Discovery of novel 3-benzylquinazolin-4(3H)-ones as potent vasodilative agents

Article abstract of DOI:10.1016/j.bmcl.2014.10.092

In the present study, a series of 3-benzylquinazolin-4(3H)-ones were synthesized and characterized. Their vasodilative effects were evaluated by wire myograph on isolated rat mesenteric arterial ring induced contraction with 60 mM KCl. The SAR of target compounds was discussed preliminarily. Among these compounds, 2a and 2c displayed potent vasodilatation action and could compete significantly the rat mesenteric arterial rings induced contraction with phenylephrine. Compounds 2a and 2c were further tested for their antihypertensive effects in SHR by oral administration. The results indicated that 2a and 2c could reduce significantly both diastolic and systolic blood pressure. Moreover, 2c displayed antihypertensive effect in a dose dependent manner, and could maintain the effects for 6 h at a dosage of 4.0 mg/kg. These findings suggest that the title compounds are novel vasodilative agents, representing a novel series of promising antihypertensive agents.

Full text of DOI:10.1016/j.bmcl.2014.10.092

Bioorganic & Medicinal Chemistry Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of novel 3-benzylquinazolin-4(3H)-ones as potent
vasodilative agents
Sai-Jie Zuo a, , Sen Li b, , Rui-Hong Yu b, Guo-Xun Zheng a, Yong-Xiao Cao b, San-Qi Zhang a,
⇑
a Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi’an Jiaotong University, Xi’an, Shaanxi 710061, PR China
b Department of Pharmacology, School of Basic Medical Sciences, Health Science Center, Xi’an Jiaotong University, Xi’an, Shaanxi 710061, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
In the present study, a series of 3-benzylquinazolin-4(3H)-ones were synthesized and characterized.
Their vasodilative effects were evaluated by wire myograph on isolated rat mesenteric arterial ring
induced contraction with 60 mM KCl. The SAR of target compounds was discussed preliminarily. Among
these compounds, 2a and 2c displayed potent vasodilatation action and could compete significantly the
rat mesenteric arterial rings induced contraction with phenylephrine. Compounds 2a and 2c were further
tested for their antihypertensive effects in SHR by oral administration. The results indicated that 2a and
2c could reduce significantly both diastolic and systolic blood pressure. Moreover, 2c displayed antihy-
pertensive effect in a dose dependent manner, and could maintain the effects for 6 h at a dosage of
4.0 mg/kg. These findings suggest that the title compounds are novel vasodilative agents, representing
a novel series of promising antihypertensive agents.
Received 22 September 2014
Revised 28 October 2014
Accepted 29 October 2014
Available online xxxx
Keywords:
3-Benzylquinazolin-4(3H)-ones
Synthesis
Vasodilation
Antihypertension
Ó 2014 Elsevier Ltd. All rights reserved.
The chemistry and biological study of quinazoline derivatives
have been an interesting field in medicinal chemistry for a long
time. Quinazoline and quinazolin-4(3H)-one have been regarded
as two important drug scaffolds in drug discovery. The compounds
derived from quinazoline or quinazolin-4(3H)-one exhibit a broad
spectrum of biological activities, such as antitumor, antimicrobial,
antifungal, anti-inflammatory, anticonvulsant and antidiabetic
activities. Several 4-arylaminoquinazoline derivatives, including
gefitinib, erlotinib and lapatinib, were studied as EGFR-TK
inhibitors and launched successfully to treat cancer clinically.1,2
4,6-Disubstituted quinazoline derivatives were identified as PI3K
inhibitors and anticancer agents.3 The progress on the biological
activities of quinazoline and quinazolin-4(3H)-one derivatives
have been reviewed, respectively.4–7
identified that 3-substituted quinazoline-2,4-diones are potent
