Regioselective synthesis of 3-benzyl substituted pyrimidino chromen-2-ones and evaluation of anti-microbial and anti-biofilm activities

Article abstract of DOI:10.1016/j.bmcl.2013.12.038

Regioselective synthesis of a number of highly functionalized 3-benzylpyrimidino chromen-2-ones (4) were accomplished in a one pot three component reaction in acetic acid and determined their anti-microbial and anti-biofilm activities. Compounds 4o and 4p showed an excellent anti-microbial activity against Micrococcus luteus MTCC 2470 at a par with standard control (Ciprofloxacin) and exhibited best activity against Staphylococcus aureus MTCC 96 and Bacillus subtilis MTCC 121. Further, compounds 4h, 4i, 4m, 4n and 4q showed promising activity against Micrococcus luteus MTCC 2470, Staphylococcus aureus MTCC 96 and Bacillus subtilis MTCC 121. Whereas, compounds 4m showed very promising biofilm inhibition activity against Staphylococcus aureus MLS 16 MTCC 2940 and 4o, 4p showed very potent activity against Staphylococcus aureus MTCC 96 at a par with Ciprofloxacin used as standard control.

Full text of DOI:10.1016/j.bmcl.2013.12.038

Bioorganic & Medicinal Chemistry Letters 24 (2014) 485–489
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Regioselective synthesis of 3-benzyl substituted pyrimidino
chromen-2-ones and evaluation of anti-microbial and anti-biofilm
activities
a
b
Narender Reddy Emmadi a, Krishnaiah Atmakur a, , Chiranjeevi Bingi , Narender Reddy Godumagadda ,
⇑
Chityal Ganesh Kumar b, Jagadeesh Babu Nanubolu c
a Division of Crop Protection Chemicals, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India
b Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India
c Laboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Regioselective synthesis of a number of highly functionalized 3-benzylpyrimidino chromen-2-ones (4)
were accomplished in a one pot three component reaction in acetic acid and determined their anti-micro-
bial and anti-biofilm activities. Compounds 4o and 4p showed an excellent anti-microbial activity against
Micrococcus luteus MTCC 2470 at a par with standard control (Ciprofloxacin) and exhibited best activity
against Staphylococcus aureus MTCC 96 and Bacillus subtilis MTCC 121. Further, compounds 4h, 4i, 4m, 4n
and 4q showed promising activity against Micrococcus luteus MTCC 2470, Staphylococcus aureus MTCC 96
and Bacillus subtilis MTCC 121. Whereas, compounds 4m showed very promising biofilm inhibition activ-
ity against Staphylococcus aureus MLS 16 MTCC 2940 and 4o, 4p showed very potent activity against
Staphylococcus aureus MTCC 96 at a par with Ciprofloxacin used as standard control.
Received 25 September 2013
Revised 4 December 2013
Accepted 10 December 2013
Available online 15 December 2013
Keywords:
6-Amino uracil
4-Hydroxy coumarin
Aldehydes
3-Benzyl substituted pyrimidino chromen-
2-ones
Ó 2013 Elsevier Ltd. All rights reserved.
Chromen-2-ones are an important class of heterocycles which
are omnipresent in natural products and synthetic origin as well.
Chromen-2-one also called as coumarin known to exhibit a broad
spectrum of biological activities such as anticancer, anti-inflamma-
tory, antioxidant, antimicrobial and anticoagulant activities.1–3
Among the coumarins family, 3-substituted-4-hydroxy coumarins
have gained popularity. More specifically, 3-benzyl substituted
4-hydroxy coumarins have received much importance due to its
abundance in medicinal scaffolds like warfarin, phenprocumon
and novobiocin (Fig. 1). Further, 3-aryl substituted coumarins have
been attractive research candidates owing to their application as
additives in food, perfumes and cosmetics.4
Similarly, pyrimidine moiety is an important class of N-contain-
ing heterocycles and widely used as key building blocks for phar-
maceutical agents. It is known to exhibit wide spectrum of
pharmacophores as it acts as analgesic,5 antifungal,6 anti-hyper-
tensive and anti-tumor7 agents (Fig. 1).
