Discovery of molluscicidal and cercaricidal activities of 3-substituted quinazolinone derivatives by a scaffold hopping approach using a pseudo-ring based on the intramolecular hydrogen bond formation

Article abstract of DOI:10.1016/j.ejmech.2016.03.037

Discovery of novel topological agents against Oncomelania hupensis snails and cercariae remains a significant challenge in current Schistosomiasis control. A pseudo-ring formed from salicylanilide by an intramolecular hydrogen bond led to the discovery of 3-substituted quinazolinone derivatives which showed a potent molluscicidal and cercaricidal activities.

Full text of DOI:10.1016/j.ejmech.2016.03.037

Accepted Manuscript
Discovery of molluscicidal and cercaricidal activities of 3-substituted quinazolinone
derivatives by a scaffold hopping approach using a pseudo-ring based on the
intramolecular hydrogen bond formation
Wei Guo, Lv-Yin Zheng, Yong-Dong Li, Ren-Miao Wu, Qiang Chen, Ding-Qiao Yang,
Xiao-Lin Fan
PII:
S0223-5234(16)30211-2
10.1016/j.ejmech.2016.03.037
EJMECH 8462
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 22 November 2015
Revised Date: 13 March 2016
Accepted Date: 14 March 2016
Please cite this article as: W. Guo, L.-Y. Zheng, Y.-D. Li, R.-M. Wu, Q. Chen, D.-Q. Yang, X.-L. Fan,
Discovery of molluscicidal and cercaricidal activities of 3-substituted quinazolinone derivatives by a
scaffold hopping approach using a pseudo-ring based on the intramolecular hydrogen bond formation,
European Journal of Medicinal Chemistry (2016), doi: 10.1016/j.ejmech.2016.03.037.
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ACCEPTED MANUSCRIPT
A pseudo-ring formed from salicylanilide by an intramolecular hydrogen bond led to
the discovery of 3-substituted quinazolinone derivatives which showed a potent
molluscicidal and cercaricidal activities.

ACCEPTED MANUSCRIPT
Discovery of molluscicidal and cercaricidal activities of 3-substituted
quinazolinone derivatives by a scaffold hopping approach using a
pseudo-ring based on the intramolecular hydrogen bond formation
Wei Guoa, Lv-Yin Zhenga, Yong-Dong Lia,*, Ren-Miao Wua, Qiang Chena, Ding-Qiao
Yangb,*, Xiao-Lin Fana,*
a Key laboratory of organo-pharmaceutical chemistry of Jiangxi province, Gannan Normal
University, Ganzhou, 341000, China
b Key Laboratory of Theoretical Chemistry of Environment, Ministry of Education, School of
Chemistry and Environment, South China Normal University, Guangzhou 510006, China.
___________________________________________________________________________
ABSTRACT
Discovery of novel topological agents against Oncomelania hupensis snails and
cercariae remains a significant challenge in current Schistosomiasis control. A
pseudo-ring formed from salicylanilide by an intramolecular hydrogen bond led to the
discovery of 3-substituted quinazolinone derivatives which showed a potent
molluscicidal and cercaricidal activities.
Keywords: Quinazolinones; molluscicidal and cercaricidal agents; structure based drug
design; scaffold hopping; intramolecular hydrogen bond.
_____________________________________________________________________
1. Introduction
Schistosomiasis is the second most prevalent endemic disease after malaria in
tropical and subtropical regions [1]. It is considered that at least 200 million people, in
over 70 countries, are currently infected, 600 million people are at risk of infection,
and about 200 000 deaths per year are associated with the severe symptoms [2].
Recent monitoring data revealed that schistosomiasis (S. japonicum) was re-emerging
in China, especially along the Yangtze River and in the lakes region of Jiangxi and
Hunan provinces [3]. Schistosomiasis control has attracted much attention again
because of the continuous increase of infection cases though the disease was
previously under control in China [4].
____________
*
Corresponding author. E-mail addresses: ydli2011@163.com
;
(Y.-D. Li);
yangdq@scnu.edu.cn (D.-Q. Yang); fanxl@gnnu.cn (X.-L. Fan).