inhibitors of African trypanosomiasis.11 Sasmal discovered that
2,4,6-trisubstituted quinazolines are melanin concentrating hor-
mone receptor 1 (MCHR1) antagonists and discussed the SAR in
detail.12 Compared with quinazoline derivatives, the research on
quinazolin-4(3H)-one is relatively less active. Some quinazolin-
4(3H)-one derivatives display better activity than saturated drugs
and could become new drugs in future. Balzarini reported that
3-(2-hydroxybenzylideneamino)-2-(4-chlorophenyl)-quinazoline-
4(3H)-one is antiviral agent.13 Saravanan discovered that 2-methyl-
3- substituted-quinazolin-4(3H)-one displays analgesic activity.14
Wang discovered that (E)-3-[2-arylideneaminoethyl]-2-[4-(triflu-
oromethoxy)-anilino]quinazoline-4(3H)-one derivatives exhibit
potent antifungal activities.15 Similarly, the quinazolin-4(3H)-one
attached a triazole fragment at 3-position exhibited broad-spec-
trum antifungal activity against resistant and emerging patho-
gens.16,17 Ahmed reported that 6,8-dibromo-4(3H)quinazolinone
derivatives show strong antiproliferative activity against MCF-7.18
Zayed described that the design, synthesis, and biological evalua-
tion studies of 3-substituted 6,8-diiodo-2-methylquinazolin-
4(3H)-ones as anticonvulsant agents.19 The compounds derived
In recent two years, the novel quinazoline and quinazolin-4(3H)-
one derivatives were reported and their new activities were
described. Russu reported that 2-phenyl-6-substituted quinazoline
derivatives could inhibit NF-jB function, and the growth of cancer
cells.8 Mowafy described the design, synthesis and antiproliferative
activity of 4,6-quinazolinediamines as potent EGFR-TK inhibitors.9
de Esch discovered that 4-amino-2-(4-methylpiperazin-1-yl)qui-
nazoline is a highly potent 5-HT3 receptor ligand.10 Huggan
from quinazoline-2,4(1H,3H)-diones also exhibit
a wealth of
biologic activities.20,21 Lately, Leivers discovered that 2-amino-
4,6-disubstituted-4(3H)quinazolinones are extremely selective
PI4KIII
1,6-disubstituted-4(3H)quinazolinones are allosteric HCV NS5B
⇑
Corresponding author. Tel./fax: +86 29 82657040.
E-mail address: sqzhang@xjtu.edu.cn (S.-Q. Zhang).
S. Zuo and S. Li contributed equally to this work.
a
inhibitors and anti HCV agents.22 Hucke discovered that
http://dx.doi.org/10.1016/j.bmcl.2014.10.092
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S.-J. Zuo et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
O
O
(see Fig. 1). Herein, we describe the synthesis, vasodilative and
antihypertensive effect of 3-benzylquinazolin-4(3H)-ones.30
The synthetic route for the title compounds 1a–1o is outlined in
Scheme 1. The mixture of substituted 2-aminobenzoic acid, triethyl
orthoformate and substituted benzylamine in ethanol was refluxed
for 2–8 h to produce the title compounds 1a–1o.31
scaffold hopping
N
N
'
R'
R
R
R
N
Figure 1. The design idea of the research subject.
4-Methoxyaniline was used as starting material to synthesize
compound 1p to compare the vasodilative action of 3-phenylqui-
nazolin-4(3H)-one with 1h (Scheme 2).
polymerase thumb pocket 2 inhibitor with picomolar cellular repli-
con potency.23 Chern identified that (E)-3-(2-ethyl-7-fluoro-4-oxo-
3-phenethyl-3,4-dihydroquinazolin-6-yl)-N-hydroxy-acrylamide
is a potent selective HDAC6 inhibitor.24
In search for novel antihypertensive agents, some derivatives
from quinazoline or quinazolin-4(3H)-one were discovered. For
example, prazosin and terazosin, derived from 4-amino-2-piperaz-
inylquinazolines, were identified as a1 adrenergic blockers using
clinically to treat hypertension.25,26 Recently, Abou El Ella discov-
ered that 2-methyl-3-arylpiperazinylaminoquinazolin-4(3H)-one
To expand the structural diversity of the substituted group at
3-position, we synthesized compound 2 with a benzyloxy group
attached to the phenyl ring of 3-benzyl group (Scheme 3).
