Synthesis and antibacterial activity of emodin and its derivatives against methicillin-resistant Staphylococcus aureus

Article abstract of DOI:10.1016/j.tetlet.2019.151004

Synthesis of the antibacterial emodin was improved using Friedel-Crafts acylation as a key step leading to 37% overall yield. In addition, 21 analogues were synthesized by structural modification of the hydroxyl and methyl groups, as well as the aromatic ring of emodin. Antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and cytotoxicity against noncancerous Vero cells were evaluated. A structure-activity relationship (SAR) study indicated that the hydroxyl groups and the methyl group in the emodin skeleton were crucial for anti-MRSA activity. Furthermore, the presence of an iodine atom or ethylamino group on the aromatic ring enhanced the anti-MRSA activity with higher selectivity indices, while derivatives containing bromine, chlorine atoms or quaternary ammonium salt were as active as emodin. The quaternary ammonium group on the aromatic ring also led to non-cytotoxicity against Vero cells.

Full text of DOI:10.1016/j.tetlet.2019.151004

Journal Pre-Proof
Synthesis and Antibacterial Activity of Emodin and its Derivatives against Me-
thicillin-Resistant Staphylococcus aureus
Thidarat Chalothorn, Vatcharin Rukachaisirikul, Souwalak Phongpaichit,
Sakawrat Pannara, Chittreeya Tansakul
PII:
S0040-4039(19)30761-0
DOI:
https://doi.org/10.1016/j.tetlet.2019.151004
TETL 151004
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 June 2019
22 July 2019
31 July 2019
Please cite this article as: Chalothorn, T., Rukachaisirikul, V., Phongpaichit, S., Pannara, S., Tansakul, C., Synthesis
and Antibacterial Activity of Emodin and its Derivatives against Methicillin-Resistant Staphylococcus aureus,
Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151004
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover
page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will
undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing
this version to give early visibility of the article. Please note that, during the production process, errors may be
discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier Ltd.

JOURNAL PRE-PROOF
1
Synthesis and Antibacterial Activity of Emodin and its
Derivatives against Methicillin-Resistant Staphylococcus aureus
Thidarat Chalothorn1, Vatcharin Rukachaisirikul1, Souwalak Phongpaichit2, Sakawrat Pannara2
and Chittreeya Tansakul1,*
1Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science,
Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand
2Department of Microbiology, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla 90112,
Thailand
*Corresponding author. e-mail address: chittreeya.t@psu.ac.th (C. Tansakul).
Abstract: Synthesis of the antibacterial emodin was improved using Friedel-Crafts acylation
as a key step leading to 37% overall yield. In addition, 21 analogues were synthesized by
structural modification of the hydroxyl and methyl groups, as well as the aromatic ring of
emodin. Antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA)
and cytotoxicity against noncancerous Vero cells were evaluated. A structure-activity
relationship (SAR) study indicated that the hydroxyl groups and the methyl group in the
emodin skeleton were crucial for anti-MRSA activity. Furthermore, the presence of an iodine
atom or ethylamino group on the aromatic ring enhanced the anti-MRSA activity with higher
selectivity indices, while derivatives containing bromine, chlorine atoms or quaternary
ammonium salt were as active as emodin. The quaternary ammonium group on the aromatic
ring also led to non-cytotoxicity against Vero cells.
Keywords: Emodin, Antibacterial Activity, Methicillin-resistant Staphylococcus aureus,
Cytotoxicity
Introduction
The widespread use of antibiotics, especially their clinical misuse, has resulted in an
increase of multidrug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus
(MRSA), which is becoming a global problem.1 Only a few antibiotics such as vancomycin,
linezolid, daptomycin, and ceftaroline have been used against infections caused by MRSA.
Emodin (Fig. 1), which belongs to the anthraquinone family, is an active component of a
traditional Chinese medicinal herb (Da Huang, rhubarb).2 It has been shown to exhibit
various biological activities including anti-inflammatory,3,4,5 anti-cancer,3 antiviral,4

