KBr): 2962, 2925–2851,
1735, 1617, 1200 cm−1; MS (m/z) 408 (M+), 203, 187; Anal. calcd for
prenyloxy-3-acetylcoumarins (10a-b, 11a-b, and 12a-b,
13a-b)
C26H32O4: C 76.44, H 7.90, found: C 76.78, H 7.98%.
To cold desired 3-acetyl hydroxycoumarins (compounds: 5, 6, 7, 9)
(0.9 mmol, 0.20 g) in dry dimethylformamide (4 ml), sodium hydride
(2 mmol, 0.064 g) was added, stirred for 30 minutes. Then prenyl bro-
mide (1.0 mmol) was added slowly to the reaction mixture at 50ꢀC.
After controlling the reaction completion using TLC within 5–10 h,
the reaction mixture was poured into cold hydrochloric acid (10%).
The resulting extracted with chloroform three times (3 × 10 ml) then
the solution of sodium hydroxide (2 × 5) was utilized for washing up
the organic layer to remove unreacted hydroxycomarin derivatives.
Finally, organic layer was dried over anhydrous Na2SO4 and concen-
trated in vacuo. The remains were purified by silica-gel thin-layer
chromatography (EtOAc/n-hexane 1:20).
5.3.3
|
3-Acetyl-6-((E)-3,7-dimethylocta-
2,6-dienyloxy)-2H-chromen-2-one (11a)
Green crystals, yield 55%; m.p. 86–87ꢀC; 1H NMR (300 MHz, CDCl3):
δ = 1.53 (s, 3H, CH3 (geranyl)), 1.59 (s, 3H, CH3 (geranyl]), 1.69 (s, 3H,
CH3 (geranyl)), 2.00–2.10 (m, 4H, 2-CH2 (geranyl)), 2.66 (s, 3H,
H(Acetyl)), 4.51 (d, J = 6.3 Hz, 2H, -OCH2 (geranyl)), 4.99–5.01 (m,
1H, =CH (geranyl)), 5.38–5.42 (t, J = 6.42 Hz, 1H, =CH (geranyl)), 6.97
(d, J = 2.64 Hz, 1H, H-5 (coumarin)), 7.16 (d, J = 2.67 Hz, 1H, H-7
(coumarin)), 7.25 (d, J = 9.09 Hz, 1H, H-8 (coumarin)), 8.38 (s, 1H, H-4
(coumarin)); 13C NMR (75 MHz, CDCl3): δ = 16.7, 17.7, 25.7, 26.2,
30.7, 39.5, 65.6, 112.2, 119.9, 123.6, 124.5, 132, 142.2, 147.4, 159.4,
168.6, 195.7 ppm; IR (KBr): 3076, 2958, 1736, 1685, 1614,
1187 cm−1; MS (m/z) 340 (M+), 203, 187, 160; Anal. calcd for
5.3.1
|
3-Acetyl-5-((E)-3,7-dimethylocta-
2,6-dienyloxy)-2H-chromen-2-one (10a)
C21H24O4: C 74.09, H 7.11, found: C 74.02, H 6.94%.
Yellow amorphous solid, 47% yield; m.p.: 43–45ꢀC; 1H NMR
(300 MHz, CDCl3): δ = 1.64 (s, 3H, CH3 (geranyl)), 1.70 (s, 3H, CH3
(geranyl)), 1.79 (s, 3H CH3 (geranyl)), 2.15-2.20 (m, 2-CH2 (geranyl)),
2.63 (s, 3H, H(Acetyl)), 4.73 (d, J = 6.3 Hz, 2H, -OCH2 (geranyl)), 5.08–
5.11 (m, 1H, =CH (geranyl)), 5.52–5.55 (t, J = 6 Hz, 1H, =CH (geranyl)),
6.85 (d, J = 8.1 Hz, 1H, H-8 (coumarin)), 7.03 (d, J = 8.1 Hz, 1H, H-6
(coumarin)), 7.65–7.70 (t, J = 8.1 Hz, 1H, H-7 (coumarin)), 9.36 (s, 1H,
H-4 (coumarin)); 13C NMR (75 MHz, CDCl3): δ = 16, 16.8, 17.7, 25.7,
26., 26.6, 39.5, 65.8, 100.9, 111.9, 114.4, 117.9, 120.4, 123.3, 131.3,
135.6, 142.9, 147.8, 157.7, 159.8, 164.6, 195.5 ppm; IR (KBr): 3060,
2966, 1759, 1679, 1606 cm−1; MS (m/z) 340 (M+), 203, 187, 160;
Anal. calcd for C21H24O4: C 74.09, H 7.11, found: C 73.02, H 7.14%.
