Bioorganic & Medicinal Chemistry Letters
Discovery of novel 2-benzylisoquinolin-1(2H)-ones as potent
vasodilative agents
Bo-Rui Kang a, Sen Li b, Shuai Mao a, Yong-Xiao Cao b, San-Qi Zhang a,
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a Department of Medicinal Chemistry, School of Pharmacy, Xi’an Jiaotong University, Xi’an, Shaanxi 710061, PR China
b Department of Pharmacology, School of Basic Medical Science, 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:
2-Benzylisoquinolin-1(2H)-ones has been proposed as vasodilative agents on the basis of scaffold hop-
ping. In the present study, a series of 2-benzylisoquinolin-1(2H)-ones were synthesized. Their vasodila-
tive effects were evaluated by wire myograph on isolated rat mesenteric arterial ring induced contraction
with 60 mM KCl. The structure–activity relationships of target compounds were discussed. Among these
compounds, C7 and C8 displayed potent vasodilative effects and significantly inhibited the contraction of
rat mesenteric arterial rings induced by phenylephrine. The antihypertensive effects of compounds C7
and C8 on SHR were further evaluated. The results indicated that oral administrational C7 and C8 can sig-
nificantly reduce both diastolic and systolic blood pressure in a dose-dependent manner. Moreover, C7
maintained the effects for 4 h at a dosage of 4.0 mg/kg. These findings suggest that the title compounds
can serve as novel vasodilative agents and promising antihypertensive agents.
Received 14 July 2015
Revised 2 October 2015
Accepted 7 October 2015
Available online 3 November 2015
Keywords:
2-Benzylisoquinolin-1(2H)-ones
Synthesis
Vasodilation
Antihypertension
Ó 2015 Published by Elsevier Ltd.
The chemical and biological study of heterocyclic compounds
has been an interesting field in medicinal chemistry for a long
time. However, the study on isoquinolin-1(2H)-one derivatives
is not active. In last 10 years, A few novel 2-substituted isoquino-
lin-1(2H)-one derivatives were synthesized and their activities
were described. 6-Cyclopropyl-8-fluro-2-phenylisoquinolin-1
(2H)-one, RN486, was discovered as a Bruton’s tyrosine kinase
(Btk) inhibitor for treating immune hypersensitivity responses.1
On basis of this research, different kinds of 2-substituted deriva-
tives were reported as small-molecule disease-modifying agents
for the treatment of rheumatoid arthritis, other autoimmune dis-
eases and B-cell malignancies.2–6 3,4-Dihydro-2-phenylisoquino-
proliferator-activated receptors, for preventing, curing or amelio-
rating cholesterol-related symptoms via regulating cholesterol
transport and metabolism.11 2-Benzyl-7-substituted derivatives
can inhibit matrix metalloproteinase for treating cardiovascular
diseases.12 Some 8-substituted-2-phenylisoquinolin-1(2H)-one
were described as endothelial growth factor receptor inhibitor.13
We discovered that 2-aryl-8-hydroxy-isoquinolin-1(2H)-one can
serve as epidermal growth factor receptor inhibitor.14 Additional
study for the discovery of new activity of isoquinolin-1(2H)-ones
are still needed.
In our effort to search for novel antihypertensive agents, we
reported a new approach to the synthesis of 2-benzyl-3,4-dihy-
droisoquinolin-1(2H)-ones and discovered that these compounds
exhibit the vasodilative effects.15 The detail results indicate that
2-benzyl-5-hydroxy-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one
(compound A in Fig. 1) induces vasodilation by inhibiting the
voltage-dependent Ca2+ channels and receptor-operated calcium
channel, and receptor-mediated Ca2+ influx and release.16 Lately,
we discovered that 3-benzylquinazolin-4(3H)-ones (compound B
in Fig. 1) displayed vasodilative and antihypertensive effects.17 In
the present study, we suspect that 2-benzylisoquinolin-1(2H)-ones
(compound C in Fig. 1) possess the similar configuration as com-
pounds A and B on basis of scaffold hopping. The similar character-
istic in structure reveals that 2-benzylisoquinolin-1(2H)-ones may
be a novel scaffold of vasodilative agents and antihypertensive
drugs (Fig. 1). Herein, we describe the synthesis, vasodilative and
antihypertensive effect of 2-benzylisoquinolin-1(2H)-ones.
lin-1(2H)-one was described as the inhibitor of 17
C
a-hydroxylase-
17,20-lyase (CYP17) for treating cancer.7 Some 2,3,4-trisubstituted
3,4-dihydro-isoquinolin-1(2H)-one derivatives can bind to human
double minute 2 and induce cellular apoptosis.8 6-(2,4-Diflurophe-
nyl)-3,4-dihydro-2-substituted isoquinolin-1(2H)-one can regulate
the release of histamine and other neurotransmitters though act-
ing on histamine-3 (H3) receptor for treating central nervous sys-
tem disorders.9 7-Alkyl-2-phenylisoquinolin-1(2H)-ones can
antagonise melanin concentrating hormone for the prevention
and treatment of obesity, diabetes.10 2-Benzyl-3-substituted
derivatives showed inhibitory effect on a cluster of nuclear recep-
tors, such as live X receptors, farnesoid X receptors and peroxisome
⇑
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0960-894X/Ó 2015 Published by Elsevier Ltd.