Design, synthesis, and structure-activity relationships of new benzofuro[3,2-b]pyridin-7-ols as DNA topoisomerase II inhibitors

Article abstract of DOI:10.1016/j.bmcl.2018.01.048

Human DNA topoisomerases have become attractive targets for developing more effective anticancer drugs. In this study, a series of new benzofuro[3,2-b]pyridin-7-ols were designed and synthesized for the first time and screened for their topoisomerase I and II inhibitory and antiproliferative activity. Structure-activity relationships revealed the position of ortho- and para-hydroxyl group at 2-phenyl ring, and meta-hydroxyl group at 4-phenyl ring of benzofuro[3,2-b]pyridin-7-ol are important for potent and selective topo II inhibitory activity. Compound 11 showed the most selective and potent topo II inhibition (100% inhibition at 100 μM) and strongest antiproliferative activity (IC₅₀ = 0.86 μM) than all the positive controls in HeLa cell line.

Full text of DOI:10.1016/j.bmcl.2018.01.048

Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis, and structure-activity relationships of new benzofuro
[3,2-b]pyridin-7-ols as DNA topoisomerase II inhibitors
a,
Aarajana Shrestha a,c, Hyunji Jo b,c, Youngjoo Kwon b, , Eung-Seok Lee
⇑
⇑
a College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea
b College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Global Top 5 Program Ewha Womans University, Seoul 120-750, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Human DNA topoisomerases have become attractive targets for developing more effective anticancer
drugs. In this study, a series of new benzofuro[3,2-b]pyridin-7-ols were designed and synthesized for
the first time and screened for their topoisomerase I and II inhibitory and antiproliferative activity.
Structure-activity relationships revealed the position of ortho- and para-hydroxyl group at 2-phenyl ring,
and meta-hydroxyl group at 4-phenyl ring of benzofuro[3,2-b]pyridin-7-ol are important for potent and
selective topo II inhibitory activity. Compound 11 showed the most selective and potent topo II inhibition
(100% inhibition at 100 mM) and strongest antiproliferative activity (IC50 = 0.86 mM) than all the positive
controls in HeLa cell line.
Received 19 December 2017
Revised 11 January 2018
Accepted 23 January 2018
Available online xxxx
Keywords:
Fused heterocycles
Benzofuro[3,2-b]pyridin-7-ol
Hydroxyl-substituent
Topoisomerase inhibition
Antiproliferative activity
Structure-activity relationship
Ó 2018 Elsevier Ltd. All rights reserved.
Topoisomerases (topos) are DNA binding nuclear protein that
regulates DNA topology by releasing the torsional stress which
occurs during cell-proliferation, transcription, recombination,
mitosis and chromosomal segregation.1 Because of their vital role,
topos are key mechanistic targets of many anticancer agents whose
inhibition impedes fundamental metabolic processes of cell
growth and cell death.2–4 In mammalian cells, based on the molec-
ular mechanism of topo enzymes, they are divided into two forms:
topo I that breaks only single strand, and topo II that cuts both
strands of DNA.5,6 Several studies based on natural and synthetic
products as novel topo inhibitors is ongoing to overcome side
effects and limitations of clinically used topo inhibitors such as
adriamycin, etoposide, and camptothecin.7,8
In the recent years, bioactive compounds with fused hetero-
cyclic rings containing nitrogen and oxygen atoms are gaining
more popularity in drug discovery due to its diverse biological
activities.9 Moreover, many studies have reported that compounds
containing benzofuran as an active pharmacophore exhibited wide
range of pharmacological effects such as anti-inflammatory, anti-
cancer, antiviral, and anti-hyperlipidemic activities.10 Our research
group has focused on study of topo inhibitory and antiproliferative
activity of various fused heterocyclic structures containing
O
O
N
N
N
benzofuro[3,2-b]pyridine
5H-indeno[1,2-b]pyridine
5H-chromeno[4,3-b]pyridine
N
N
N
N
S
5,6-dihydro[1,10]phenanthroline
5,6-dihydrobenzo[h]quinoline 5,6-dihydrothieno[2,3-h]quinoline
Fig. 1. Fused heterocyclic structures containing pyridine ring.