The reaction of the commercial available hydroxyl benzalde-
hyde with benzyl bromide produced compound 3. The latter was
reduced with sodium borohydride to produce the corresponding
benzyl alcohol 4, which was then converted to benzyl chloride 5
by the reaction with thionyl chloride. Benzyl amine 6 was prepared
by employing the Gabriel reaction of
5 with phthalimide.
derivatives are also
a1-adrenoreceptor antagonists and show
Compounds 2a–2h were synthesized by the same reaction with
preparation of compound 1.
hypotensive effects in vivo.27 Although, a few studies provide the
diversity of quinazolin-4(3H)-one derivatives on activity and
structure, additional studies for discovering the novel activities of
quinazolin-4(3H)-one derivatives are still called for.
Compounds 2j–2l can also be synthesized from compound
2a, 6,7-dimethoxy-3-(4-(benzyloxy)-3-methoxyphenylmethyl)
quinazolin-4(3H)-one. The O-benzyl in 2a was removed by cata-
lytic hydrogenolysis with Pd-C in H2 atmosphere to produce com-
pound 2i. The subsequent nucleophilic substitution reaction
produced the compounds 2j–2l (Scheme 4). The catalytic amount
of silver carbonate was added to accelerate the reaction.
The isolated rat mesenteric arterial rings induced contraction
with 60 mM KCl MOPS solution were used in the screening exper-
iment. The vasodilative effects of title compounds were evaluated
by wire myograph with the concentrations ranged from 10À10 M to
10À4 M. The results of title compounds 1 and 2 are listed in Table 1
and Table 2, respectively.
In our previous work, we reported a new approach to the
synthesis of 2-benzyl-3,4-dihydro-1(2H)-isoquinolinones and dis-
covered that these compounds exhibit the vasodilative effects.28,29
The detail results indicate that 2-benzyl-5-hydroxy-6-methoxy-
3,4-dihydro-1(2H)-isoquinolinone induces vasodilation by inhibit-
ing the VDCC and ROCC, and receptor-mediated Ca2+ influx and
release. In order to seek a novel scaffold of antihypertensive agents,
we assume that 3-benzylquinazolin-4(3H)-ones possess the simi-
lar configuration as 2-benzyl-3,4-dihydro-1(2H)-isoquinolinone
on basis of scaffold hopping. The similar characteristic in structure
reveals that 3-benzylquinazolin-4(3H)-ones may be
scaffold of vasodilative agents and antihypertensive drugs
a novel
As we expected, all compounds exhibited significantly vasodila-
tive effects. The maximal vasodilative effect (Emax) range from 78.3%
R3
O
N
R3
R6
R1
R2
CO2H
NH2
R4
R5
R1
R2
R4
R5
H2N
N
a
+ HC(OC2H5)3
+
R6
1a-1o
Scheme 1. Reagent and condition: (a) C2H5OH, reflux, 2–8 h.
OCH3
O
O
OCH3
H3CO
a
H3CO
H3CO
OH
N
+
HC(OC2H5)3
+
H2N
NH2
H3CO
N
1p
Scheme 2. Reagent and condition: (a) C2H5OH, reflux, 6 h.
CHO
CHO
CH2OH
b
a
HO
+
BnO
BnBr
BnO
R
R
R
O
4
3
R = H, F, Cl, OCH3
CH2Cl
H3CO
H3CO
CH2NH2
c
N
d
e
OBn
BnO
BnO
N
R
R
R
2a-2h
6
5
Scheme 3. Reagents and conditions: (a) K2CO3, CH3COCH3, reflux, 3–4 h. (b) NaBH4, MeOH, rt, 3 h. (c) SOCl2, DMF, rt, 1 h. (d) i: phthalimide, K2CO3, DMF, 120 °C, 6 h; ii:
hydrazine hydrate, EtOH, reflux, 4 h. (e) 2-amino-4,5-dimethoxybenzoic acid, CH(OEt)3, EtOH, reflux, 4 h.
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S.-J. Zuo et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
3
O
O
N
O
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
N
a
N
b
N
N
OBn
OCH3
OR
OCH3
N
OH
OCH3
2i
2j-2l
2a
Scheme 4. Reagents and conditions: (a) H2, Pd–C, THF, rt, overnight. (b) Substituted benzyl chloride, Cs2CO3, Ag2CO3, DMF, 120 °C, 6 h.