JOURNAL PRE-PROOF
2
antiulcerogenic,6 vasorelaxant7 and T-cell and B-cell immunosuppressive4 effects. In
particular, it showed antibacterial activities against MRSA252 and 36 clinical MRSA strains
with MIC values in the range of 2-8 µg/mL,8 as well as MRSA-SK1 with a MIC value of 4
µg/mL.9 The anti-MRSA mechanism of emodin which involves damaging the cell membrane
has been investigated.8 There have been a number of literature precedents for the anti-MRSA
activity of emodin analogues obtained either from natural sources or simple semisyntheses.10-
22
However, there are only a few derivatives, for example aloe emodin, which displayed
strong activity.10 There have been several reports regarding the synthesis of emodin. Usually,
a Diels-Alder reaction23-27or Friedel-Crafts acylation28-31 was utilized as a key step. However,
there are some drawbacks of the reported syntheses, such as the requirement of expensive,
toxic or controlled substances, difficult set-up, harsh conditions or low yields.
As part of an ongoing search for biologically active compounds from fungi, our
research group has found that emodin and its derivatives: isorhodoptilometrin and
penicillanthranin A, isolated from the marine-derived fungus Trichoderma aureoviride PSU-
F9512 and the sea fan-derived fungus Penicillium citrinum PSU-F51,13 respectively, displayed
antibacterial activity against MRSA with respective MIC values of 4, 16 and 16 µg/mL.
Interestingly, emodin was weakly cytotoxic to noncancerous Vero cells (African green
monkey kidney fibroblasts) with an IC50 value of 42.5 µM, and its citrinin-substituted
derivative, penicillanthranin A, was non-cytotoxic to Vero cells. Owing to the antibacterial
potential of emodin and its derivatives, we pursued the improved synthesis and chemical
structure modification of emodin as well as an evaluation of the antibacterial activity of
emodin analogues against MRSA, together with cytotoxicity against noncancerous Vero
cells. Accordingly, emodin derivatives with stronger activity and higher selectivity indices
were discovered, and a structure-activity relationship (SAR) was also established.
OH
O
OH
9
1
3
8
6
10
OH
O
Emodin
Figure 1. Structure of emodin.
Results and Discussion
The improved synthesis of emodin commenced with the methylation of 4-
methylsalicylic acid (1), followed by hydrolysis of the resulting methyl ester 2 to give

JOURNAL PRE-PROOF
3
carboxylic acid 3 (Scheme 1). Acid chloride 4 was obtained by treating the carboxylic acid 3
with oxalyl chloride and cat. DMF. An intermolecular Friedel-Crafts acylation between acid
chloride 4 and methyl 3,5-dimethoxybenzoate (5) in the presence of aluminum chloride
resulted in the formation of benzophenone 6. In contrast to the previously reported
synthesis,30 deprotection of the methyl groups was not observed under these conditions, and it
also provided a better yield. Conversion of 6 into the corresponding acid chloride 8 was
achieved in two high-yielding steps: hydrolysis of the methyl ester 6 to give the carboxylic
acid 7, followed by reaction with oxalyl chloride and cat. DMF. Intramolecular Friedel-Crafts
acylation of 8 was accomplished using aluminum chloride and cat. triflic acid32 to furnish
anthraquinone 9. This step required a much lower temperature (83 C) than that (170 C)
used in the reported intramolecular cyclization of carboxylic acid 7.30 Finally, demethylation
using boron tribromide gave emodin. The synthesis afforded emodin in 8 steps in 37%
overall yield, which was higher than the previously reported one from the same starting
material (11% overall yield).30
COCl
CO2H
OH
CO2Me
OMe
CO2H
OMe
(COCl)2
cat.DMF
1M NaOH
reflux
Me2SO4, K2CO3
acetone, reflux
OMe
CH2Cl2
0 C to rt
97%
98%
99%
1
4
2
3
OMe
OMe O
OMe
OMe O
HO2C
OMe
5
1M NaOH
reflux
MeO2C
OMe
OMe
OMe
MeO2C
94%
AlCl3, CH2Cl2
reflux, 89%
7
6
BBr3
OH
O
O
OH
OH
O
O
OH
OMe O
O
OMe
(COCl)2, cat.DMF
AlCl3, DCE
cat.TfOH
CH2Cl2, 0 C
CH2Cl2, 0 C
98%
OMe
97%
OH
reflux
OMe
50%
9
8
Cl
Emodin
Scheme 1. Synthesis of emodin.
In order to evaluate the effect of the hydroxyl groups of emodin on anti-MRSA
activity, the first series of analogues were synthesized by chemical modification at these
groups (Scheme 2). The methylation of emodin was achieved by treatment with either
iodomethane or methyl sulfate in the presence of K2CO3 to give monomethylated emodin, 3-
methoxyemodin (9), and fully methylated emodin, 1,3,8-trimethoxyemodin (10),