⇑
Corresponding authors.
E-mail addresses: ykwon@ewha.ac.kr (Y. Kwon), eslee@yu.ac.kr (E.-S. Lee).
Authors have contributed equally.
c
https://doi.org/10.1016/j.bmcl.2018.01.048
0960-894X/Ó 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Shrestha A., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.01.048

2
A. Shrestha et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
bitory activity and antiproliferative activity by incorporating a
R
R = H / OH
hydroxyl substituent at 7-position of benzofuro[3,2-b]pyridine
ring (Fig. 2). Therefore, in this report, we systematically designed
and synthesized a novel series of sixteen benzofuro[3,2-b]pyri-
din-7-ol derivatives (1–16), and evaluated for antiproliferative
activity and topo I/II inhibitory activity. In addition, presence of
ortho/meta/para-hydroxyl group at 2- and/or 4-position of phenyl
ring allowed us to explore structure-activity relationships of
hydroxylated benzofuro[3,2-b]pyridin-7-ols. To the best of our
knowledge, this is the first study of benzofuro[3,2-b]pyridin-7-ol
as a novel scaffold for developing topo II-targeted antiproliferative
agents.
Antiproliferation
Topo II inhibition
4
2
N
R
2,4-diphenyl 5H-indeno[1,2-b]pyridines
R
Ar
N
Hydroxylation
at 7 position
4
O
O
2
7
Ar
N
HO
R
The synthesis of target compounds (benzofuro[3,2-b]pyridin-7-
ols) 1–16 was in three steps (Scheme 1) using modified Kröhnke
pyridine synthesis based on previously reported methods.16,17 At
first, four different non/mono-hydroxylated phenyl pyridinium
iodine salts II (R = a–d) were synthesized in 80–94% yields by
Ar = Aryl group
R = H / OH
benzofuro[3,2-b]pyridin-7-ols
benzofuro[3,2-b]pyridines
Fig. 2. Designed target compounds.
refluxing non/mono-hydroxy acetophenone
I (R = a–d) and
pyridine ring (Fig. 1).11–15 Recently, we reported importance of
hydroxyl group in 2- and/or 4-phenyl rings of benzofuro[3,2-b]pyr-
idine and 5H-indeno[1,2-b]pyridine.13,14 Inspired by these results,
we were encouraged to further investigate the effect on topo inhi-
iodine in pyridine at 140 °C for 3 h. In parallel, a series of four
hydroxylated benzofuranone intermediates (V, VI, VII, and VIII)
were synthesized in 89–96% yields using commercially
available 6-hydroxy-3-coumaranone (III) and benzaldehyde or
I
R
CH3
R
Step I
N
O
O
(i)
I (R=a-d)
II (R=a-d)
HO
HO
II (R=a-d)
O
O
(iv)
Step III
(ii)
N
R
HO
O
V
1-4
OH
R
II (R=a-d)
O
O
OH
(iv)
Step III
(ii)
R
H
N
HO
O
VI
O
5-8
HO
O
IV (R=a-d)
OH
R
Step II
O
OH
III
II (R=a-d)
HO
O
O
(iii)
(iv)
Step III
N
HO
O
VII
9-12
OH
OH
II (R=a-d)
HO
O
O
O
(iv)
Step III
(iii)
N
R
HO
13-16
VIII
OH
OH
HO
R1
=
c
a
b
d
Scheme 1. Synthetic route of compounds 1–16. Reagents and conditions: (i) iodine (1.0 equiv.), pyridine, 3 h, 140 °C, 80–94% yield; (ii) aq. 5 M NaOH, Ethanol, 2–3 h, 0 °C,
89–96% yield; (iii) SOCl2, Ethanol, 1–2 h, 0 °C, 90–95% yield; (iv) NH4OAc in methanol, 12–30 h, 110–125 °C, 7–37% yield.