moiety as a core unit are important targets and are known to exhi-
bit various pharmaceutical activities.10–12
In view of the biological significance of coumarin and pyrimi-
dine moieties and also as
a part of our ongoing research
programme on the bioactive coumarin derivatives,13 we planned
to take-up the synthesis of 3-benzyl substituted pyrimidino cou-
marins as a molecular scaffold and determine anti-microbial and
anti-biofilm activities. In this context, literature review at this
stage revealed that a number of methods is available on the
synthesis of pyranochromenes,14 benzylpyrazolylcoumarins15 and
pyridine based coumarins.16 However, it is surprising to note that
there are no reports available on a molecular skeleton having
pyrimidine and coumarin fragments joined through a benzyl
functional. With this background, herein report for the first time,
synthesis of highly functionalized 3-benzyl substituted pyrimidino
chromen-2-ones (4) and their anti-microbial and anti-biofilm
activity studies.
Further, natural products with a pyrimidine skeleton such as
Initially a model reaction was conducted with 6-amino-1,3-di-
methyl uracil (1) (1.0 mmol), 4-cyano benzaldehyde (2) (1.1 mmol)
and 4-hydroxy-6-methyl coumarin (3a) (1.0 mmol) under solvent
free condition at 130 °C for 2 h (Table 1, entry 1). Interestingly,
the formation of two products 4 and 5 were observed in 30 and
20% yields. Subsequently, a series of reactions were conducted to
optimize the reaction conditions for exclusive formation of 4 by
8
vitamin B1 and nucleotide bases9 play an important role in life
science studies. In addition, organic compounds with pyrimidine
⇑
Corresponding author. Tel.: +91 40 27191436; fax: +91 40 27193382.
E-mail addresses: srikrishnua@yahoo.com, krishnu@iict.res.in (K. Atmakur).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.12.038

486
N. R. Emmadi et al. / Bioorg. Med. Chem. Lett. 24 (2014) 485–489
O
O
OH
OH
OH
O
H2N
MeO
O
O
OH
O
H
N
OH
O
O
F
O
O
O
O
Phenprocoumon
O
Warfarin
Novobiocin
HN
OCH3
C6H5
C2H5
NH2
N
H3CO
H3CO
N
NH2
O
O
N
N
HO
N
O
N
H
O
N
H
O
NH2
Trimethoprim
N3
Zidovudine
Methyl phenobarbital
Flucytocine
Figure 1. 4-Hydroxy coumarin and pyrimidine moieties containing drugs.
Table 1
Catalysts screening and optimization of reaction conditions for regioselective formation of 4
CN
CN
O
N
CHO
NH2
N
OH
O
NH2
N
OH
O
CH3
CH3
O
N
H3C
+
H3C
+
O
H3C
CH3
O
Conditions
N
+
H2N
O
N
CH3
O
NH2
O
N
CH3
O
O
N
CH3
O
CH3
CN
2
4
1
5
3
Entry
Solvent
Catalyst (mol %)
Time (h)
T (°C)
Yielda (%) 4
Yielda (%) 5
1
2
3
4
5
6
7
None
H2O
Ethanol
Ethanol
Ethanol
H2O
—
2
1
1
1
1
1
1
130
100
80
80
80
30
70
55
44
45
48
73
20
24
30
40
38
40
19
PTSA (20)
PTSA (20)
CeCl3 (20)
FeCl3 (20)
InCl3 (20)
100
80
Ethanol
L-Proline (20)
8
9
10
11
12
Ethanol
AcOH
AcOH
AcOH
AcOH
SnCl2Á2H2O (20)
1
2
1
1
3
80
RT
80
120
120
60
30
50
82
79
28
50
35
10
10
—
—
—
—
Bold values indicate the higher yields and in fact reflects the preferred reaction parameter.
a
4-Hydroxy coumarin (3a) (1 mmol), p-cyanobenzaldehyde (2), (1 mmol), 6-amino uracil (1 mmol) and catalyst were heated to the specified temperature.
R
OH
O
NH2
N
OH
O
RI
RI
CH3
O
O
O
N
CH3
O
4a-q
3a : RI= CH3
3b
I
: R = F
R
OH
OH
O
NH2
N
CH3
O
O
N
CH3
1
H3C
O
CH3
O
O
N
H3C
O O
N
3c
Acetic acid
Reflux
CH3
R
CHO
4r-s
H2N
OH
O
2
R
OH
NH2
O
CH3
N
3d
O
N
O
O
O
CH3
4t-v
Scheme 1. One pot three component synthesis of pyrimidino chromene derivatives.
employing various Lewis acid catalysts in ethanol/water as a sol-
vent. However, these studies resulted in improved yields of both
4 (44–70%) and 5 (24–40%).
