Synthesis and antimicrobial activity of new prenylated 2-pyrone derivatives

Article abstract of DOI:10.1080/00397911.2020.1718710

A series of new monoprenylated and diprenylated 2-pyrone derivatives with different halogen substituents were synthesized from the corresponding 6-aryl-4-hydroxy-2-pyrones by prenylation reactions. The compounds were evaluated for antibacterial activity and displayed significant in vitro activity with the highest activity shown by the monoprenylated 6-aryl-2-pyrones. All the compounds except the bromine-containing analogs were active against one or more tested bacteria, with Escherichia coli being the most susceptible of the test organisms. With the remarkable antibacterial activity of eight of the compounds against a drug-resistant β-lactamase-producing Klebsiella pneumoniae, a synergistic evaluation between each of these compounds and ampicillin was undertaken. Out of the eight combinations studied, synergistic effects were observed with two compounds, 4-(3-methylbut-2-enoxy)-6-phenyl-2H-pyran-2-one and 6-(4-fluorophenyl)-4-(3-methylbut-2-enoxy)-2H-pyran-2-one. Both compounds, at half the individual MIC values, were able to lower the MIC of ampicillin in combinations from 2500 to 2.4 μg/mL (1/1041 of MIC).

Full text of DOI:10.1080/00397911.2020.1718710

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis and antimicrobial activity of new
prenylated 2-pyrone derivatives
Grace Obi, Jude C. Chukwujekwu & Fanie R. van Heerden
To cite this article: Grace Obi, Jude C. Chukwujekwu & Fanie R. van Heerden (2020): Synthesis
and antimicrobial activity of new prenylated 2-pyrone derivatives, Synthetic Communications, DOI:
10.1080/00397911.2020.1718710
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https://doi.org/10.1080/00397911.2020.1718710
Synthesis and antimicrobial activity of new prenylated
2-pyrone derivatives
Grace Obi, Jude C. Chukwujekwu, and Fanie R. van Heerden
School of Chemistry and Physics, University of KwaZulu-Natal, Scottsville, Pietermaritzburg, South Africa
ABSTRACT
ARTICLE HISTORY
Received 25 October 2019
A series of new monoprenylated and diprenylated 2-pyrone deriva-
tives with different halogen substituents were synthesized from the
corresponding 6-aryl-4-hydroxy-2-pyrones by prenylation reactions.
The compounds were evaluated for antibacterial activity and dis-
played significant in vitro activity with the highest activity shown by
the monoprenylated 6-aryl-2-pyrones. All the compounds except the
bromine-containing analogs were active against one or more tested
bacteria, with Escherichia coli being the most susceptible of the test
organisms. With the remarkable antibacterial activity of eight of the
compounds against a drug-resistant b-lactamase-producing Klebsiella
pneumoniae, a synergistic evaluation between each of these com-
pounds and ampicillin was undertaken. Out of the eight combina-
tions studied, synergistic effects were observed with two
compounds, 4-(3-methylbut-2-enoxy)-6-phenyl-2H-pyran-2-one and
KEYWORDS
Antibacterial activity;
halogenated aromatics;
prenylated pyrone;
2-pyrone
6-(4-fluorophenyl)-4-(3-methylbut-2-enoxy)-2H-pyran-2-one.
Both
compounds, at half the individual MIC values, were able to lower the
MIC of ampicillin in combinations from 2500 to 2.4 mg/mL (1/
1041 of MIC).
GRAPHICAL ABSTRACT
Introduction
Over the years, great strides have been made to combat bacterial infections, and new
antibiotics were developed from different sources. Notwithstanding all the efforts and
achievements, bacterial infections still constitute a threat to public health, mainly due to
the continuous development and spread of multidrug-resistant bacteria. Drug resistance
continues to hamper the effectiveness of available antibiotics and thereby exacerbating
the burden of bacterial infections.[1,2] Furthermore, first-line drugs show no effects on
CONTACT Fanie R. van Heerden
vanheerdenf@ukzn.ac.za
School of Chemistry and Physics, University of
KwaZulu-Natal, Private Bag X01, Scottsville, Pietermaritzburg, 3209, South Africa.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

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G. OBI ET AL.