Please cite this article in press as: Shrestha A., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.01.048

A. Shrestha et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
3
mono-hydroxy benzaldehyde IV (R = a–d) in the presence of aque-
ous sodium hydroxide (5 M NaOH) or thienyl chloride (SOCl2) in
ethanol (Scheme 1 Step II).18 Finally, both the hydroxylated benzo-
furanone intermediates (V–VIII) and pyridinium salts, II (R = a–d)
were refluxed in methanol at 110–125 °C for 12–30 h in the pres-
ence of ammonium acetate (NH4OAc) to synthesize corresponding
target compounds 1–16 in 7–37% yields. Structures of synthesized
compounds are shown in Fig. 3. Though the protection of hydroxyl
moiety was not required, yield of compounds with ortho-phenol
ring at 2-position of pyridine (2, 6, 10, and 14) were relatively
low, which may be due to intermolecular hydrogen bonding as
well as steric hindrance. Physical properties including yield (%),
melting point (°C), retention time (min) and percentage purity
obtained by HPLC are listed in Table S1 (Supporting Information).
O
O
O
O
O
O
O
O
OH
OH
OH
N
HO
HO
N
N
N
HO
HO
HO
HO
HO
HO
OH
OH
1
2
3
4
OH
OH
OH
OH
OH
OH
OH
OH
N
N
N
N
5
6
8
7
OH
O
O
O
O
OH
OH
N
HO
N
N
N
HO
HO
HO
OH
9
10
11
12
OH
OH
OH
OH
O
O
O
O
OH
OH
N
HO
N
N
N
HO
HO
HO
OH
13
14
15
16
Fig. 3. Structures of synthesized benzofuro[3,2-b]pyridin-7-ol derivatives.
Fig. 4. Topoisomerase I and II
topoisomerase I + camptothecin; Lane 1–27: pBR322 DNA + topoisomerase I + compound 1–16; (B) Lane D: pBR322 DNA only; Lane T: pBR322 DNA + topoisomerase II
E: pBR322 DNA + topoisomerase II + etoposide; Lane 1–27: pBR322 DNA + topoisomerase II + compound 1–16.
a
inhibitory activities of compounds. (A) Lane D: pBR322 DNA only; Lane T: pBR322 DNA + topoisomerase I; Lane C: pBR322 DNA +
a
; Lane
a
a
Please cite this article in press as: Shrestha A., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.01.048

4
A. Shrestha et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Table 1
Topo I and II inhibitory activity and antiproliferative activity of the prepared compounds 1–16.
Compounds
% Inhibition
Topo II
IC50
(lM)
Topo I
100
HCT15
T47D
HeLa
100
l
M
20
lM
l
M
20 lM
Camptothecin
Etoposide
Adriamycin
85.1a/83.9b
45.6a/47.8b
0.05 0.01
2.94 0.10
0.51 0.09
0.07 0.02
0.40 0.03
0.31 0.04
1.37 0.14
9.21 0.16
1.50 0.01
76.6a/61.9b
39.5a/49.7b
1
2
3
4
5
6
7
8
18.3
83.1
46.3
78.4
52.5
46.0
63.0
87.3
98.0
99.1
100.0
66.1
0.4
NT
30.8
18.2
15.9
43.9
14.2
30.1
33.9
3.3
27.4
25.6
22.4
66.3
30.3
39.9
71.7
33.8
0
>50
1.60 0.06
>50
>50
5.74 0.10
>50
2.5 0.1
1.26 0.09
4.11 0.01
6.96 0.70
1.22 0.07
3.73 0.23
>50
9.34 0.38
23.88 0.82
4.21 0.06
>50
>50
4.11 0.11
>50
>50
6.93 0.01
>50
3.63 0.18
2.86 0.19
3.27 0.30
3.39 1.98
0.86 0.02
2.16 0.10
>50
3.62 1.26
29.11 2.60
3.32 0.10
52.6
32.5
72.2
19.1
38.0
12.0
29.0
41.9
76.0
74.1
55.1
NT
NT
NT
0
NT
0
0.71 0.02
2.79 0.14
5.30 0.39
0.74 0.02
1.03 0.04
0.64 0.06
0.62 0.01
0.34 0.03
1.26 0.19
0.59 0.01
0.19 0.02
>50
0
NT
NT
NT
NT
38.1
0.0
0.0
60.9
18.6
9
10
11
12
13
14
15
16
100.0
58.4
71.0
70.8
45.1
65.9
1.97 0.29
5.25 0.31
0.17 0.02
Each datum represents mean S.D. from three different experiments performed in triplicate.