In order to improve the regioselectivity of 4, a reaction was
conducted in acetic acid without added catalyst and found that
the yield of compound 4 was dramatically improved. However,

N. R. Emmadi et al. / Bioorg. Med. Chem. Lett. 24 (2014) 485–489
487
Table 2
Synthesis of 3-benzyl substituted pyrimidino chromen-2-ones (4a–v) in acetic acid under reflux conditions
Entry
R
Coumarin
Producta
Yieldb (%)
Mp (°C)
Entry
R
Coumarin
Producta
Yieldb (%)
72
Mp (°C)
MeO
1
3a
4a
76
166–168
12
3b
4l
227–229
251–253
NC
HO
OMe
Ph
2
3
4
5
3a
3a
3a
3a
4b
4c
4d
4e
82
74
75
77
169–171
155–157
94–95
13
14
15
16
3b
3b
3b
3b
4m
4n
4o
4p
84
75
79
77
F
N
N
Ph
MeO
248–250
243–246
257–259
MeO
N
N
Ph
N
N
Ph
Cl
151–153
N
N
Ph
O2N
6
3a
4f
80
233–234
17
3b
4q
82
272–274
F3C
N
N
Ph
EtO
HO
7
8
3a
3a
4g
4h
69
78
140–141
258–259
18
19
3c
3c
4r
4s
78
70
140–142
171–173
F3C
Ph
N
N
Ph
MeO
9
3a
4i
76
249–251
20
3d
4t
74
230–232
NC
N
N
Ph
MeO
MeO
10
11
3b
3b
4j
80
70
248–250
183–185
21
22
3d
3d
4u
4v
78
76
254–255
167–169
NC
MeO
4k
HO
F3C
a
All the products are confirmed by NMR , IR and mass spectrometry.
Yields refers to pure products after column chromatography.
b
experiments in acetic acid were further continued by varying the
temperature and best results (82%) were obtained17 at reflux tem-
perature (Table 1, entry 11). Regioselective formation of 4 in the re-
flux condition may be attributed to rapid keto-enol tautomerism of
compound 3 that may help in predominate reaction with Knoeve-
nagel product of aldehyde and uracil, at the same time, ring deac-
tivation of second molecule of compound 1 as the lone pair
electrons on the amine functional are suppose to involve in driving
the reaction in favor of 5 are trapped with hydrogen bonding which
reaction condition (Scheme 1) and furnished 4 as a racemic com-
pound in moderate to good yields (Table 2). In order to cyclize
the compound 4, reflux in acetic acid was further continued
overnight. However, there was no formation of any cyclized
product. Further attempts for cyclization by employing acid cat-
18,19
alysts such as PTSA, P2O5, H2SO4 and InCl3
in toluene under
reflux condition were unsuccessful. Whereas, when PCl5, POCl3,
SOCl2, and NCS employed for cyclization, formation of insepara-
ble mixture of compounds observed and the compound 4 was
decomposed.
results in shifting the adjacent
p electrons.
Encouraged by the remarkable results obtained in acetic acid,
the generality and scope of this coupling protocol was demon-
strated by synthesizing a series of 3-benzyl substituted pyrimidi-
The structure of 4 was well characterized by proton NMR spec-
tra where –NH2 protons appeared at d 6.46 (D2O exchangeable)
and two singlet’s corresponding to –NCH3 protons appeared at d
3.57, 3.33 followed by aromatic protons at d 7.76–7.23. Mass spec-
tra confirmed the molecular ion peak. Further, structure of a repre-
sentative compound was unambiguously confirmed by single
no coumarin derivatives 4a–v.
A wide range of aldehydes
(aromatic, hetero aromatic, aliphatic) and different coumarin
derivatives (3a, 3b, 3c, 3d) were well tolerated under these

488
N. R. Emmadi et al. / Bioorg. Med. Chem. Lett. 24 (2014) 485–489
crystal X-ray diffraction analysis (Fig. 2) and the data deposited20
at the CCDC 930245.
