Anti HIV-1 agents 6. Synthesis and anti-HIV-1 activity of indolyl glyoxamides

Article abstract of DOI:10.2174/157340612802084270

In order to discover compounds with superior anti-human immunodeficiency virus type 1 (HIV-1) activity, 9 new indolyl glyoxamide derivatives (3a-i) were synthesized and preliminarily evaluated as HIV-1 inhibitors in vitro. Among all the derivatives, espec

Full text of DOI:10.2174/157340612802084270

Medicinal Chemistry, 2012, 8, 831-833
831
Anti HIV-1 Agents 6. Synthesis and Anti-HIV-1 Activity of Indolyl
Glyoxamides
Yi Wanga,#, Ning Huangb,c,#, Xiang Yua, Liu-Meng Yangb, Xiao-Yan Zhia and Yong-Tang Zheng*,b
and Hui Xu*,a
aLaboratory of Pharmaceutical Design & Synthesis, College of Sciences, Northwest A&F University, Yangling 712100,
P. R. China
bKey Laboratory of Animal Models and Human Diseases Mechanisms of Chinese Academy of Sciences and Yunnan
Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, P. R. China
cGraduate School of the Chinese Academy of Sciences, Beijing 100039, P. R. China
Abstract: In order to discover compounds with superior anti-human immunodeficiency virus type 1 (HIV-1) activity, 9
new indolyl glyoxamide derivatives (3a-i) were synthesized and preliminarily evaluated as HIV-1 inhibitors in vitro.
Among all the derivatives, especially compounds 3e and 3h showed the potent anti-HIV-1 activity with EC50 values of
6.83 and 4.35 μg/mL, and TI values of >27.15 and 49.45, respectively. It demonstrated that introduction of the substituent
R3 as the halogen atom and the position of R3 were generally important to their activity.
Keywords: Indolyl glyoxamide, Acquired immunodeficiency syndrome, Human immunodeficiency virus-1, Inhibitor.
INTRODUCTION
RESULTS AND DISCUSSION
Chemistry
Recently, we have found that diaryl ethers (I, Fig. 1)
showed the promising antifungal activity against phytopa-
thogenic fungi in vitro [1]. In the meantime, indibulin (II,
Fig. 1) was identified as a tubulin inhibitor by exerting anti-
tumor activity [2]. Nowadays, fragment-based lead discovery
has emerged as a more rational and focused approach for
molecular modification and drug design. Based on the above
observations, and in continuation of our program aimed at
the discovery and development of bioactive molecules [3-5],
consequently, we designed a series of indolyl glyoxamide
derivatives (3, Fig. 1) by combining the diaryl ethers group
with indolyl glyoxamine moiety. On the other hand, since
the first case of acquired immunodeficiency syndrome
(AIDS) was reported in 1981, the human immunodeficiency
virus (HIV)/AIDS has always been a global health threat and
the leading cause of deaths [6-11]. The rapid worldwide
spread of AIDS, therefore, has prompted an intense research
effort to discover new, selective and safe drugs for the treat-
ment of HIV/AIDS. Especially Wang and co-workers de-
scribed that indolyl glyoxamide piperazines showed the anti-
HIV-1 activity [12]. In this paper, nine new indolyl glyox-
amide derivatives (3a-i) were synthesized and preliminarily
evaluated as HIV-1 inhibitors in vitro.
Indolyl glyoxamide derivatives (3a-i) were prepared as
depicted in Scheme 1 [13]. Benzylindoles (1) were firstly
treated with oxalyl chloride in dichloromethane to furnish
the glyoxylyl chlorides as intermediates (4), which were then
allowed to react with phenoxy phenylamines (2a or 2b) in
the presence of triethylamine to afford 3a-i in 21-74% yields.
The structures of all the target compounds were well identi-
fied by 1H NMR, MS, and m.p.
Biological Activity
Target compounds 3a-i were evaluated for their inhibi-
tory activity against HIV-1 replication in acutely infected
C8166 cells in vitro according to the previously described
method [3]. The assay results of 3a-i were presented in Table
1. Among all the derivatives, especially compounds 3e and
3h exhibited the potent anti-HIV-1 activity with EC50 values
of 6.83 and 4.35 μg/mL, and TI values of >27.15 and 49.45,
respectively. Meanwhile, preliminary structure-activity rela-
tionships (SAR) showed the following interesting character-
istics: (1) In general, introduction of the phenoxy group on
the para position led to the more potent compound than that
bearing the one on the ortho position (3b vs 3g). (2) Intro-
duction of the substituent R3 as the chloro atom on the para
position would generally lead to the more potent compound
than that bearing the chloro one on the ortho position (3d vs
3c). For example, the EC50 and TI values of 3c and 3d were
47.12/9.50 μg/mL, and >4.28/>19.98, respectively (3). When
R1 was the cyano group, introduction of the substituent R3 as
the chloro atom could lead to the more potent compound
*Address correspondence to these authors at the Laboratory of Pharmaceu-
tical Design & Synthesis, College of Sciences, Northwest A&F University,
Yangling 712100, China; Tel: +86-(0)29-87091952; Fax: +86-(0)29-
87091952; E-mails: orgxuhui@nwsuaf.edu.cn, zhengyt@mail.kiz.ac.cn
#These authors contributed equally to this work.
1875-6638/12 $58.00+.00
© 2012 Bentham Science Publishers