5.3.4
|
3-Acetyl-6-(((2E,6E)-
3,7,11-trimethyldodeca-2,6,10-trienyloxy)-2H-
chromen-2-one (11b)
Green crystals, yield 50%; m.p. 72–74ꢀC; 1H NMR (300 MHz, CDCl3):
δ = 1.63 (s, 6H, CH3 (farnesyl)), 1.71 (s, 3H, CH3 (farnesyl)), 1.80
(s, 3H CH3 (farnesyl)), 1.99–2.15 (m, 8H, 4-CH2 (farnesyl)), 2.76
(s, 3H, H(Acetyl)), 4.61 (d, J = 6.51 Hz, 2H, -OCH2 (farnesyl)), 5.08–
5.13 (m, 2H, =CH (farnesyl)), 5.48–5.52 (t, J = 6.39 Hz, 1H, =CH
(farnesyl)), 7.08 (d,
J = 2.67 Hz, 1H, H-5 (coumarin)), 7.26 (d,
J = 2.73 Hz, 1H, H-7 (coumarin)), 7.34 (d, J = 10.98 Hz, 1H, H-8 (cou-
marin)), 8.48 (s, 1H, H-4 (coumarin)); 13C NMR (75 MHz, CDCl3):
δ = 16, 16.7, 17.6, 25.6, 26.1, 26.7, 30.5, 39.5, 39.6, 65.7, 112.2,
123.5, 123.5, 124.2, 124.6, 131.3, 135.6, 142.2, 147.3, 149.9, 155.6,
159.4, 195.7 ppm; IR (KBr): 2962, 2925–2851, 1735, 1617,
1200 cm−1; MS (m/z) 408 (M+), 203, 187; Anal. calcd for C26H32O4: C
76.44, H 7.90, found: C 76.08, H 7.68%.
5.3.2
|
3-Acetyl-5-(((2E,6E)-
3,7,11-trimethyldodeca-2,6,10-trienyloxy)-2H-
chromen-2-one (10b)
Yellow amorphous solid, yield 40%; m.p. 39–41ꢀC; 1H NMR (300 MHz,
CDCl3): δ = 1.52 (s, 3H, CH3 (farnesyl)), 1.54 (s, 3H, CH3 (farnesyl)),
1.60 (s, 3H CH3 (farnesyl)), 1.70 (s, 3H, CH3 (farnesyl)), 1.89–2.08
(m, 8H, 4-CH2 (farnesyl)), 2.60 (s, 3H, H(Acetyl)), 4.64 (d, J = 6.6 Hz,
2H, -OCH2 (farnesyl)), 4.98–5.03 (m, 2H=CH (farnesyl)), 5.41–5.45 (t,
J = 6.3 Hz, 1H, =CH (farnesyl)), 6.76 (d, J = 8.4 Hz, 1H, H-8 (coumarin)),
6.93 (d, J = 8.4 Hz, 1H, H-6 (coumarin)), 7.55–7.61 (t, J = 8.4 Hz, 1H,
H-7 (coumarin)), 9.26 (s, 1H, H-4 (coumarin)), 2H, -OCH2 (farnesyl)),
5.08–5.13 (m, 2H, =CH (farnesyl)), 5.48–5.52 (t, J = 6.39 Hz, 1H, =CH
(farnesyl)), 7.08 (d, J = 2.67 Hz, 1H, H-5 (coumarin)), 7.26 (d,
J = 2.73 Hz, 1H, H-7 (coumarin)), 7.34 (d, J = 10.98 Hz, 1H, H-8 (cou-
marin)), 9.26 (s, 1H, H-4 (coumarin)); 13C NMR (75 MHz, CDCl3):
δ = 16, 16.8, 17.7, 25.7, 26.1, 26.6, 30.6, 39.5, 39.6, 65.8, 101, 111.9,
114.4, 117.9, 120.4, 123.3, 124.2, 131.3, 131.4, 135.6, 142.9, 147.8,
5.3.5
|
3-Acetyl-7-((E)-3,7-dimethylocta-
2,6-dienyloxy)-2H-chromen-2-one (12a)