Next, compounds in 4 series were subjected to anti-microbial
and anti-biofilm activity screening as the symbiosis of coumarin
and pyrimidine moieties as a single unit could become a better
molecule from a biological activity point of view and also on ac-
count of a very few scaffolds such as halogenated furanones,21 ana-
logues of the sponge derived marine natural alkaloids oroidin and
bromoageliferin,22–25 2-aminoimidazoles and imidazopyridinium
salts26 have been studied for anti-biofilm activity. The outcome
of the anti-microbial activity screening (Table 3) showed that the
compounds in 4 series with pyrazolophenyl substitution on the
carbon attached to coumarin and pyrimidine ring made a very sig-
nificant impact against various Gram-positive and Gram-negative
bacterial strains. Specifically compounds 4o and 4p (entries 15
and 16) showed very promising activity against Micrococcus luteus
MTCC 2470 at par with standard control (Ciprofloxacin) and exhib-
ited promising activity against Staphylococcus aureus MTCC 96 and
Bacillus subtilis MTCC 121. Compounds 4m and 4v (entries 13 and
22) showed activity against all the tested Gram-positive strains.
Further, compounds 4j, 4k, 4r and 4u (entries 8, 9, 14 and 17)
showed good activity against Gram-positive strains like Micrococ-
cus luteus MTCC 2470, Staphylococcus aureus MTCC 96 and Bacillus
Figure 2. X-ray crystallography structure of 4a.
Table 3
Antimicrobial activity of synthesized compounds 4a–v
S. No.
Test compounds
Minimum inhibitory concentration (
l
g/ml)
S.No
Test compounds
Minimum inhibitory concentration (
l
g/ml)
M.la
S.ab
S.ac
B.sd
P.ae
M.la
S.ab
S.ac
B.sd
P.ae
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
>150
>150
75.0
75.0
75.0
18.75
9.37
2.34
2.34
>150
9.37
>150
>150
>150
75.0
>150
>150
75.0
4.68
4.68
75.0
75.0
150
150
>150
37.50
75.0
18.75
9.37
9.37
9.37
2.34
2.34
75.0
9.37
>150
>150
>150
>150
>150
9.37
12
13
14
15
16
17
18
19
20
21
22
4l
18.75
2.34
2.34
0.58
0.58
2.34
>150
>150
150
>150
2.34
4.68
2.34
1.17
4.68
>150
>150
>150
>150
9.37
37.50
1.17
>150
4.68
2.34
1.17
1.17
2.34
150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
4m
4n
4o
4p
4q
4r
4s
4t
4u
4v
75.0
75.0
150
18.75
9.37
>150
>150
75.0
37.50
>150
>150
>150
>150
>150
>150
37.50
9.37
9.37
>150
>150
>150
>150
150
9
10
11
37.50
18.75
9.37
4j
4k
>150
18.75
2.34
Ciprofloxacin (standard control)
0.58
0.58
0.58
0.58
0.58
Ciprofloxacin (standard control)
0.58
0.58
0.58
0.58
0.58
a
b
c
Micrococcus luteus MTCC 2470.
Staphylococcus aureus MTCC 96.
Staphylococcus aureus MLS-16 MTCC 2940.
Bacillus subtilis MTCC 121.
d
e
Pseudomonas aeruginosa MTCC 2453.
Table 4
Biofilm inhibition assay
S.No.
Test compounds
Minimum biofilm eradication concentration (MBEC) (
lg/ml)
S.aa
S.ab
P.ac
*
1
2
3
4
5
6
7
8
4f
—
—
20
10
—
—
40
4
—
—
—
—
20
20
—
—
—
—
—
—
—
—
—
4g
4h
4i
4k
4m
4n
4o
4p
4q
4v
10
10
—
10
10
4
9
10
11
4
10
10
10
Ciprofloxacin (standard control)
4
4
4
*
No activity.
a
Staphylococcus aureus MTCC 96.
Staphylococcus aureus MLS-16 MTCC 2940.
b
c
Pseudomonas aeruginosa MTCC 2453.

N. R. Emmadi et al. / Bioorg. Med. Chem. Lett. 24 (2014) 485–489
489
4. Murray, R. D. H.; Mendez, J.; Brown, S. A. The Nature of Coumarins: Chemistry
and Biochemistry; Wiley: New York, 1982.