NT: Not tested, acontrol value for compounds 1–8; bvalue for compounds 9–16.
HCT15: human colorectal adenocarcinoma cell line; T47D: human ductal breast cancer cell line; HeLa: human cervix tumor cell line.
Camptothecin: positive control for topo I inhibition and antiproliferative activity; Etoposide: positive control for topo II inhibition and antiproliferative activity; Adriamycin:
positive control for antiproliferative activity.
OH
O
N
(A)
O
OH
N
HO
Non-hydroxylated
O
>
>
benzofuropyridine [15]
N
HO
OH
O
N
O
Di-hydroxylated
benzofuro[3,2-b]pyridin-7-ols
N
HO
HO
OH
Non-hydroxylated
benzofuro[3,2-b]pyridin-7-ol
Mono-hydroxylated
benzofuro[3,2-b]pyridin-7-ols
Strong topo II inhibition
Strong antiproliferation
Weak topo II inhibition
Weak antiproliferation
Moderate to strong topo II inhibition
Weak to moderate antiproliferation
Fig. 5. SAR study based on importance of hydroxyl group at 2- and 4-phenyl ring of benzofuro[3,2-b]pyridin-7-ol.
The newly synthesized benzofuro[3,2-b]pyridin-7-ols 1–16
and 4 containing ortho- and para-hydroxyl group at 2-phenyl ring,
respectively, showed stronger topo II inhibitory activity than eto-
poside both at 100 and 20 mM. Among the compounds containing
hydroxyl group both at 2- and 4-phenyl ring of benzofuro[3,2-b]
pyridin-7-ol, compounds 8, 10–12, 14, and 16 exhibited strong
topo II inhibitory activity with moderate to strong antiproliferative
activity in all cancer cell lines. Compounds 10–12, 14, and 16 dis-
played selective and potent topo II inhibitory activity with the
range from 55.1 to 76.0% as compared to etoposide (49.7%) at 20
mM. Compounds 11 and 14 exhibited 100% topo II inhibition at
100 mM. It is interesting to note that all the compounds (9–12) con-
taining meta-hydroxyl group at 4-phenyl of benzofuro[3,2-b]pyri-
din-7-ol showed potent topo II inhibitory activity and strong
antiproliferative activity (IC50 = 0.19–6.96 mM) in HCT15 and
T47D cell lines. Furthermore, compound 11 with meta-hydroxyl
group at both 2- and 4-phenyl ring of benzofuro[3,2-b]pyridin-7-
ol showed highly selective and potent topo II inhibition along with
strongest antiproliferative activity (IC50 = 0.86 mM) than all the
positive controls in HeLa cell line. In addition, results from Table 1
were evaluated for both topo I and II inhibitory activity, and
in vitro antiproliferative activity against three different human can-
cer cell lines: HCT15 (colorectal adenocarcinoma cell line), T47D
(ductal breast cancer cell line), and HeLa (cervix tumor cell line).
Camptothecin, etoposide, and adriamycin were used as positive
control to compare the biological results and study structure-activ-
ity relationship of the synthesized compounds. Fig. 4 and Table 1
summarize the topo I and II inhibitory activity of compounds 1–
16 at 100 and 20 mM, and antiproliferative activity measuring
IC50 value.
Interestingly, all the new compounds showed weaker topo I
inhibitory activity than positive control, camptothecin, both at
100 and 20 mM (Table 1) with the exception of 15. Compound 1
without hydroxyl group at 2- and 4-phenyl ring of benzofuro
[3,2-b]pyridin-7-ol showed very weak topo I/II inhibition and
antiproliferative activity in all tested cell lines. Except 13, com-
pounds 2–5, and 9 with an additional hydroxyl group either in 2-
or 4-phenyl ring exhibited comparable or stronger topo II inhibi-
tory activity (46.3–98.0%) at 100 mM. Particularly, compound 2
also indicated that T47D cancer cell lines are very sensitive (IC50
=
Please cite this article in press as: Shrestha A., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.01.048

A. Shrestha et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
5
Table 2
Relative topo II inhibitory potencies of synthesized compounds compared to etoposide.