Scheme 1. Synthetic route to prenylated 2-pyrones 3a–3j and 4a–4j.
methicillin-resistant Staphylococcus aureus and in most cases, second-line drugs are
administered that are more expensive and have side effects. Therefore, there is an
urgent need to overcome these challenges by discovering new antibiotic drugs that are
safe and inexpensive to combat antibacterial drug resistance.
The 2-pyrone moiety is present in many naturally occurring and synthetic com-
pounds that display important medicinal and biological activities.[3–6] Some of these
compounds are shown to have anti-HIV, antimycobacterial, anticancer, antimicrobial,
antifungal, and antityrosinase activities.[7] The biological activity of 2-pyrone deriva-
tives has been extensively reviewed by Bhat et al.[7] In addition, the 2-pyrone moiety
has also been recognized to interact with proteins in various biological systems,[7,8]
and is also an active building block for the synthesis of complex heterocycles.[9,10]
The prenyl group is a unique structural moiety present in many naturally occurring
compounds with latent benefits to human health.[11–13] Prenyl may refer to several types
of chains such as 3,3-dimethylallyl, geranyl (E-3,7-dimethyl-2,6-octadienyl), and 1,1-
dimethylallyl substituents, but most commonly refers to the 3,3-dimethylallyl
group.[11,14] This motif is reported to be a versatile tool for modulating different types
of biological activities by enhancing the affinity to cell membranes and thus interacting
with targeted proteins.[15] Prenylated aromatic natural products display a wide range of
bioactivities.[14] The addition of a prenyl chain to aromatic secondary metabolites has
been shown to enhance the physicochemical properties of the parent compound such as
lipophilicity and increase hydrophobicity thereby resulting in increased antibacterial
activity.[13,16–19] Consequently, prenylated compounds have improved membrane parti-
tioning and interact better with the targeted sites compared to non-prenylated counter-
parts.[12,20] The parent structures can be O-prenylated where the prenyl group is
incorporated on an oxygen atom or C-prenylated where the prenyl group is attached to
a carbon atom.
The biological significance of the 2-pyrone moiety and interesting activities of preny-
lated compounds prompted us to combine these structural moieties to synthesize a

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3
Scheme 2. Proposed mechanism for the synthesis of prenylated 2-pyrones.
series of prenylated (3,3-dimethylallylated) 2-pyrone derivatives and screen the com-
pounds for in vitro antibacterial activity.
Results and discussion
Ten monoprenylated and ten diprenylated 2-arylpyrones, which include eight halo-
genated and one unsubstituted methyl derivative, were synthesized according to a
four-step reaction sequence as shown in Scheme 1. The final compounds were
obtained by prenylation of 2a-2j with prenyl bromide and potassium carbonate in
DMF. In these reactions, both monoprenylation (O-prenylation) and diprenylation
(O-prenylation and C-prenylation on C-3) were observed. The series of 2-pyrones
includes 6-aryl substituents with a fluorine atom on the ortho-, meta-, or para-posi-
tions (3b–3d and 4b–4d), two fluorine atoms on the 3- and 4-positions (3e and 4e),
a bromine atom on the 3-position (3f and 4f), a chlorine atom on the ortho- or
meta-position (3g–3h and 4g–4h), an iodine on the ortho-position (3i and 4i) or a
methyl group on the ortho position (3j and 4j). Compounds 3a–3j, the major prod-
ucts of these reactions, were obtained in yields between 64 and 74%, with the minor
products 4a–4j in 22–30% yield.
The proposed mechanism for the synthesis of monoprenylated (3) and diprenylated
(4) is an SN2 reaction.
In this reaction, there is a competition between O-prenylation and C-prenylation.
According to Le Noble,[21] an aprotic polar solvent (acetone) and a large counterion
(potassium) favor O-prenylation. Therefore, it is suggested that the O-prenylation reac-
tion occurs first, followed by a C-prenylation. The hydroxy proton of compound 2 is
removed by the strong base, resulting in a nucleophile (unstable anionic intermediate),
which then attacks the carbon of the prenyl bromide to give 3. Delocalization of lone
pairs of electrons on the oxygen atom of the prenyl chain of 3 resulted in an

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G. OBI ET AL.