Table 1
Vasodilative effects of compounds 1a–1p on rat mesenteric arterial rings (n = 8)
O
R3
R1
R2
R4
R5
N
N
R6
Compd
R1
R2
R3
R4
R5
R6
pEC50
Emax (%)
DMSO
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
Nitren
0
0
H
Br
H
H
F
H
H
H
H
H
H
H
H
Cl
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
F
F
F
H
H
H
H
H
H
H
H
H
H
H
H
H
4.0 0.1
4.3 0.1
4.2 0.2
4.3 0.2
4.1 0.1
4.4 0.1
4.6 0.1
4.6 0.2
4.4 0.1
4.5 0.1
4.2 0.2
4.3 0.1
4.7 0.1
6.3 0.1
5.1 0.2
4.2 0.1
8.4 0.2
78.3
96.4
101.2
97.0
87.7
98.2
97.8
100.2
98.3
97.3
86.2
85.6
100.6
103.8
98.6
96.3
103.5
3
4
H
Cl
Cl
F
OMe
OMe
OMe
OMe
OMe
OMe
OMe
3
OMe
OMe
H
5
2
2
3
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OCH2O
OMe
OMe
F
OMe
H
H
NO2
CN
OMe
OMe
3
4
2
1
2
H
OMe
OCH2O
3
4
Figure 2. The vasorelaxant effect of 2a and 2c on rat mesenteric artery induced
contraction with the 60 mM K+. Data were shown as mean SEM, n = 8 for each
group. **p < 0.01 2a, 2c and nitrendipine groups versus DMSO group.
OMe
OMe
OMe
4
3
4
pEC50 = Àlog EC50; Emax: maximal vasodilative effects; Nitren: nitrendipine.
and 1f (pEC50 = 4.4, Emax = 98.2%) were more potent than com-
pounds 1a (pEC50 = 4.0, Emax = 78.3%) and 1b (pEC50 = 4.3,
Emax = 96.4%) indicates that the compounds with 6,7-dimethoxy
may improve the vasodilative effects. Compound 1h (pEC50 = 4.6)
exhibited a little stronger vasodilative effect than that of compounds
1k (pEC50 = 4.2) and 1l (pEC50 = 4.3), which suggests that a substitu-
ent with electron-donating property at R5 position may contribute
the vasodilative effects. Meanwhile, we find that the activities of
title compounds are improved as the number of methoxy substitu-
ent increasing by comparing the vasodilative effect of compounds
1h (pEC50 = 4.6, Emax = 100.2%), 1o (pEC50 = 5.1, Emax = 98.6%) and
1n (pEC50 = 6.3, Emax = 103.8%) with compound 1f (pEC50 = 4.4,
Emax = 98.2). Compound 1p (pEC50 = 4.2) with a 3-phenyl at the
3-position of quinazolinone ring displayed weaker activity than
compound 1h (pEC50 = 4.6), which supports our design assumption.
The data in Table 1 indicate that the substituted groups at the
phenyl of benzyl contribute significantly the vasodilative effects
of title compounds. Thus, we intend to change the substituted
groups linked to the phenyl in benzyl to improve the activity. Ben-
zyloxy, substituted benzyloxy, fluoride or chloride were attached
to the phenyl in 3-benzyl to synthesize compound 2.