ACCEPTED MANUSCRIPT
The lifecycle of schistosome includes adult worm, worm egg, miracidium larva,
mother sporocyst, daughter sporocyst, cercariae, and schistosomulum steps [5]. The
effective control of the disease should be based on an integrated approach
incorporating chemotherapy, control of the snail host using molluscicides, and
ecological and biological control methods to destroy the life cycle of schistosomes [6].
Nevertheless, eliminating snail played an extremely important role because of the
expanding snail area, especially the spreading from epidemic region to historically
snail-free area [7]. Meanwhile, the cercariae infecting their final hosts (e.g. man and
mammals) by penetrating the skin are the key step resulting in schistosomiasis [8].
The cercariae are also the most frangible stage in their life cycle of schistosome.
Killing the cercariae is the other efficient strategy to control the development of the
disease [9,10].
Niclosamide, 5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxy-benzamide (I), is the
current salicylanilide molluscicide of choice in China and exhibits cercaricidal
activities to cercariae of S. japonicum [11,12]. However, niclosamide suffers from
some drawbacks involving lower solubility, expensive cost and hazard toxicity for
aquatic plants, birds, fish and mammals. Also, it has to be applied continuously over a
longer period of time to realize long-term snail control that may lead to drug
resistance. Hence, developing of alternative new chemical molluscicidal and
cercaricidal agents is still highly desirable [13]. Niclosamide contains a fundamental
structure of salicylamide, and the character of 2’-substituted Cl group makes it form a
psedu six-membered ring via a strong hydrogen bond between OH and NH, taking a
fairly rigid and planar conformation (II). The conformational similarity of (II) to
3-substituted quinazolinone (III) is based on the hypothesis that the pseudo
six-member ring may function as a mimic of the pyrimidin-4(3H)-one ring of the
3-phenylquinazolin-4(3H)-one (Fig. 1) [14,15]. Recently, quinazolinone derivatives
have been identified with novel anticancer, antitumor and antituberculosis inhibitors
[16–18]. However, the molluscicidal and cercaricidal activities of quinazolinones
have not been reported previously. Herein, we describe the synthesis and investigation
of the molluscicidal and cercaricidal activities of 3-substituted quinazolinones derived
from salicylanilide as potential drug candidates against schistosomiasis at
transmission stages.
Fig. 1 Scaffold hopping of niclosamide to 3-substituted quinazolinone
2. Results and discussion
2.1 Synthesis

ACCEPTED MANUSCRIPT
The synthetic route, chemical structure and yields of the products (3a–3t) were
given in Scheme 1. Briefly, the 3-substituted quinazolinone were synthesized
smoothly through Bi(NO3)2 catalyzed procedure by using 2-aminobenzoic acid,
aniline and CH(OEt)3 as the starting materials. The transformation was performed on
the solvent-free conditions. To our delight, aryl-substituted amines proceeded
smoothly to generate N-aryl substituted quinazolinones in good yields (3a–3j). The
di- and tri- substituted anilines only affords the corresponding products in moderate
yields owing to the steric effects (3k–3r). Furthermore, alkyl amines were also
investigated and provided the desired product in moderate yields (3s–3t). The detail
experiment process and characterization data were available in Supporting
information.
O
COOH
R'
R' NH2
N
Bi(NO3)3 5H2O (10 mol%)
80 o
R
+
+
CH(OEt)3
R
C
NH2
N
1
2
3
R3
R3
O
O
O
N
R1
R1
R1
N
N
N
R4
N
N
R2
R2
R2
3k: R1 = Cl, R2 = H, R3 = R4 = CH3, 62%
3l: R1 = Cl, R2 = H, R3 = R4 = OCH3, 56%
3m: R1 = R2 = Cl, R3 = R4 = CH3, 64%
3n: R1= R2 = Cl, R3 = R4 = OCH3, 54%
3o: R1= R2 = Cl, R3 = NO2, R4 = OCH3, 47%
3s: R1 = Cl, R2 = H, 37%
3a: R1 = Cl, R2 = H, R3 = H, 83%
3b: R1 = Cl, R2 = H, R3 = CH3, 79%
3c: R1 = Cl, R2 = H, R3 = OCH3, 74%
3d: R1 = NO2, R2 = H, R3 = H, 65%
3e: R1 = NO2, R2 = H, R3 = CH3, 59%
3f: R1 = R2 = Cl, R3 = H, 77%
3g: R1 = R2 = Cl, R3 = CH3, 69%
3h: R1 = R2 = Cl, R3 = OCH3, 61%
3i: R1 = R2 = Cl, R3 = N(CH3)2, 45%
3j: R1 = R2 = Cl, R3 = NO2, 67%
R3
O
R3
R3
R1
O
N
R1
N
N
R2
N
R2
3t: R1 = Cl, R2 = H, 41%
3p: R1 = Cl, R2 = H, R3 = OCH3, 46%
3q: R1 = NO2, R2 = H, R3 = OCH3, 39%
3r: R1 = R2 = Cl, R3 = OCH3, 44%
Scheme 1 Synthesis of 3-substituted quinazolinones
2.2 Molluscicidal and cercaricidal activities
Oncomelania hupensis is the unique host in the transmission of S. japonicum in
China, and also a target for molluscicidal studies. Meanwhile, control of cercariae of S.
japonicum is an important approach to prevent the infection of man and mammals.
The examination results of the synthesized compounds against Oncomelania hupensis
snails and cercariae show their molluscicidal and cercaricidal potency (Table 1).
Delightfully, all of the N-aryl substituted quinazolinones exhibited good activities
(LC50 2.69–10 ppm for snails and LC50 0.68–2.51 ppm for cercariae, respectively). A
loss of activity is observed with N-alkyl substituted (3s and 3t). For example, 3s