R1
O
N
HO
R
Mono-hydroxylated benzofuro[3,2-b]pyridin-7-ols
Topo II
Dihydroxylated benzofuro[3,2-b]pyridin-7-ols
Topo II
100 mM
20 mM
100 mM
20 mM
2: R = ortho-OH, R1 = H
5: R = H, R1 = ortho-OH
1.08
0.69
1.33
0.48
6: R = ortho-OH, R1 = ortho-OH
10: R = ortho-OH, R1 = meta-OH
14: R = ortho-OH, R1 = para-OH
7: R = meta-OH, R1 = ortho-OH
11: R = meta-OH, R1 = meta-OH
15: R = meta-OH, R1 = para-OH
8: R = para-OH, R1 = ortho-OH
12: R = para-OH, R1 = meta-OH
16: R = para-OH, R1 = para-OH
0.60
1.60
1.62
0.82
1.62
0.94
1.12
1.07
1.15
0.96
1.53
1.42
0.31
1.49
0.91
0.73
1.11
1.33
3: R = meta-OH, R1 = H
9: R = H, R1 = meta-OH
0.60
1.58
0.82
0.84
4: R = para-OH, R1 = H
13: R = H, R1 = para-OH
1.02
NA
1.83
NT
*Relative potency (RP):% inhibition of compound/% inhibition of positive control, NT: Not Tested, NA: Not Active.
OH
N
OH
O
O
OH
O
OH
OH
N
HO
HO
N
HO
2
14
RP=1.62
10
RP=1.60
RP=1.08
OH
OH
OH
O
O
O
OH
N
HO
N
N
HO
HO
12
RP=1.07
OH
9
11
RP=1.62
RP=1.58
OH
OH
O
O
O
N
HO
N
N
HO
HO
OH
16
RP=1.15
OH
4
OH
8
RP=1.02
RP=1.12
Relative potency (RP) : % inhibition of compound / % inhibition of positive control etoposide
Fig. 6. Structure of compounds with stronger topo II inhibitory activity than positive control, etoposide, at 100 mM.
0.17–5.25 mM) to all the compounds (6–8, 10–12, 14–16) with 2,4-
diphenol moieties at benzofuro[3,2-b]pyridin-7-ol ring.
xyl group, relative topo II inhibitory potencies of the synthesized
compounds compared to the positive control, etoposide, are listed
in Table 2.
Structure-activity relationships (SAR) from the preliminary bio-
logical results of compounds (2–16), in comparison with 1 and pre-
viously synthesized non-hydroxylated benzofuropyridine (A),15
revealed the importance of hydroxyl group in 2- and 4-position
of benzofuro[3,2-b]pyridin-7-ol structure. Introduction of hydroxyl
group at 2- and 4-phenyl ring of benzofuro[3,2-b]pyridin-7-ol scaf-
fold enhances the selectivity and potency of topo II inhibitory
activity with stronger antiproliferative activity in T47D cancer cell
line (Fig. 5). Moreover, to determine the effect of position of hydro-
Results from Table 2 and Fig. 6 indicated that compounds 2, 10,
and 14 with ortho- hydroxyl group at 2-phenyl ring of benzofuro
[3,2-b]pyridin-7-ol with the exception of 6 showed stronger topo
II inhibitory activity (Relative potency > 1) than positive control,
etoposide, at both 100 and 20 mM. Similarly, compounds 4, 8, 12,
and 16 with para-hydroxyl group at 2-phenyl ring of benzofuro
[3,2-b]pyridin-7-ol with the exception of 8 at 20 mM showed stron-
ger topo II inhibitory activity (Relative potency > 1) at both 100 and
Please cite this article in press as: Shrestha A., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.01.048

6
A. Shrestha et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
OH
R
R
R
N
O
O
O
OH
N
HO
N
HO
HO
OH
ortho- and para- hydroxyl group at 2- phenyl ring
meta- hydroxyl group at 4- phenyl ring
Fig. 7. Summary of SAR based on importance of position of hydroxyl group at 2- and 4-phenyl ring of benzofuro[3,2-b]pyridin-7-ol.