JOURNAL PRE-PROOF
4
respectively. Treatment of 10 with boron tribromide resulted in demethylation at only the 8-
position to give 1,3-dimethoxyemodin (11). Since previous study disclosed that the
antibacterial activity of methacrylate monomers against Staphylococcus aureus increased
with an increase in the alkyl chain length by penetration through bacterial cells to disrupt
membranes,33 alkylation of the nonchelated hydroxyl group was performed by treating
emodin with 2-[2-(2-iodoethoxy)ethoxy]ethanol or 1-bromododecane in the presence of
K2CO3 to give alkoxy analogues 12 and 13, respectively.
OR1
O
OR2
OH
O
OH
a, b, c, d or e
8
1
3
OR3
OH
O
O
Emodin
1
2
3
9
: R = R = H; R = Me; condition a, 77%
1
2
3
10
11
12
13
: R = R = R = Me; condition b, 98%
1
2
3
: R = H, R = R = Me; condition c, 96%
1
2
3
: R = R = H; R = (CH2CH2O)2(CH2)2OH; condition d, 56%
1
2
3
: R = R = H; R = (CH2)11CH3; condition e, 78%
Scheme 2. Structure modification at the hydroxyl groups. Reagents and conditions: (a) MeI, K2CO3, acetone,
reflux; (b) Me2SO4, K2CO3, MeCN, reflux; (c) MeI, K2CO3, acetone, reflux, then BBr3, CH2Cl2, 0 C to rt; (d)
2-[2-(2-iodoethoxy)ethoxy]ethanol, K2CO3, acetone, reflux; (e) 1-bromododecane, K2CO3, DMF, 70 C.
With the aim to identify the importance of the methyl group, which is located at C-6,
the second series of emodin analogues were prepared (Scheme 3). The bromination of
trismethylated emodin 10 using N-bromosuccinimide and dibenzoyl peroxide as an initiator,
followed by oxidation with silver nitrate were performed according to literature procedures to
give emodin analogues 14 and 15, respectively.34 Oxime 16, carboxylic acid 17 and primary
alcohol 18 were synthesized from aldehyde 15 by condensation with hydroxylamine
hydrochloride, oxidation with sodium chlorite, and reduction with sodium borohydride,
respectively. Derivatives 19-21 were obtained after the demethylation of 16-18, respectively,
with boron tribromide. However, attempts to demethylate aldehyde 15 were unsuccessful.

