Bioorganic & Medicinal Chemistry Letters
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.
S. Zuo and S. Li contributed equally to this work.
a
inhibitors and anti HCV agents.22 Hucke discovered that
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.