Synthesis and biological evaluation of indole-3-carboxamide derivatives as antioxidant agents

Article abstract of DOI:10.1016/j.cclet.2019.04.044

Oxidative stress results in various pathologies and as consequence antioxidant agents have attracted uninterrupted attention. In this paper, a novel series of indole-3-carboxamide derivatives (6a–6l) were designed and synthesized based on the melatonin structure as novel antioxidants. All of them were evaluated for the antioxidant activities in vitro against human neuroblastoma SH-SY5Y cell line using H₂O₂ radical scavenging assay. The target compounds 6a, 6f and 6i indicated better activities than the positive control, ascorbic acid, and 6a exhibited the best antioxidant activity. In addition, the structure-activity relationships of the target compounds were also preliminarily summarized based on the obtained experimental data.

Full text of DOI:10.1016/j.cclet.2019.04.044

Accepted Manuscript
Title: Synthesis and biological evaluation of
indole-3-carboxamide derivatives as antioxidant agents
Authors: Erfang Huang, Lan Zhang, Chuying Xiao,
Guangpeng Meng, Bingqi Zhang, Jianshu Hu, David
Chi-Cheong Wan, Qingguo Meng, Zhe Jin, Chun Hu
PII:
DOI:
Reference:
S1001-8417(19)30214-1
https://doi.org/10.1016/j.cclet.2019.04.044
CCLET 4937
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
27 February 2019
15 April 2019
16 April 2019
Please cite this article as: Huang E, Zhang L, Xiao C, Meng G, Zhang B, Hu J, Wan
DC-Cheong, Meng Q, Jin Z, Hu C, Synthesis and biological evaluation of indole-
3
-carboxamide derivatives as antioxidant agents, Chinese Chemical Letters (2019),
https://doi.org/10.1016/j.cclet.2019.04.044
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Communication
Synthesis and biological evaluation of indole-3-carboxamide derivatives as
antioxidant agents
a
a
b
a
a
b
Erfang Huang , Lan Zhang , Chuying Xiao , Guangpeng Meng , Bingqi Zhang , Jianshu Hu ,
b
c
a,*
a,*
David Chi-Cheong Wan , Qingguo Meng , Zhe Jin , Chun Hu
a
b
c
Key Laboratory of Structure-based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
Department of Pharmacy, Yantai Univeristy, Yantai 264005, China
*
Corresponding authors.
E-mail addresses: jinzheln@163.com (Z. Jin), chunhu1999@163.com (C. Hu).
Graphical abstract
A novel series of indole-3-carboxamide derivatives (6a–6l) have been designed, synthesized and evaluated for their antioxidant activity
against human neuroblastoma SH-SY5Y cell line using H
2 2
O radical scavenging assay. Biological activity evaluation showed that
compounds 6a, 6f and 6i exhibited significant in vitro activities, which could have the potential to be developed for novel antioxidants.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Oxidative stress results in various pathologies and as consequence antioxidant agents have
attracted uninterrupted attention. In this paper, a novel series of indole-3-carboxamide
derivatives (6a–6l) were designed and synthesized based on the melatonin structure as novel
antioxidants. All of them were evaluated for the antioxidant activities in vitro against human
Available online
2 2
neuroblastoma SH-SY5Y cell line using H O radical scavenging assay. The target
Keywords:
Heterocycle
Melatonin
Indole-3-carboxamide derivatives
Synthesis
compounds 6a, 6f and 6i indicated better activities than the positive control, ascorbic acid,
and 6a exhibited the best antioxidant activity. In addition, the structure-activity relationships
of the target compounds were also preliminarily summarized based on the obtained
experimental data.
Antioxidant activity
Structure-activity relationship
Oxidative stress, which is mainly caused by the imbalance between cellular antioxidant response systems and reactive oxygen
species (ROS) production, results in DNA damage, lipid peroxidation and even cell death [1]. It has been revealed that ROS are a
chemically heterogenic group of highly reactive molecules and they are naturally produced by metabolic redox reactions of biological
systems [2,3]. Accumulating evidence suggested that ROS are responsible for human’s aging and various pathologies such as
inflammation, diabetes, rheumatoid arthritis, Alzhimer’s disease and carcinogenesis [4-7]. The study on the significance of ROS in the
pathogenesis of various diseases and the research for the discovery of novel, small molecules as antioxidant agents have attracted
uninterrupted attention.
As known, the basic heterocyclic structures play a significant role in the drug design. Among them, indole derivatives have drawn
great attention due to their excellent biological activities. It was reported that melatonin (Fig. 1) and its derivatives showed antioxidant
property in both in vitro and in vivo models [8-10]. Melatonin is an endogenous chemical mediator excreted by pineal gland according