JOURNAL PRE-PROOF
5
NBS
OMe O
OMe
OMe O
OMe
OMe O
OMe
dibenzoyl peroxide
CCl4, reflux
AgNO3
EtOH/H2O
O
Br
OMe
OMe
OMe
92%
97%
H
O
15
Br
O
14
O
10
a, b or c
OH
O
O
OH
OMe O
OMe
BBr3, CH2Cl2
0 C to rt
R
OH
R
OMe
O
16
17
18
: R = CH=NOH; condition a, 91%
: R = COOH; condition b, 91%
: R = CH2OH; condition c, 89%
19
20
21
: R = CH=NOH; 76%
: R = COOH; 81%
: R = CH2OH; 65%
Scheme 3. Structure modification at the methyl group. Reagents and conditions: (a) NH2OH•HCl, NaOH,
EtOH/H2O, reflux; (b) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH/H2O, 0 C to rt; (c) NaBH4, MeOH, 0 C
to rt.
Structure modification at the aromatic ring afforded the third series of emodin
analogues (Scheme 4). 2,4-Dichloro, 2,4-dibromo and 2,4-diiodo emodin (22, 23 and 25)
were synthesized by treatment of emodin with N-chlorosuccinimide, N-bromosuccinimide
and excess iodine, respectively.35 Monoiodination at the 2-position could be achieved using
only 1.5 eq of iodine to give 2-iodoemodin (24). Carbon-carbon bond formation at the C-2
position could be achieved via a Mannich reaction using dimethylamine and benzaldehyde to
provide emodin Mannich base 26.36 Amination at the 4-position gave analogues 27 and 28
using the corresponding amines.37 Quaternary ammonium compounds have been reported as
broad spectrum cationic antimicrobials by binding to the cell membrane to cause cytoplasmic
leakage, and have low toxicity.38 Therefore, amino analogue 28 was doubly methylated to
afford quaternary ammonium iodide 29.
OH
O
OH
OH
O
O
OH
a, b, c, d, e or f
OH
R1
2
4
OH
R2
O
Emodin
1
2
22
: R = R = Cl; condition a, 77%
1
2
23
24
25
26
27
28
29
: R = R = Br; condition b, 90%
1
2
: R = I; R = H; condition c, 78%
1
2
: R = R = I; condition c, 67%
1
2
: R = CHPhNMe2; R = H; condition d, 75%
1
2
: R = H; R = NH(CH2)2NH2; condition e, 95%
1
2
: R = H; R = NHEt; condition e, 87%
1
2
+
: R = H; R = N Me2Et; condition f, 86%

JOURNAL PRE-PROOF
6
Scheme 4. Structure modification at the aromatic ring. Reagents and conditions: (a) NCS, cat. ZrCl4, 1,4-
dioxane, 70 C; (b) NBS, THF, rt; (c) I2 (1.5 or 8 eq), NaHCO3, THF/H2O, 0 C to rt; (d) Me2NH, PhCHO, 1,4-
dioxane, 75 C; (e) NH2(CH2)2NH2 or NH2Et, PhI(OAc)2, rt; (f) NH2Et, PhI(OAc)2, rt, then MeI, MeCN, 60 C.
Emodin and its analogues 9-29 were evaluated for antibacterial activity against
MRSA-SK1 using a colorimetric broth microdilution test39 and cytotoxic activity against
noncancerous Vero cells using the green fluorescent protein (GFP)-based assay.40 Results of
active compounds 22-29 are shown in Table 1. Vancomycin and ellipticine were used as
positive controls for the anti-MRSA and cytotoxic activities, respectively. The parent
compound, emodin, exhibited moderate anti-MRSA activity with a MIC value of 4 µg/mL
and weak cytotoxicity against Vero cells with an IC50 value of 42.5 µM. All analogues
modified at the chelated and non-chelated hydroxyl groups (9-13) were inactive towards
MRSA at 200 µg/mL, and non-cytotoxic against Vero cells at 50 µg/mL. Analogues 12 and
13 with long chain alkoxy groups at the 3-position also lacked anti-MRSA activity and
cytotoxicity. The importance of all of the hydroxyl groups of emodin to anti-MRSA activity
was emphasized by the previous observation that pachybasin, an anthraquinone containing
hydrogen atoms at the 1- and 3-positions instead of the hydroxyl groups in emodin, was
inactive against MRSA-SK1.12 The absence of the hydroxyl group at the 3-position resulted
in chrysophanol inactivity against MRSA.16 Physcion (9) containing the methoxyl group at
the 3-position also showed no antibacterial effects on four strains of MRSA.10 Moreover,
emodin-8-O-glucoside has been reported to exhibit no activity against MRSA-252.14
Similarly, all derivatives modified at the 6-methyl group (14-21) were also inactive and non-
cytotoxic, although it has been shown that -hydroxyemodin (21) could limit Staphylococcus
aureus quorum sensing-mediated pathogenesis and inflammation.41 These results were
supported by the inactivity of 1,3,6,8-tetrahydroxyanthraquinone and other hydroxyl
alkylated analogues against MRSA-252,14 and strongly suggested that the methyl group
played an important role on anti-MRSA activity.
All modified analogues at the aromatic ring (22-29) were active against MRSA (Table
1). Three derivatives: 4-ethylaminoemodin (28), 2,4-diiodoemodin (25) and 2-iodoemodin
(24), showed stronger anti-MRSA activity than emodin with MIC values of 0.5, 1 and 2
µg/mL, respectively, and higher selectivity indices (ratio of cytotoxic IC50 (µg/mL) to MIC).
The order of selectivity index is as follows: 2,4-diiodoemodin 25 (14.8), 4-ethylaminoemodin
28 (9.3), 2-iodoemodin 24 (7.6). The higher selectivity index indicates the greater selective
toxicity towards pathogens over host cells.42 An iodine atom on the aromatic ring (24 and 25)
increased the antibacterial activity, whereas chlorine (22) and bromine (23) substitution