5. Regnier, G.; Canevar, L.; Le, R. J.; Douarec, J. C.; Halstop, S.; Daussy, J. J. Med.
Chem. 1972, 15, 295.
6. Kotaiah, Y.; Hari, K. N.; Naga Raju, K.; Rao, C. V.; Jonnalagadda, S. B.; Suresh, M.
J. Korean Chem. Soc. 2012, 56, 1.
subtilis MTCC 121. While, compounds 4f and 4g (entries 6 and 7)
showed good activity against Pseudomonas aeruginosa MTCC 2453
along with Micrococcus luteus MTCC 2470, Staphylococcus aureus
MLS-16 MTCC 2940 and Bacillus subtilis MTCC 121.
Subsequently, compounds that have exhibited high anti-micro-
bial activity against Staphylococcus aureus MTCC 96, Staphylococcus
aureus MLS-16 MTCC 2940, Pseudomonas aeruginosa MTCC 2453
strains were subjected to anti-biofilm screening studies. The out-
come of the study (Table 4) showed that once again the com-
pounds with pyrazolophenyl substitution on the carbon attached
to coumarin and pyrimidine ring displayed a very remarkable bio-
film inhibition activity. Specifically, compound 4m has exhibited
an excellent activity against Staphylococcus aureus MLS 16 MTCC
2940 and 4o, 4p showed very potent activity against Staphylococ-
cus aureus MTCC 96 at par with
Ciprofloxacin used as standard control. Further, compounds 4h–
i, 4m–n and 4q, 4v showed promising activity against Staphylococ-
cus aureus MTCC 96 and 4g, 4v displayed very good activity against
Staphylococcus aureus MLS 16 MTCC 2940.
In conclusion, we have developed an efficient one pot protocol
to synthesize a series of novel and highly functionalized 3-benzyl
substituted pyrimidino chromen-2-ones (4) in a single pot reaction
with simple reaction conditions that resulted in high yields with
high compatibility and determined their anti-microbial and anti-
biofilm activities. Some of the compounds, specifically 4m, 4o
and 4p have showed a very potent anti-microbial and biofilm inhi-
bition activities and the data is helpful to design and synthesize
more such derivatives to be taken-up for further studies.
7. Deshmukh, M. B.; Salunkhe, S. M.; Patil, D. R.; Anbhule, P. V. Eur. J. Med. Chem.
2009, 44, 2651.
8. Knight, B. C. J. G. Biochem. J. 1937, 31, 731.
9. Guo, J.; Yu, L.; Turro, N. J.; Ju, J. Acc. Chem. Res. 2009, 43, 551.
10. Ibrahim, D. A.; El-Metwally, A. M. Eur. J. Med. Chem. 2010, 45, 1158.
11. Gasse, C.; Douguet, D.; Huteau, V.; Marchal, G.; Munier-Lehmann, H.; Pochet, S.
Bioorg. Med. Chem. 2008, 16, 6075.
12. Hassan Hilmy, K. M.; Khalifa, M. M. A.; Allah Hawata, M. A.; AboAlzeen Keshk,
R. M.; El-Torgman, A. A. Eur. J. Med. Chem. 2010, 45, 5243.
13. Narender, R. E.; Krishnaiah, A.; Kumar, C. G.; Sujitha, P.; Jagadeesh, B. N. Bioorg.
Med. Chem. Lett. 2012, 22, 7261.
14. Gen, Z.; Yaohu, Z.; Jiexi, Y.; Ru, C.; Shoulei, W.; Yunxia, M.; Rui, W. J. Org. Chem.
2012, 77, 878.
15. Partha, P. G.; Gargi, P.; Asish, R. D. Green Chem. 2012, 14, 2691.
16. Abu, T. K.; Deb, K. D.; Kobirul, I.; Pradipta, D. Tetrahedron Lett. 2012, 53, 6418.
17. General procedure for the preparation of compound 4: A mixture of hydroxy
coumarin (3a/3b/3c/3d) (1 mmol), aldehyde (2) (1 mmol), 6-amino uracil (1)
(1 mmol) and acetic acid (5 ml) in 25 ml round bottomed flask was refluxed in
a preheated oil bath for 1 h. Then the reaction mixture was evaporated, leftover
residual mass taken into ethyl acetate, washed with NaHCO3 solution followed
by with water and brine respectively. Organic phase was dried over anhydrous
Na2SO4, evaporated by rotary evaporator under reduced pressure to give the
crude product which was purified by column chromatography over silica gel
by using hexane and ethyl acetate as the eluent to furnish 4.