Table 2
Vasodilative effects of compounds 2a–2l on rat mesenteric arterial rings (n = 8)
O
R1
H3CO
N
N
R2
H3CO
Compd
R1
R2
pEC50
Emax (%)
DMSO
2a
2b
2c
2d
2e
2f
2g
2h
2i
0
0
OMe
OBn
OMe
OMe
OMe
H
Cl
F
OMe
OMe
OMe
OMe
OBn
OMe
6.4 0.1
4.5 0.1
6.6 0.2
6.0 0.1
5.5 0.1
4.0 0.1
5.0 0.1
5.1 0.1
4.5 0.2
4.7 0.1
6.2 0.1
4.9 0.2
8.4 0.2
102.8
95.0
103.4
99.6
99.7
50.3
98.9
99.1
87.6
93.5
98.4
97.8
103.5
4
3
4
2
3
2
4
3
2
3
2
3
3
OCH2Ph-4-F
OCH2Ph-3-F
OCH2Ph-3,4-diOMe
OCH2Ph-4-F
OCH2Ph-4-F
OCH2Ph-4-F
OH
2j
2k
2l
Nitren
OCH2Py-4
OCH2Py-3
OCH2Ph-2,4-diCl
The vasodilative data summarized in Table 2 indicate that (1)
benzyloxy group at R2 is beneficial for the vasodilative activity (com-
pound 2a, pEC50 = 6.4, Emax = 102.8%). However, when benzyloxy
group is attached at R1, the vasodilative activity dropped dramati-
cally (compound 2b, pEC50 = 4.5, Emax = 95.0%); (2) the vasodilative
effect declined when R1 changes from methoxy group to halogens
or hydrogen (compared compound 2c with 2f–2h); (3) the
compound with a 3-pyridinylmethoxy group at R2 displayed better
activity than that of the compound with a 4-pyridinylmethoxy
group; (4) the compound with a methoxy at R1 position and a
pEC50 = Àlog EC50; Emax: maximal vasodilative effects; Nitren: nitrendipine.
to 103.8%. In order to investigate structure–activity relationship
(SAR) of 3-benzylquinazolin-4(3H)-ones on vasodilative effects,
the two structural fragments of the target compound, quinazolinone
ring and phenyl ring in benzyl, were modified with different substi-
tuted groups. The fact that compounds 1g (pEC50 = 4.6, Emax = 97.8%)
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S.-J. Zuo et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
The title compounds displayed the characteristics of working
slowly and maintaining a long time on vasodilative effect. The
dose–effect curves of compounds 2a and 2c are shown in Figure 2.
Compounds 2a and 2c can relax significantly the isolated rat
mesenteric arterial rings induced contraction with 60 mM KCl
MOPS solution. Whether compounds 2a and 2c can compete the
contraction induced with phenylephrine (PE) on rat mesenteric
arterial rings. The mesenteric artery segments were pretreated
wiÀth6 the compounds 2a or 2c at the concentration of 10À5 M or
10
M M to
for 30 min, respectively. Then, the PE at 10À8
10À4 M was cumulatively added to baths. The obtained concentra-
tion- response curves are shown in Figure 3, respectively.
The curves in Figure 3 indicated that compounds 2a and 2c can
decrease significantly the contraction induced with PE on rat mes-
enteric arterial rings. As our previous work demonstrated,29 the
title compounds may play the role of inducing vasodilative effect
through multiple approaches.
Compounds 2a and 2c displayed potent vasodilative effect.
Therefore, compounds 2a and 2c were further investigated.
Next, the antihypertensive effects of compounds 2a and 2c were
evaluated by oral administration in spontaneously hypertensive
rats (SHR). Nitrendipine was chosen as positive drug. The blood
pressure was measured before (0 h) and after (1 h) drug adminis-
tration. The results are summarized in Table 3. The data in Table 3
indicate that compound 2a and 2c exhibit significantly antihyper-
tensive effects in SHR. The effects of compound 2c are more potent
than that of compound 2a. This may be associated with a fluoro-
substituted in compound 2c. The effects of compound 2a at the
dosage of 4 mg/kg are weaker than that of nitrendipine at the
dosage of 2 mg/kg. The effects of compound 2c at the dosage of
4 mg/kg are in close proximity to that of nitrendipine at the dosage
of 2 mg/kg.
Thus, 2c was further evaluated for its hypotensive dose–effect
relationship and time–effect relationship. The data are listed in
Tables 4 and 5, respectively. The compound 2c was tested at the
dosage of 0.5, 1.0, 2.0 4.0 and 8.0 mg/kg. The data in Table 4
showed that the antihypertensive effect of compound 2c was dose
dependent.
The data in Table 5 indicated that the solvent did not affect both
DBP and SBP in SHR. Meanwhile, compound 2c can maintain the
antihypertensive effect for 6 h at a dosage of 4.0 mg/kg.