JOURNAL PRE-PROOF
7
maintained the activity with higher cytotoxic activities. It has been reported that 2,4-
diiodoemodin (25)15 and naturally chlorinated emodin, 1,3,8-trihydroxy-4-chloro-6-methyl-
anthraquinone,17 inhibits the growth of various strains of Gram-positive bacteria including
MRSA in the range of 2-32 µg/mL. 2,4-Dibromoemodin (23) could be considered as a
bactericidal agent since its MBC was 4-fold greater than its MIC.43 In contrast, the MBCs of
emodin and other active derivatives (22 and 24-29) were at least 16-fold greater than their
MICs. Accordingly, they could only be used as bacteriostatic agents. In contrast to 2-
iodoemodin (24), Mannich base 26, an analogue solely substituted at C-2, was 4-fold less
active than emodin. While an ethylamino substituent at C-4 (28) significantly increased the
anti-MRSA activity of emodin by 8-fold, an ethylenediamino substituent (27) reduced the
activity to the same extent. Interestingly, quaternary ammonium iodide analogue 29, derived
from 4-ethylaminoemodin (28), was as potent as emodin against MRSA without cytotoxicity
against Vero cells.
Table 1. Antibacterial activity against MRSA and cytotoxic activity against Vero cells of compounds 22-29.
OH
O
OH
R1
8
1
3
6
OH
O
R2
Anti-MRSA
(µg/mL)
Cytotoxicity
(Vero) (µM)
Selectivity
Index
Compound
R1
R2
MIC
MBC
Emodin
H
Cl
Br
I
H
Cl
Br
H
I
4
4
4
2
1
16
32
0.5
4
1
-
>200
200
16
>200
32
>200
>200
8
42.5
9.7
2.9
0.28
1.9
7.6
14.8
0.58
0
9.3
0
-
22
23
24
25
26
27
28
18.7
38.6
28.4
23.0
NA
14.9
NA
-
I
CHPhNMe2
H
H
H
H
NH(CH2)2NH2
NHEt
29
N+Me2Et
64
1
-
Vancomycina
Ellipticineb
3.97
-
MIC = minimum inhibitory concentration; MBC = minimum bactericidal concentration
NA refers to “not active” which is indicative of no inhibition at >50 g/mL of a compound tested.
Selectivity Index is ratio of cytotoxic IC50 (g/mL) to MIC (g/mL).
a Positive control for antibacterial assay; b Positive control for cytotoxicity assay
Conclusion
In conclusion, we report the improved synthesis of emodin in 37% overall yield
using Friedel-Crafts acylation as a key step. To the best of our knowledge, this is the first
SAR study of emodin derivatives. Simple chemical modification of the hydroxyl and methyl