Table 1. Antibacterial activity of monoprenylated 2-pyrones.
Antibacterial activity (MIC, mg/mL)
Gram –ve
Gram þ ve
Sa
0.78
15.63
31.25
31.25
15.63
>250.00
7.80
Drug-resistant Gram –ve
Compounds
Ec
0.05
1.56
3.90
1.56
1.56
Pa
1.56
Kp
3a
3b
3c
3d
3e
3f
3g
1.56
31.25
62.50
31.25
31.25
>250.00
15.63
7.80
62.50
31.25
31.25
15.63
>250.00
3.90
>250.00
3.90
3h
3i
3j
3.90
0.39
15.63
3.90
15.63
0.12
0.20
1.56
0.98
6.25
15.63
0.98
31.25
31.25
0.24
Neomycin
MIC: minimum inhibitory concentration; Sa: Staphylococcus aureus; Ec: Escherichia coli; Pa: Pseudomonas aeruginosa; Kp:
Klebsiella pneumoniae.
electrophilic aromatic substitution by the attack on the excess prenyl bromide to form
the diprenylated pyrone 4, as shown in Scheme 2. Further evidence for the proposed
mechanism is the fact that mono-O-prenylated compounds were isolated, but no mono-
C-prenylated analogs could be detected.
Nuclear magnetic resonance (NMR), IR and mass spectrometry were the key techniques
used to confirm the structure of the products of the prenylation reactions. The chemical
shifts and splitting patterns of the aryl ring of 3 and 4 are similar to those of compound
1
2.[22] In the H NMR spectrum of 3a–3j, the two protons on the pyrone ring resonated as
doublets at dH 5.39–5.54 and dH 6.28–6.85, with coupling constants of 1.9–2.1 Hz.
Compounds 3a–3j and 4a–4j showed two upfield methyl singlets of the cis-allylic methyl
protons at dH 1.73–1.75 and the trans-allylic methyl protons at dH 1.79–1.82. The doublet
signals, assigned to two allylic protons of the O-prenyl chains, appeared at dH 4.55
(J ¼ 6.9 Hz) for 3a–3j and at dH 4.64– 4.69 (J ¼ 6.7 Hz) for 4a–4j. The vinylic protons signals
of the O-prenyl chain of 3a–3j and 4a–4j appeared as multiplets at dH 5.41–5.47 and dH
5.39–5.45, respectively. The C-prenyl chains of 4a–4j have two upfield methyl singlets at dH
1.67–1.70 and dH 1.75–1.78 corresponding to the cis-allylic methyl protons and trans-allylic
protons, respectively, of the C-prenyl chains. Doublet integrating for two protons appeared
at dH 3.17–3.19 (J ¼ 7.3 Hz) for the methylene protons of the C-prenyl chains of 4a–4j. A
vinyl proton resonance for the C-prenyl chain was observed as multiplets at dH 5.18–5.28.
The replacement of the hydrogen on the 2-pyrone ring of 4 with a prenyl group was con-
firmed by the presence of only one vinyl proton at dH 6.27–6.74 as a singlet. In addition, the
13C NMR spectra and high-resolution mass data further confirmed the structures and all
data are reported in the experimental section.
The results of the antibacterial activity of the mono- and diprenylated 2-pyrone ana-
logs are presented in Tables 1 and 2. All the compounds, except 3f and 4f, were active
against one or more test organisms. Escherichia coli, a Gram-negative bacteria, was the
most susceptible of all the test organisms. It was susceptible to all the compounds,
except 3f and 4f. Compound 3a was the most active of all the prenylated 2-pyrones
with an MIC range of 1.56–0.049 mg/mL. It exhibited a broad spectrum activity (active
against all the test organisms). More important, it was also active against the drug-
resistant b-lactamase-producing Klebsiella pneumoniae at an MIC value of 1.56 mg/mL.

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Table 2. Antibacterial activity of diprenylated 2-pyrones.