ACCEPTED MANUSCRIPT
estimated LC50 > 100 ppm, and hence it is considered inactive. It is worth noting that
3p displayed the excellent molluscicidal and cercaricidal activities (the LC50 are 2.69
and 0.68 ppm, respectively). Although the comparison of the activities of the
synthesized compounds with WPN showed our compounds were a little weak, 3p still
seems promising after some modifications which will be considered in a future study.
The preliminary structure-activity relationship in the group of compounds 3a–3r
could be drawn from the experimental results: (1) The Cl group at the 6 position of
the A ring was general more potent than NO2. However, 6,8-dichloro-quinazolines
produced inferior activities; (2) The aromatic rings were essential for C section; (3)
The electron-donating groups on the C ring were optimal for activity.
Fig. 2 The structure of 3-substituted quinazolinone
Table 1 Molluscicidal and cercaricidal activities of compounds 3a-3t
Snail
Cercariae
LC50 (ppm)
Compound
LC50 (ppm) LC90 (ppm)
LC90 (ppm)
1.55
1.35
1.23
2.34
1.91
2.19
1.57
3.31
2.04
1.52
1.45
1.19
1.78
2.15
1.72
0.89
1.66
3.28
>50
3a
3b
3c
4.68
4.07
3.80
7.07
5.75
6.61
4.71
10.00
6.17
4.65
4.36
3.78
5.37
6.55
5.34
2.69
5.01
9.95
>100
>100
<1
6.16
5.37
5.01
9.33
7.58
8.71
6.21
13.18
8.13
6.11
5.75
4.97
7.08
8.62
7.03
3.55
6.61
12.95
>100
>100
<1
1.17
1.02
0.95
1.78
1.45
1.66
1.19
2.51
1.55
1.15
1.10
0.91
1.35
1.64
1.31
0.68
1.26
2.49
>50
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
>50
<0.1
>50
<0.1
WPN

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2.3 Toxicity against tadpole
In order to explore the toxicity of 3p to aquatic organisms for the future practical
application in infected area, tadpoles were tested as models at 12, 24, 48 72, 96 and
120 h (Table 2). Control group lethality exhibited zero percent for the all experiments.
For 3p, the lethality of tadpoles did not occurred at the concentrations of 10 ppm –
0.3125 ppm within the first 24 h. Only 10 % average lethality occurred after 96 h at 5
ppm, so 3p was of safety for aquatic organisms such as tadpoles within the effective
cercaricidal concentrations from 0.3125 ppm to 2.5 ppm.
Table 2 The average lethality rates of 3p for tadpoles at different concentrations
Conc
Tadpoles
number
Lethality
48 h
(%)
(ppm)
12 h
24 h
72 h
96 h
120 h
10
5
10
10
10
10
10
10
10
0
0
0
0
0
0
0
0
0
0
0
0
0
0
10
0
10
0
20
10
0
20
10
0
2.5
0
0
1.25
0.625
0.3125
water
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
3. Conclusion
In conclusion, the pseudo six-membered ring formed by the intramolecular
hydrogen bond in salicylanilides, which further lead to the discovery of 3-substituted
quinazolinones through scaffold hopping approaches. The best compound 3p
displayed excellent molluscicidal and cercaricidal activities, as well as low toxicity.
The electron-denoting groups on N-substituted aromatic ring are beneficial for the
increase in the activity. The novel design strategy may offer a novel effective and
environment-friendly approach to reduce the population infection rate. Further
exploration of the SAR and molluscicidal and cercaricidal activities of the
3-substituted quinazolinones will be reported in due course.
4 Experimental sections
4.1 General
Melting points were measured using a melting point instrument and are uncorrected.
The infra-red spectra were recorded on a Perkin-Elmer 1730 FT–IR spectrometer
1
13
using KBr discs as stated. The H NMR and C NMR spectra were recorded on a
Varian Inona 400 MHz in CDCl3 or DMSO-d6 solutions using TMS as an internal
standard, and multiplicities were given as s (singlet), d (doublet), or m (multiplet).
The MS were taken on a MALDI-TOF spectrometer (Autoflex III). HRMS was
carried out on a high-resolution mass spectrometer (LCMS-IT-TOF). Reactions were
monitored by thin layer chromatography (TLC) with silica Plate. The products were