In the present study, we assumed that the 3-benzylquinazolin-
4(3H)-ones may exhibit vasodilative effects and antihypertensive
effects. A series of 3-benzylquinazolin-4(3H)-ones were synthe-
sized and characterized. Their vasodilative effects were evaluated
by wire myograph on isolated rat mesenteric arterial ring induced
contraction with KCl (60 mM). The SAR of target compounds was
discussed preliminarily. The compounds 2a and 2c displayed
potent vasodilatation action and can significantly compete the
rat mesenteric arterial rings induced contraction with PE. The
antihypertensive effects of 2a and 2c were evaluated by oral
administration with SHR model. Compounds 2a and 2c can
significantly reduce both diastolic and systolic blood pressure.
Figure 3. Inhibitory effects of 2a (A) and 2c (B) on artery contraction induced by
phenylephrine. Data were shown as mean SEM, n = 8 for each group. *p < 0.05,
**p < 0.01 versus DMSO group.
4-fluorobenzyloxy group at R2 position exhibited the best vasodila-
tive effect among the evaluated compounds (compound 2c,
pEC50 = 6.6, Emax = 103.4%); (5) the activity of compound 2i
(pEC50 = 4.2, Emax = 70.3), removed O-benzyl at R2, dropped
dramatically.
Table 3
ꢀ
Effects of compounds 2a and 2c on SBP and SDP in SHR at 1 h (mmHg, x Æ s, n = 8)
Drug
Dose
DBP
DBP
Reduced value
SDP
SBP
Reduced value
(mg/kg)
(0 h)
(1 h)
(0 h)
(1 h)
Solventa
2a
2c
0
134
127
131
130
7
7
6
7
136
108 11
97
100
3
À2
19
34
30
182
178
184
180
3
7
3
4
181
130
124
129
7
9
5
4
1
48
60
51
4.0
4.0
2.0
3
6
Nitrendipine
a
NMP/PEG400/H2O = 1:7:2 (5 ml/kg).
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S.-J. Zuo et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
5
Table 4
ꢀ
The hypotensive dose–effect relationship of 2c in SHR (mmHg, x Æ s, n = 8)
Drug
Dose
DBP
DBP
Reduced value
SDP
SBP
Reduced value
(mg/kg)
(0 h)
(1 h)
(0 h)
(1 h)
Solventa
2c
0
134
133
133
128
131
137
130
7
3
6
3
6
4
7
134
124
118
101 10
97
94
9
1
6
À2
9
182
183
181
182
178
184
180
3
1
4
3
7
3
4
181
171
153
141
124
120
129
7
4
8
4
5
5
4
1
12
28
41
60
64
51
0.5
1.0
2.0
4.0
8.0
2.0
15
18
34
43
30
3
4
6
Nitrendipine
100
a
NMP/PEG400/H2O = 1:7:2 (5 ml/kg).
Table 5
The hypotensive time–effect relationship of 2c in SHR (mmHg, x Æ s, n = 8)
ꢀ
Time (h)
Solventa
2c (4 mg/kg)
DBP
SBP
DBP
Reduced DBP
SBP
Reduced SBP
0
0.5
1
2
4
134
134
136
135
135
134
137
7
9
3
3
3
2
4
182
180
181
178
180
181
184
3
4
7
2
2
2
2
131
101
97
108
114
121
137
6
3
3
3
5
5
4
184
138
124
142
148
163
182
3
4
5
6
4
5
4
20
34
23
17
10
46
60
42
36
21
2
6
8
a
NMP/PEG400/H2O = 1:7:2 (5 ml/kg).
12. Sasmal, S.; Balasubrahmanyam, D.; Kanna Reddy, H. R.; Balaji, G.; Srinivas, G.;
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The antihypertensive effect of compound 2c was dose dependent,
and can maintain 6 h at 4.0 mg/kg. These findings suggest that
the title compounds are novel vasodilative agents and compound
2c is a novel potent antihypertensive agent.
Acknowledgment
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Financial support from The Innovation Project on Science and
Technology of Shaanxi Province, China (No. 2012KPCL03-20) is
gratefully acknowledged.
Supplementary data
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Please cite this article in press as: Zuo, S.-J.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.10.092