Antibacterial activity (MIC, mg/mL)
Gram –ve
Gram þ ve
Drug-resistant Gram –ve
Compounds
Sa
Ec
0.195
0.39
0.39
Pa
7.80
7.80
7.80
Kp
4a
4b
3.90
7.80
7.80
7.80
7.80
7.80
4c
4d
7.80
0.78
7.80
7.80
4e
4f
4g
15.63
>250.00
7.80
0.78
>250.00
0.39
7.80
>250.00
7.80
15.63
>250.00
7.80
4h
4i
4j
7.80
0.39
1.56
1.56
0.98
3.90
7.80
15.63
15.63
0.12
15.63
15.63
0.98
31.25
62.50
0.24
Neomycin
MIC: minimum inhibitory concentration; Sa: Staphylococcus aureus; Ec: Escherichia coli; Pa: Pseudomonas aeruginosa; Kp:
Klebsiella pneumoniae.
Table 3. Combined effects of different pyrones with ampicillin against drug-resistant
Klebsiella pneumoniae.
Combinations
Individual MIC (mg/mL) Combination MIC (mg/mL) Individual FIC FIC Index (FICI) Interpretation
3a þ ampicillin
3h þ ampicillin
4a þ ampicillin
4b þ ampicillin
4c þ ampicillin
4d þ ampicillin
4g þ ampicillin
4h þ ampicillin
1.56/2500
7.80/2500
7.80/2500
7.80/2500
7.80/2500
7.80/2500
7.80/2500
7.80/2500
0.78/2.40
3.90/2.40
7.81/2.40
7.81/2.40
7.81/2.40
7.81/2.40
15.63/2.40
7.81/2.40
0.5/0.00096
0.5/0.00096
1.0/0.00096
1.0/0.00096
1.0/0.00096
1.0/0.00096
2.0/0.00096
1.0/0.00096
0.50
0.50
1.00
1.00
1.00
1.00
2.00
1.00
Synergistic
Synergistic
No interaction
No interaction
No interaction
No interaction
No interaction
No interaction
MIC: minimum inhibitory concentration; FIC: fractional inhibitory concentration.
Halogenation of the phenyl ring of both the mono- and diprenylated 2-pyrones seems
to decrease the antibacterial activity of the compounds. The substitution of one of the
hydrogen atoms on the aryl ring with bromine rendered the 2-pyrones analogs ineffect-
ive against all the test organisms (MIC >250 mg/mL).
During the past decades, combination therapy has become one of the most effective
strategies in combating bacterial infections caused by drug-resistant pathogens. The
rationale is to enhance the activity by the achievement of a synergistic effect. K. pneu-
moniae (ATCC 700603) is a b-lactamase-producing organism and will hydrolyze b-lac-
tam antibiotics, such as ampicillin, thereby becoming resistant to these antibiotics.
Considering the antibacterial activity of 3a, 3h, 4a, 4b, 4c, 4d, 4g, and 4h against the
drug-resistant K. pneumoniae, the synergistic evaluation of these compounds in combin-
ation with ampicillin was undertaken. The MICs obtained by the combinations of the
2-pyrones with ampicillin against drug-resistant K. pneumoniae are presented in Table 3.
Many chemical compounds are known to possess antimicrobial activity. However, when
used in combination, some of these compounds have the potential to either inhibit the
modified target or exhibit a synergy by blocking one or more of the targets in the meta-
bolic pathway, thus acting as a modifier of multidrug-resistance mechanisms.[23]
A
drug-resistant strain of K. pneumoniae was used in the present study. It is an extended-
spectrum beta-lactamase strain that produces the enzyme SHV-18. Out of the eight

6
G. OBI ET AL.
combinations studied, only two synergistic effects were detected (Table 3). These were
the combinations 3a/ampicillin and 3h/ampicillin. Given the FICI values (0.5) (see
Experimental section for an explanation of FICI values), the interactions could be
described as borderline synergistic effects.[24] However, both compounds, at half of the
individual MIC values, were able to lower the MIC of ampicillin in the combinations
from 2500 to 2.4 mg/mL (1/1041 of MIC).