20 mM. Likewise, it is interesting to note that, all compounds with
meta-hydroxyl group at 4-phenyl ring of benzofuro[3,2-b]pyridin-
7-ol showed stronger topo II inhibitory activity (Relative potency >
1) than positive control, etoposide. As shown in Fig. 7, the overall
structure-activity relationships indicated that ortho- and para-
hydroxyl group at 2-phenyl ring, and meta-hydroxyl group at 4-
phenyl ring of benzofuro[3,2-b]pyridin-7-ol is vital for potent topo
II inhibitory activity.
In conclusion, novel series of benzofuro[3,2-b]pyridin-7-ols
incorporating hydroxyl moiety were designed, synthesized, and
evaluated for topo I/II inhibitory activity and antiproliferative
activity. Results of topo II inhibitory and anti-proliferative activity
indicated importance of addition of hydroxyl moiety in 2- and/or
4-phenyl position of benzofuro[3,2-b]pyridin-7-ols for the activity.
Moreover, comparison of relative topo II inhibition potency based
on position of hydroxyl moiety at 2- and 4-phenyl ring of benzo-
furo[3,2-b]pyridin-7-ol revealed that ortho- and para-hydroxyl
group at 2-phenyl ring, and meta-hydroxyl group at 4-phenyl ring
of benzofuro[3,2-b]pyridin-7-ol are crucial for potent and selective
topo II inhibitory activity.
Acknowledgement
This research was supported by the 2016 Yeungnam University
Research Grant.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.bmcl.2018.01.048.
References
1. Wang JC. Nat Rev Mol Cell Biol. 2002;3:430–440.
2. Vos SM, Tretter EM, Schmidt BH, Berger JM. Nat Rev Mol Cell Biol.
2011;12:827–841.
3. Forterre P, Gribaldo S, Gadelle D, Serre MC. Biochimie. 2007;89:427–446.
4. Champoux JJ. Ann Rev Biochem. 2001;70:369–413.
5. Pommier Y. Chem Rev. 2009;109:2894–2902.
6. Christensen MO, Larsen MK, Barthelmes HU, et al. J Cell Biol. 2002;157:31–44.
7. Pommier Y. Nat Rev Cancer. 2006;6:789–802.
8. Bailly C. Chem Rev. 2012;112:3611–3640.
9. Gomtsyan A. Chem Heterocycl Compd. 2012;48:7–10.
10. Khanam H. Eur J Med Chem. 2015;97:483–504.
Among all the benzofuro[3,2-b]pyridin-7-ol derivatives, com-
pound 11 showed the most potent and selective topo II inhibition
as well as stronger antiproliferative activity than all the positive
controls in HeLa cell line. Based on these findings, further opti-
mization and mechanistic study on compound 11 is underway,
and the results will be reported elsewhere. We believe that the
present study provides useful information for designing a new
strategy to develop topo II-targeted anticancer drugs.
11. Thapa U, Thapa P, Karki R, et al. Eur J Med Chem. 2011;46:3201–3209.
12. Thapa P, Karki R, Yoo HY, et al. Bioorg Chem. 2012;40:67–78.
13. Kadayat TM, Park C, Jun KY, et al. Eur J Med Chem. 2015;90:302–314.
14. Park S, Magar TBT, Kadayat TM, et al. Eur J Med Chem. 2017;127:318–333.
15. Thapa P, Jahng Y, Park PH, Jee JG, Kwon Y, Lee E-S. B Korean Chem Soc.
2013;34:3073–3082.
16. Kröhnke F. Angew Chem Int Ed. 1963;2:225–238.
17. Kröhnke F. Synthesis. 1976;1976:1–24.
18. Kadayat TM, Banskota S, Gurung P, et al. Eur J Med Chem. 2017;137:575–597.
Please cite this article in press as: Shrestha A., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.01.048