4-((6-Amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)(4-hydroxy-
6-methyl-2-oxo-2H-chromen-3-yl)methyl) benzonitrile (4a): mp 169–171 °C; 1H
NMR (CDCl3, 300 MHz): d 13.27 (s, 1H), 7.76 (s, 1H), 7.58 (d, J = 8.31 Hz, 2H),
7.40 (d, J = 8.31 Hz, 1H), 7.31 (d, J = 8.31 Hz, 2H), 7.28–7.23 (m, 1H), 6.46 (br s,
2H, D2O exchangeable), 5.74 (s, 1H), 3.57 (s, 3H), 3.33 (s, 3H), 2.42 (s, 3H) ppm;
13C NMR (75 MHz, CDCl3): 168.0, 165.4, 164.5, 154.9, 150.4, 143.7, 134.4,
133.7, 132.2, 127.2, 124.1, 118.9, 116.6, 116.0, 103.1, 88.4, 36.8, 30.0, 28.7,
20.9 ppm. IR (KBr): 3396, 3215, 2924, 2227, 1699, 1664, 1578, 1507 cmÀ1
HRMS (ESI) Anal. Calcd for
445.15079.
;
C
24H21O5N4 m/z 445.15065 [M+H]+. Found:
Acknowledgments
18. Verma, G. K.; Raghuvanshi, K.; Kumar, R.; Singh, M. S. Tetrahedron Lett. 2012,
53, 399.
Authors are thankful to Director IICT for constant support and
ENR is thankful to CSIR New Delhi for SRF.
19. Seetham, N. P.; Borah, P.; Bhuyan, P. Tetrahedron Lett. 2012, 53, 4015.
20. CCDC 930245 contains the supplementary crystallographic data for this Letter.
These data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html [or from the Cambridge Crystallographic Data Centre (CCDC),
12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 (0) 1223 336 033; email:
deposit@ccdc.cam.ac.uk].
21. Steenackers, H. P.; Levin, J.; Janssens, J. C.; De Weerdt, A.; Balzarini, J.;
Vanderleyden, J.; De Vos, D. E.; De Keersmaecker, S. C. Bioorg. Med. Chem. 2010,
18, 5224.
Supplementary data
Supplementary data (X-ray crystallographic data, experimental
procedure and spectroscopic data of all the compounds) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.bmcl.2013.12.038.
22. Huigens, R. W., 3rd; Richards, J. J.; Parise, G.; Ballard, T. E.; Zeng, W.; Deora, R.;
Melander, C. J. Am. Chem. Soc. 2007, 129, 6966.
23. Richards, J. J.; Ballard, T. E.; Melander, C. Org. Biomol. Chem. 2008, 6, 1356.
24. Rogers, S. A.; Melander, C. Angew. Chem., Int. Ed. 2008, 47, 5229.
25. Richards, J. J.; Ballard, T. E.; Huigens, R. W., 3rd; Melander, C. ChemBioChem
2008, 9, 1267.
26. Steenackers, H. P. L.; Ermolatev, D. S.; Bharat, S.; De Weerdt, A.; De Coster, D.;
Anamic, S.; Van der Eycken, E. V.; De Vos, D. E.; Vanderleyden, J.; Sigrd, C. J.;
Keersmaecker, D. Bioorg. Med. Chem. 2011, 19, 3462.
References and notes
1. Su, C. R.; Yeh, S. F.; Liu, C. M.; Damu, A. G.; Kuo, T. H.; Chiang, P. C.; Bastow, K. F.;
Lee, K. H.; Wu, T. S. Bioorg. Med. Chem. 2009, 17, 6137.
2. Nicolaides, D. N.; Gautam, D. R.; Litinas, K. E.; Hadjipavlou-Litina, D. J.;
Fylaktakidou, K. C. Eur. J. Med. Chem. 2004, 39, 323.
3. Jung, J. C.; Park, O. S. Molecules 2009, 14, 4790.