Conclusion
In conclusion, the syntheses of mono- and diprenylated 2-pyrone derivatives have been
achieved by the prenylation of 6-aryl-4-hydroxy-2-pyrones with prenyl bromide. All com-
pounds are reported here for the first time. The obtained compounds were evaluated for
antibacterial activity, and all except the bromine-containing derivative were active against
one or more of the test organisms. E. coli, a Gram-negative bacteria, was the most suscep-
tible of all the test organisms. With regards to the antibacterial activity of eight of the
compounds against a drug-resistant b-lactamase-producing K. pneumoniae, an evaluation
of the synergistic effect between each of these eight pyrones with ampicillin was investi-
gated. Out of the eight combinations studied, two synergistic effects were detected. Both
compounds 3a and 3h, at half of the individual MIC values, were able to lower the MIC
of ampicillin in the combinations from 2500 to 2.4 mg/mL (1/1041 of MIC).
Experimental
General experimental procedure
All air- and moisture-sensitive reactions were performed in flame-dried glassware under
an inert gas (argon or nitrogen) atmosphere. Reactions were monitored using thin-layer
chromatography (TLC, silica, aluminum-backed). Visualization of the TLC plates was
achieved by using an iodine tank or fluorescence on exposure to short wavelength UV
(254 nm). Solvents were dried and purified following standard procedures. Compounds
1
were characterized using a Bruker 400 MHz Avance III (for H and 13C experiments) or
a 500 MHz Avance III UltraShield NMR spectrometer (for 19F experiments) at frequen-
cies of 400 MHz (1H NMR), 100.4 MHz (13C NMR) and 470 MHz (19F NMR) at 298 K
with chemical shifts (d) given in parts per million (ppm) downfield from tetramethylsi-
1
lane as the internal standard and coupling constants (J) in Hertz (Hz). H and 13C
NMR spectra were referenced to residual solvent signals, and 19F NMR spectra were ref-
erenced to chlorotrifluoromethane. High-resolution mass spectrometry (HRMS) was
performed on a Waters LCT Premier time-of-flight mass spectrometer with electrospray
ionization in the positive mode [HRMS-ESI-(þ)]. IR spectra were recorded on a Perkin
Elmer Spectrometer (100 FT-IR) with universal ATR sampling accessory. Melting points
were recorded using a Stuart melting point apparatus and were uncorrected.
General procedure for the preparation of compounds 3a–3j and 4a–4j
The 6-aryl-4-hydroxy-2-pyrone (1.0 mmol) was added to a suspension of dry DMF
(5 mL) and potassium carbonate (0.44 g, 3.0 mmol) under nitrogen in the absence of

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7
light. The resulting mixture was allowed to stir for 1 h at 60 ꢀC, cooled to room tem-
perature and prenyl bromide (0.23 g, 1.5 mol) was added dropwise. After addition, the
mixture was again heated to 60 ꢀC and stirred for another 3 h. On completion of the
reaction, as indicated by TLC monitoring, the reaction mixture was cooled to room
temperature and water (30 mL) was added. The aqueous phase was extracted with
chloroform (4 ꢁ 30 mL) and the combined organic extracts were washed with water
(5 ꢁ 30 mL), brine (40 mL) and dried over anhydrous MgSO4. The solvent was evapo-
rated and the crude residue was purified by column chromatography using
hexanes–EtOAc (9:1) to afford products 3 and 4.[25]
Determination of antibacterial activity
Preparation of microorganisms
The bacteria used in this study were one Gram-positive (S. aureus ATCC 12600), two
Gram-negative (Pseudomonas aeruginosa ATCC 10145, E. coli ATCC 11775), and one
drug-resistant Gram-negative (K. pneumoniae ATCC 700603) bacterial strains. The cul-
tures of bacteria were maintained on Mueller Hinton Agar slants at 4 ꢀC throughout the
study and used as stock cultures.