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purified by re-crystallized from ethanol. Unless otherwise noted, purchased chemicals
were used without further purification.
50% Wettable powder of niclosamide ethanolamine salt (WPN) was purchased
from Wujiang Medicine Co., Ltd in China. The infected Oncomelania hupensis were
obtained from Hunan Provincial Institute of Yueyang Schistosomiasis of China.
Tadpoles, the infancy form of frogs, were captured in ditches after rain events and
housed in pure water for 3 days before the tests. The length of tadpoles were 1.25 ±
0.25 cm. Tests were conducted at room temperature.
4.2 General procedure for the preparation of 3-substituted quinazolinones
(3a–3t)
An oven-dried round-bottom flask was charged with 2-aminobenzoic acid (0.5
mmol), aniline (0.6 mmol), Bi(NO3)3 (0.05 mmol), and CH(OEt)3 (2 mL), and the
o
mixture was stirred in a preheated oil bath at 80 C for 12 h. After cooling to room
temperature, the reaction mixture was admixed with hot CH2Cl2. The prude products
were collected by filtration and then re-crystallized from ethanol to afford pure
3-substituted quinazolinones (3a–3t).
4.3 Molluscicidal activity tests
The molluscicidal activity tests were carried out for synthetic compounds by
determination of the half lethal dose LC50 and sublethal dose LC90 of each compound
under investigation. Oncomelania hupensis snails (ca. 7 mm shell diameter) were
collected from the field (water canals) and maintained under laboratory conditions for
a period of 10 days before the tested and fed daily with lettuce leaves. Then, the snails
were examined to ensure that they were free from parasitic infection. Different
concentrations ranging from 2.5 ppm to 20 ppm of each compound under
investigation were prepared. The required amount of the compound under
investigation was mixed thoroughly with few drops of Tween 20 followed by addition
of the appropriate volume of untreated raw water (taken directly from the River
Gangjiang) to get a homogeneous suspension with the necessary concentration, it was
poured in glass jar vessels 15×25 ×20 cm dimensions fitted with air bubbles. Ten
snails having the same size and diameter (ca. 7 mm) were used in each experiment
and maintained in the tested solution under laboratory conditions at ambient
temperature for 24 h. Each experiment was repeated three times. WPN was used as
the positive control, which was taken by placing 10 snails in water containing few
drops of Tween 20 and 2 mL DMSO. These bioassays are in accordance with the
W.H.O. guidelines [19], slightly modified by using two mixed solvents to dissolve the
compounds.
4.4 Cercaricidal activity tests
Cercariae were collected from the infected Oncomelania hupensis snails. Certain
quantities of cercaricides were pumped out with minim injector and injected into
water, formed different the concentrations from 0.3125 ppm to 10 ppm. The activities
of the cercariae were explored by a color television microscopy with time lasted for

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120 min. The activities of cercariae were recorded on time. WPN was used as the
positive control.
4.5 Toxicity against tadpole
The toxic experiments of 3-substituted quinazolinones to tadpoles were carried out
in glass tank at different concentrations. Tadpoles were divided into experimental
group and control group (pure water), 10 tadpoles each group. Each group was
repeated three times. The activity and survival time of tadpoles were recorded on
time.
Acknowledgements
We are grateful to the Jiangxi Natural Science Foundation (20151BAB203011), the
Innovation Research Teams Project of Jiangxi Province (No. 20133BCB24011), Key
Technology R&D Program of Jiangxi Province (No. 20141BBG70070), the Science
Project of Jiangxi Provincial Department of Education (No. GJJ150989), the Natural
Science Foundation of Gannan Normal University (2015-34), the Natural Science
Foundation of Guangdong Province (S2013020013091), and the City of Guangzhou
Science and Technology Plan Projects (156300018) for financial support.
Appendix A. Supplementary data
Supplementary
data
related
to
this
article
can
be
found
at
http://dx.doi.org/10.1016/j.ejmech.
Conflict of interest
No conflict of interest.
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Highlights
1. The pseudo six-membered ring formed by the intramolecular hydrogen bond in
salicylanilides, which further lead to the discovery of 3-substituted
quinazolinones.
2. The best quinazolinone 3p displayed excellent molluscicidal and cercaricidal
activities, as well as low toxicity.
3. The novel design strategy offers a novel effective and environment-friendly
approach to reduce the population infection rate at transmission stages.