JOURNAL PRE-PROOF
8
groups as well as the aromatic ring of emodin provided 21 analogues. The resulting
antibacterial activity and cytotoxicity established a SAR, which revealed that the hydroxyl
groups as well as the methyl group were crucial for anti-MRSA activity. Analogues modified
at the aromatic ring were all active against MRSA. The presence of an iodine atom or
ethylamino group enhanced the anti-MRSA activity of emodin, whereas analogues containing
quaternary ammonium groups were as active as emodin, and non-cytotoxic against Vero
cells. Moreover, the presence of two iodine atoms on the aromatic ring led to the greatest
selective toxicity towards MRSA over Vero cells.
Acknowledgements
This work was financially supported by the NSTDA Chair Professor grant (the fourth
Grant) of the Crown Property Bureau Foundation and the National Science and Technology
Development Agency. T. Chalothorn is grateful to the Faculty of Science Research Fund,
Prince of Songkla University, contract no. 1-2559-02-007 for a research assistantship, the
Center of Excellence for Innovation in Chemistry (PERCH-CIC), Ministry of Higher
Education, Science, Research and Innovation, the Graduate School and the Department of
Chemistry, Faculty of Science, Prince of Songkla University for partial support. The National
Center for Genetic Engineering and Biotechnology (BIOTEC) is acknowledged for cytotoxic
assays. Finally, we also thank Nattawut Decha, Arthit Pikulngam, Prompat Promphet and
Jirapon Sae-Jew for helping in column chromatography and structure elucidation.
Supplementary data
Supplementary data associated with this article can be found, in the online version,
at….
References
1.
2.
Li B, Webster TJ. J. Orthop. Res. 2018; 36: 22–32.
Wang X, Xu W. Bull. Korean Chem. Soc. 2005; 26: 1923-1924.
3. Shrimali D, Shanmugam MK, Kumar AP, Zhang J, Tan BKH, Ahn KS, Sethi G.
Cancer Lett. 2013; 314: 139-149.
4. Li D, Zhang N, Cao Y, Zhang W, Su G, Sun Y, Liu Z, Li F, Liang D, Liu B, Guo M,
Fu Y, Zhang X, Yang Z. Eur. J. Pharmacol. 2013; 705: 79-85.
5.
6.
Zhu X, Zeng K, Qiu Y, Yan F, Lin C. Inflammation 2013; 36: 1253-1259.
Goel RK, Das Gupta G, Ram SN, Pandey VB. Indian J. Exp. Biol. 1991; 29: 230-
232.
7.
Ma J, Wang S, Che B, Liu Z, Ke X, Liu T, Fu J. Int. J. Oncol. 2015; 46: 1619-
1628.
8. Liu M, Peng W, Qin R, Yan Z, Cen Y, Zheng X, Pan X, Jiang W, Li B, Li X, Zhou H.
Appl. Microbiol. Biotechnol. 2015; 99: 7699-7709.
9. Promgool T, Pancharoen O, Deachathai S. Songklanakarin J. Sci. Technol. 2014; 36:
459-463.