Determination of minimum inhibitory concentration (MIC)
The MIC values of compounds against the bacterial strains were determined using a rapid
p-iodonitrotetrazolium chloride (INT) colorimetric assay.[26] Stock solutions of test com-
pounds (10 mg/mL) were prepared in DMSO. Prior to the assay, stock solutions were
diluted with sterilized distilled water to a concentration of 1 mg/mL. Solutions were then
added to Mueller Hinton Broth (MHB) and serially diluted twofold in a 96-well micro-
plate to a final concentration range of 250–1.95 mg/mL. Compounds with MIC values less
than 1.95 mg/mL were further assayed at a final concentration range of 50–0.012 mg/mL to
determine the individual MIC values. Bacterial strains were cultured overnight at 37 ꢀC
on MHB and adjusted to a final density of 106 cfu/mL with MHB. These were used as
inocula. One hundred microliters (100 mL) of inoculum was added to each well. The plates
were covered with a sterile plate sealer and then incubated at 37 ꢀC for 20 h. Wells con-
taining 10% DMSO, MHB and 100 mL of inoculum served as the negative controls while
neomycin was used as a positive control. The total volume in each well was 200 mL. The
MICs of the compounds were observed after 20 h incubation at 37 ꢀC, and subsequent
30 min incubation after the addition of 40 mL of 0.2 mg/mL INT. Clear wells with INT
after incubation indicated inhibition of bacterial growth. MIC values were recorded as the
lowest concentration of the test compound that completely inhibited bacterial growth.
The assay was repeated twice in duplicate per sample and values represent the averages.
The standard deviations/errors were not included because they were insignificant.
Determination of in vitro synergistic activity
Combinations of compounds that recorded an MIC value ꢂ7.8 mg/mL and ampicillin
against drug-resistant beta-lactamase-producing Gram-negative K. pneumoniae were

8
G. OBI ET AL.
tested by the checkerboard method. For each compound and ampicillin combination,
50 mL of MHB was added in each well of a 96-well microplate. About 50 mL of each
compound solution was added in row A and was twofold serially diluted down to row
H. 50 mL of appropriate dilutions of ampicillin was added in columns with column one
having the highest concentration and column twelve the lowest concentration of anti-
biotic. To the 100 mL of different combinations in each of the 96-well microplates,
100 mL of bacterial inoculum as described earlier, was added. The final concentration of
the compound and ampicillin in combinations ranged from 1/64 ꢁ MIC to 2 ꢁ MIC.
Plates were incubated for 20 h. Interpretation of the data was achieved by calculating
the fractional inhibitory concentration index (FICI) as follows:
FICI ¼ FIC A þ FIC B:
where
FIC A ¼ (MIC of compound A in combination with antibiotics/MIC of compound
A alone).
FIC B ¼ (MIC of antibiotics B in combination with compound/MIC of antibiotics
B alone).
The results were interpreted as follows: FICI ꢂ0.5, synergistic; 0.5 < FICI <4, no
interaction; and FICI ꢃ4 antagonistic.
Funding
This work was supported by the National Research Foundation (South Africa) under [Grant
number 98345] and the University of KwaZulu-Natal.
References
[1] Eliopoulos, G. M.; Bush, K. New -Lactamases in Gram-Negative Bacteria: Diversity and
Impact on the Selection of Antimicrobial Therapy. Clin. Infect. Dis. 2001, 32, 1085–1089.
DOI: 10.1086/319610.
[2] Shi, C.; Zhang, Y.; Wang, T.; Lu, W.; Zhang, S.; Guo, B.; Chen, Q.; Luo, C.; Zhou, X.;
Yang, Y. J. Med. Chem. 2019, 62, 2950–2973. DOI: 10.1021/acs.jmedchem.8b01750.
[3] Burns, M. J.; Ronson, T. O.; Taylor, R. J.; Fairlamb, I. J. Beilstein J. Org. Chem. 2014, 10,
1159–1165. DOI: 10.3762/bjoc.10.116.
[4] Sabitha, G.; Reddy, D. V.; Reddy, S. S. S.; Yadav, J. S.; Kumar, C. G.; Sujitha, P. RSC Adv.
2012, 2, 7241–7247. DOI: 10.1039/c2ra20830j.
[5] Bhat, Z. S.; Rather, M. A.; Syed, K. Y.; Ahmad, Z. Future Med. Chem. 2017, 9, 2053–2067.
DOI: 10.4155/fmc-2017-0116.
[6] Bhat, Z. S.; Lah, H. U.; Rather, M. A.; Maqbool, M.; Ara, T.; Ahmad, Z.; Yousuf, S. K.
Med. Chem. Commun. 2018, 9, 165–172. DOI: 10.1039/C7MD00366H.
[7] Bhat, Z. S.; Rather, M. A.; Maqbool, M.; Lah, H. U.; Yousuf, S. K.; Ahmad, Z. Biomed.