to a circadian rhythm. And it has low toxicity and limitation in pharmacokinetic issues just like short half-life and bioavailability [11-
4]. Therefore, melatonin was chosen as a lead compound in the present work and some structural modifications were devoted to
1
preliminarily evaluate the antioxidant activities of melatonin derivatives.
In this study, twelve novel indole-3-carboxamide derivatives (Fig. 1) as melatonin analogs were obtained, and their in vitro
antioxidant activities were evaluated via H O radical scavenging tests.
2 2
Fig. 1. Chemical structures of N-acetyl-5-methoxytryptamine (Melatonin) and the target indole-3-carboxamide derivatives.
The synthetic routes of the target compounds are depicted in Scheme 1. Intermediate 2a or 2b was obtained by reactions of the
commercially available ethyl acetoacetate (1) with methylamine or ethylamine at ambient temperature, which was converted to indole-
3
-carboxylate 3a or 3b via Nenitzescu reaction with benzoquinone. Hydrolysis of 3a or 3b using sodium hydroxide in ethanol and
water gave indole-3-carboxylic acid 4a or 4b. Treatment of 4a or 4b with benzylamine or 4-fluorobenzylamine in the presence of
EDCI and HOBt provided key intermediates 5a−5d. Reaction of 5a−5d with corresponding 2-chloroacetamide derivatives by using
anhydrous K
information.
2
CO
3
and KI gave indole-3-carboxamide derivatives 6a−6l, respectively. The details are given in the Supporting
o
Scheme 1. Synthetic route of the target indole-3-carboxamide derivatives. Reagents and conditions: (a) R
1
NH
2
, r.t., 3 h; (b) benzoquinone, acetone, 30 C, 2 h;
2 3 2 3
o
(
c) NaOH, H O, ethanol, reflux, 12 h; (d) EDCI, HOBt, triethylamine, DMF, CH Cl , r.t., 24 h; (e) ClCH CONR R , K CO , KI, DMF, 80 C, 16 h.
2
2
2
2
Using ascorbic acid as a control, the target compounds 6a−6l were evaluated for the antioxidant activities in vitro against human
neuroblastoma SH-SY5Y cell line by H radical scavenging assay [15-17], and the procedures are given in the Supporting
2
O
2
information. The results expressed as cell viability were summarized in Table 1.
The SARs analysis revealed as follows: (1) Compared to the target compound 6g, the target compound 6a exhibited better
antioxidant activity, which implies methyl in 1-position of indole structure is superior to ethyl; (2) The target compound 6a exhibited
better activity than the target compound 6d. These results show that the introduction of 4-fluorobenzylamino group in 3-position
resulted in a decrease or loss of the activity; (3) By comparison, compounds 6a-6c showed variant activity. In general, the introductions
of 2-oxo-2-(piperidin-1-yl)ethoxy and [2-(2-methoxyphenoxy)ethyl]amino group exhibit strong antioxidant activity, However, the
introduction of 2-(morpholin-4-yl)-2-oxoethoxy in to the 5-position results in a decrease or loss of the activity; (4) The target
compounds 6a (Fig. 2a), 6f (Fig. 2b) and 6i (Fig. 2c) indicated better activity than the positive control, and 6a exhibited the best
antioxidant activity.
Table 1
In vitro cell viability of the target compounds.
Compd.
Cell viability (% of Control)
SD
6
6
6
a
b
c
78.5
15.4
51.9
4.01
3.28
1.04

6
6
6
6
6
6
6
6
6
d
e
f
g
h
i
j
k
l
50.1
8.6
0.47
3.70
3.18
2.46
0.63
7.62
0.76
1.81
0.29
1.67
63.2
43.5
27.1
58.8
33.4
20.5
48.3
50.3
Ascorbic acid
Fig. 2. Effect of 6a (a), 6f (b) and 6i (c) on ROS production induced by H
P<0.01; ***: P<0.001).
2 2
O in SH-SY5Y cells, the statistical significance was calculated (*: P<0.05; **:
In conclusion, a novel series of indole-3-carboxamide derivatives were designed and synthesized. All of the target compounds were
evaluated for the antioxidant activity in vitro against human neuroblastoma SH-SY5Y cell line via H radical scavenging assay. The
2
O
2
target compounds 6a, 6f and 6i demonstrated excellent strong antioxidant activity. What is more, a new antioxidant scaffold and a
preliminary discussion on their SARs provide promising opportunities to guide further research on indole-3-carboxamide derivatives as
novel antioxidant agents.
Acknowledgments
This work was supported by the National Science Foundation of China (NSFC) (No. 21342006), the Program for Innovative
Research Team of the Ministry of Education of China (No. IRT_14R36).
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