Creamy crystals, yield 67%; m.p. 60–64ꢀC; 1H NMR (300 MHz, CDCl3):
δ = 1.62 (s, 3H, CH3 (geranyl)), 1.69 (s, 3H, CH3 (geranyl)), 1.79 (s, 3H
CH3 (geranyl)), 2.00–2.07 (m, 4H, 2-CH2 (geranyl)), 2.73 (s, 3H,
H(Acetyl)), 4.66 (d, J = 6.48 Hz, 2H, -OCH2 (geranyl)), 5.09–5.11 (m, 1H,
=CH (geranyl)), 5.47–5.51 (t, J = 6.21 Hz,1H, =CH (geranyl)), 6.85 (s,
1H, H-8 (coumarin)), 6.9–6.93 (dd, J = 1.89 and 8.64 Hz, 1H, H-6 (cou-
marin)), 7.55 (d, J = 8.67 Hz, 1H, H-5 (coumarin)), 8.52 (s, 1H, H-4 (cou-
marin)); 13C NMR (75 MHz, CDCl3): δ = 16, 16.8, 17.7, 25.7, 26.1, 30.6,
65.8, 101, 117.9, 123.4, 124.2, 131.4, 135.6, 142.9, 147.8, 157.7,

8
ZERANGNASRABAD ET AL.
159.8, 164.6, 195.5 ppm; IR (KBr): 3068, 2965, 2855, 1736, 1670,
ACKNOWLEDGMENTS
1618, 1129 cm−1; MS (m/z) 340 (M+), 340, 203, 187; Anal. calcd for
The authors are grateful to Ferdowsi University of Mashhad for the
financial support of this work. The results described in this article
were part of an MSc student thesis proposal.
C21H24O4: C 74.09, H 7.11, found: C 74.20, H 7.22%.
5.3.6
|
3-Acetyl-7-((2E,6E)-
CONFLICT OF INTEREST
3,7,11-trimethyldodeca-2,6,10-trienyloxy)-2H-
The authors declare no conflict of interest.
chromen-2-one (12b)
DATA AVAILABILITY STATEMENT
Creamy crystals, yield 57%; m.p. 70–72ꢀC; 1H NMR (300 MHz,
CDCl3): δ = 1.52 (s, 6H, CH3 (farnesyl)), 1.59 (s, 3H, CH3 (farnesyl)),
1.7 (s, 3H CH3 (farnesyl)), 1.88–2.05 (m, 8H, 4-CH2 (farnesyl)), 2.63(s,
3H, H (Acetyl)), 4.57 (d, J = 5.88 Hz, 2H, -OCH2 (farnesyl)), 4.99–5.01
(m, 2H, =CH (farnesyl)), 5.39 (t, J = 5.58 Hz, 1H, =CH (farnesyl)), 6.47
(s, 1H, H-8 (coumarin)), 6.80–6.83 (d, J = 8.22 Hz, 1H, H-6 (coumarin)),
6.7–7.54 (d, J = 8.4 Hz,1H H-5 (coumarin)), 8.42 (s, 1H, H-4 (couma-
rin)); 13C NMR (75 MHz, CDCl3): δ 16, 16.8, 17.7, 25.7, 26.1, 26.6,
30.6, 39.5, 39.6, 65.8, 100.9, 118, 120.4, 123.4, 124.2, 131.3, 131.4,
135.6, 142.9, 147.8, 157.7, 159.8, 164.6, 195.5 ppm; IR (KBr): 3071,
2920, 2851, 1735, 1674, 1618, 1130 cm−1; MS (m/z) 408 (M+), 203;
Anal. calcd for C26H32O4: C 76.44, H 7.90, found: C 76.68, H 8.00%.