Pharmacother. 2017, 91, 265–277. DOI: 10.1016/j.biopha.2017.04.012.
[8] Thaisrivongs, S.; Romero, D. L.; Tommasi, R. A.; Janakiraman, M. N.; Strohbach, J. W.;
Turner, S. R.; Biles, C.; Morge, R. R.; Johnson, P. D.; Aristoff, P. A.; et al. J. Med. Chem.
1996, 39, 4630–4642., DOI: 10.1021/jm960228q.
[9] Huang, J.; Li, L.; Chen, H.; Xiao, T.; He, Y.; Zhou, L. J. Org. Chem. 2017, 82, 9204–9209.
DOI: 10.1021/acs.joc.7b01470.
[10] Lee, J. S. Mar. Drugs 2015, 13, 1581–1620. DOI: 10.3390/md13031581.

R
SYNTHETIC COMMUNICATIONSV
9
[11] Chen, X.; Mukwaya, E.; Wong, M.-S.; Zhang, Y. Pharm. Biol. 2014, 52, 655–660. DOI: 10.
3109/13880209.2013.853809.
[12] Araya-Cloutier, C.; Vincken, J. P.; van de Schans, M. G. M.; Hageman, J.; Schaftenaar, G.;
den Besten, H. M. W.; Gruppen, H. Sci. Rep. 2018, 8, 9267. DOI: 10.1038/s41598-018-
27545-4.
[13] Araya-Cloutier, C.; den Besten, H. M.; Aisyah, S.; Gruppen, H.; Vincken, J. P. Food Chem.
2017, 226, 193–201. DOI: 10.1016/j.foodchem.2017.01.026.
[14] Epifano, F.; Genovese, S.; Menghini, L.; Curini, M. Phytochemistry. 2007, 68, 939–953.
DOI: 10.1016/j.phytochem.2007.01.019.
[15] Lozinski, O.; Bennetau-Pelissero, C.; Shinkaruk, S. Chem. Select. 2017, 2, 6577–6603. DOI:
10.1002/slct.201700863.
[16] Nakatani, K.; Nakahata, N.; Arakawa, T.; Yasuda, H.; Ohizumi, Y. Biochem. Pharmacol.
2002, 63, 73–79. DOI: 10.1016/S0006-2952(01)00810-3.
[17] Araya-Cloutier, C.; Vincken, J. P.; van Ederen, R.; den Besten, H. M. W.; Gruppen, H.
Food Chem. 2018, 240, 147–155. DOI: 10.1016/j.foodchem.2017.07.074.
[18] Akihara, Y.; Ohta, E.; Nehira, T.; Omura, H.; Ohta, S. Chem. Biodiv. 2017, 14, e1700196.
DOI: 10.1002/cbdv.201700196.
[19] Tsuchiya, H.; Sato, M.; Miyazaki, T.; Fujiwara, S.; Tanigaki, S.; Ohyama, M.; Tanaka, T.;
Iinuma, M. J. Ethnopharmacol. 1996, 50, 27–34. DOI: 10.1016/0378-8741(96)85514-0.
[20] Botta, B.; Menendez, P.; Zappia, G.; de Lima, R.; Torge, R.; Monache, G. CMC. 2009, 16,
3414–3468. DOI: 10.2174/092986709789057662.
[21] Le Noble, W. Synthesis. 1970, 1970, 1–6. DOI: 10.1055/s-1970-21573.
[22] Obi, G.; Chukwujekwu, J. C.; Venables, L.; Van de Venter, M.; van Heerden, F. R. Med.
Chem. Res. 2019, Submitted for publication.
[23] Hemaiswarya, S.; Kruthiventi, A. K.; Doble, M. Phytomedicine. 2008, 15, 639–652. DOI:
10.1016/j.phymed.2008.06.008.
[24] Odds, F. C. J. Antimicrob. Chemother. 2003, 52, 1–1. DOI: 10.1093/jac/dkg301.
[25] Klaper, M.; Fudickar, W.; Linker, T. J. Am. Chem. Soc. 2016, 138, 7024–7029. DOI: 10.
1021/jacs.6b01555.
[26] Eloff, J. N. Planta Med. 1998, 64, 711–713. DOI: 10.1055/s-2006-957563.