JOURNAL PRE-PROOF
9
10. Hatano T, Uebayashi H, Ito H, Shiota S, Tsuchiya T, Yoshida T. Chem. Pharm. Bull.
1999; 47: 1121-1127.
11. Hazni H, Ahmad N, Hitotsuyanagi Y, Takeya K, Choo CT Planta. Med. 2008; 74:
1802-1805.
12. Khamthong N, Rukachaisirikul V, Tadpetch K, Kaewpet M, Phongpaichit S,
Preedanon S, Sakayaroj J. Arch. Pharm. Res. 2012; 35: 461-468.
13. Khamthong N, Rukachaisirikul V, Phongpaichit S, Preedanon S, Sakayaroj J.
Tetrahedron 2012; 68: 8245-8250.
14. Cao F, Peng W, Li X, Liu M, Li B, Qin R, Jiang W, Cen Y, Pan X, Yan Z, Xiao K,
Zhou H. Can. J. Physiol. Pharmacol. 2015; 93: 1-9.
15. Duan F, Li X, Cai S, Xin G, Wang Y, Du D, He S, Huang B, Guo X, Zhao H, Zhang
R, Ma L, Liu Y, Du Q, Wei Z, Xing Z, Liang Y, Wu X, Fan C, Ji C, Zeng D, Chen Q,
He Y, Liu X, Huang W. J. Med. Chem. 2014; 57: 3707-3714.
16. Omosa LK, Midiwo JO, Mbaveng AT, Tankeo SB, Seukep JA, Voukeng IK, Dzotam
JK, Isemeki J, Derese S, Omolle RA, Efferth T, Kuete V. SpringerPlus 2016; 5: 901-
915.
17.
Duan F, Xin G, Niu H, Huang W. Sci. Rep. 2017; 7; 12721-12730.
18. Wang W, Liao Y, Tang C, Huang X, Luo Z, Chen J, Cai P. Mar. Drugs 2017; 15;
348-357.
19. Bara R, Zerfass I, Aly AH, Goldbach-Gecke H, Raghavan V, Sass P, Mándi A, Wray
V, Polavarapu PL, Pretsch A, Lin W, Kurtán T, Debbab A, Brötz-Oesterhelt H,
Proksch, P. J. Med. Chem. 2013; 56; 3257-3272.
20. Balachandran C, Arun Y, Duraipandiyan V, Ignacimuthu S, Balakrishna K, Al-Dhabi,
NA. Appl. Biochem. Biotechnol. 2014; 172: 3513-3528.
21.
Wang W, Chen R, Luo Z, Wang W, Chen J. Nat. Prod. Res. 2018; 32: 558-563.
22. He KY, Zhang C, Duan YR, Huang GL, Yang CY, Lu XR, Zheng CJ, Chen GY. J.
Antibiot. 2017: 1-5.
23. Banville J, Brassard P. J. Org. Chem.1976; 41: 3018-3020.
24. Krohn K. Tetrahedron Lett. 1980; 21: 3557-3560.
25.
Ahmed SA, Bardshiri E, Simpson TJ. J. Chem. Soc., Chem. Commun. 1987; 883-
884.
26.
27.
Khan AT, Blessing B, Schmidt RR. Synthesis 1994: 255-257.
Motoyoshiya J, Masue Y, Nishi Y, Aoyama H. Nat. Prod. Commun. 2007; 2: 67-
70.
28.
29.
30.
31.
32.
33.
34.
Jacobsen RA, Adams R. J. Am. Chem. Soc.1924; 46: 1312-1316.
Hirose Y, Kroiwa M, Yamashita H. Chem. Pharm. Bull. 1973; 21: 2790-2793.
Liang J, Bai W, Che Q, Xing G, Sun Y. Chinese Patent CN1827574A, 2006.
Chen X, Wang K. Chinese Patent CN101033178A, 2007.
Li H, Qi X, Zhang Y. Chinese Patent CN106083550A, 2016.
Lu G, Wu D, Fu R. React. Funct. Polym. 2007; 67: 355–366.
Salama TA, Lackner B, Falk H. Monatsh. Chem. 2003; 134: 1113-1119.
35. Koerner SK, Hanai J, Bai S, Jernigan FE, Oki M, Komaba C, Shuto E, Sukhatme VP,
Sun L. Eur. J. Med. Chem. 2017; 126: 920-928.
36. Zhao LM, Zhang LM, Ma FY, Wang XS, Jin HS. Tetrahedron Lett. 2013; 54: 2802-
2805.
37. Teich L, Daub KS, Krügel V, Nissler L, Gebhardt R, Eger K. Bioorg. Med. Chem.
2004; 12: 5961-5971.
38.
Gerba CP. Appl. Environ. Microbiol. 2015; 81: 464-469.
39. Phongpaichit S, Rungjindamai N, Rukachaisirikul V, Sakayaroj J. FEMS Immunol.
Med. Microbiol. 2006; 48: 367-372.

JOURNAL PRE-PROOF
10
40.
Hunt L, Jordan M, De Jesus M, Wurm FM. Biotechnol. Bioeng. 1999; 65: 201-
205.
41. Daly SM, Elmore BO, Kavanaugh JS, Triplett KD, Figueroa M, Raja HA, El-Elimat
T, Crosby HA, Femling JK, Cech NB, Horswill AR, Oberlies NH, Hall PR.
Antimicrob. Agents Ch. 2015; 59: 2223-2235.
42. Bagla VP, McGaw LJ, Elgorashi EE, Elof JN. BMC Complem. Altern. M. 2014; 14:
383.
43.
Levison ME, Levison JH. Infect Dis. Clin. North Am. 2009; 23: 791-815.

JOURNAL PRE-PROOF
11

JOURNAL PRE-PROOF
12
 Improved synthesis of emodin was reported using Friedel-Crafts
acylation.
 Semisynthesis of 21 analogues of emodin was reported.
 SAR of emodin analogues on anti-MRSA and cytotoxic activities was
revealed.
 Iodine and ethylamine enhance anti-MRSA activity with higher selectivity
indices.
 Quaternary ammonium salt maintains anti-MRSA activity with no
cytotoxicity.