The data that support the findings of this study are available from the
corresponding author upon reasonable request.
ORCID
Atena Jabbari
https://orcid.org/0000-0002-1623-0172
https://orcid.org/0000-0001-7894-5002
Hamid Sadeghian
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5.3.7
|
3-Acetyl-8-((E)-3,7-dimethylocta-
2,6-dienyloxy)-2H-chromen-2-one (13a)
Orange liquid, yield 58%; 1H NMR (300 MHz, CDCl3): δ = 1.62(s, 3H,
CH3 (geranyl)), 1.69 (s, 3H, CH3 (geranyl)), 1.78 (s, 3H, CH3 (geranyl)),
2.12 (m, 4H, 2-CH2 (geranyl)), 2.75(s, 3H, CH3 (Acetyl)), 4.75 (d,
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124.7, 132, 141.9, 145.4, 158.8, 195.8; IR (CHCl3): 3035, 2966, 2827,
1734, 1681, 1604, 1186 cm−1; MS (m/z) 340 (M+), 203, 187, 160;
Anal. calcd for C21H24O4: C 74.09, H 7.11, found: C 73.50, H 6.67%.
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5.3.8
|
3-Acetyl-8-((2E,6E)-
3,7,11-trimethyldodeca-2,6,10-trien1yloxy)-2H-
Iranshahi, M., Jabbari, A., Orafaie, A., Mehri, R., Zeraatkar, S., Ahmadi, T.,
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chromen-2-one (13b)
Orange liquid, yield 56%; 1H NMR (300 MHz, CDCl3): δ = 1.62 (s, 6H,
2-CH3 (farnesyl)), 1.70 (s, 3H, CH3 (farnesyl)), 1.79 (s, 3H, CH3 (farne-
syl)), 1.96–2.20 (m, 8H, 4-CH2 (farnesyl)), 2.75(s, 3H, CH3(Acetyl)),
4.76 (d, J = 6.4 Hz, 2H, -OCH2 (farnesyl)), 5.08–5.12 (m, 2H, =CH
(farnesyl)), 5.53–5.57 (t, J = 6.3 Hz, 1H, =CH (farnesyl)), 7.18–7.29 (m,
3H, H-7,H-6, H-5 (coumarin)), 8.5 (s, 1H, H-4 (coumarin)); 13C NMR
(100 MHz, CDCl3): δ = 16, 16.8, 17.7, 25.7, 26.1, 26.7, 30.6, 39.5,
39.7, 66.4, 117.8, 121.4, 123.5, 124.3, 124.6, 124.7, 131.3, 135.5,
142, 145.4, 158.8, 195.69 ppm; IR (CHCl3): 3031, 2965, 1737, 1690,
1604, 1184 cm−1; MS (m/z) 408 (M+), 203, 188; Anal. calcd for
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15-lipoxygenase metabolites play an important role in the
C
26H32O4: C 76.44, H 7.90, found: C 76.20, H 7.77%.

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How to cite this article: Zerangnasrabad S, Jabbari A, Khavari
Moghadam E, Sadeghian H, Seyedi SM. Design, synthesis, and
structure–activity relationship study of O-prenylated 3-
acetylcoumarins as potent inhibitors of soybean 15-
lipoxygenase. Drug Dev Res. 2021;1–9. https://doi.org/10.
1002/ddr.21787