832 Medicinal Chemistry, 2012, Vol. 8, No. 5
Wang et al.
O
H
N
R1
O
O
Combinatorial optimization
O
R3
N
I
R3
O
R2
3
H
N
O
N
N
Cl
II
Fig. (1). Design Strategy of the Target Compounds 3.
O
H
N
R1
O
O
N
O
3a-b
Cl
R2 = H
3a: R1 = H; 3b: R1 = 6-Me
2a/Et3N
O
R1
1 h
1 h
O
R1
N
oxalyl chloride
H
N
N
DCM, 0-5 oC
R1
O
1-3 h
O
2b/Et3N
N
R2
4
R2
1
R3
R2
3c-i
O
2a =
3c: R1 = 4-Me, R2 = H, R3 = 2-Cl; 3d: R1 = 4-Me, R2 = H, R3 = 4-Cl
3e: R1 = 5-CN, R2 = H, R3 = 2-Cl; 3f: R1 = H, R2 = NO2, R3 = H
3g: R1 = 6-Me, R2 = R3 = H; 3h: R1 = 6-Me, R2 = H, R3 = 2-Br
3i: R1 = 5-CN, R2 = H, R3 = 2-Br
NH2
NH2
O
2b =
R3
Scheme 1. Synthetic Route of 3a-i.
than that bearing the bromo one (3e vs 3i). For example, the
cytotoxicity (CC50), EC50 and TI values of 3e and 3i were
>185.46/26.07 μg/mL, 6.83/10.94 μg/mL, and >27.15/2.41,
respectively. Obviously, the cytotoxicity of 3e was more
than sevenfold less than that of 3i, while the TI values of 3e
was more than elevenfold more potent than that of 3i. (4)
When R1 was the 6-methyl group, introduction of the sub-
stituent R3 as the bromo atom gave the more potent com-
pound than that having no substituent (3h vs 3g). For exam-
ple, the CC50 and TI values of 3h and 3g were 98.18/3.14
μg/mL, and 49.45/0.97, respectively.
CONCLUSION
In conclusion, we have reported 9 new indolyl glyox-
amide derivatives (3a-i) evaluated as HIV-1 inhibitors in
vitro. Among all the derivatives, especially 3e and 3h exhib-
ited the potent anti-HIV-1 activity with EC50 values of 6.83

Anti-HIV-1 Activity of Indolyl Glyoxamides
Medicinal Chemistry, 2012, Vol. 8, No. 5 833
Table 1. Anti-HIV-1 Activity of Indolyl Glyoxamide Derivatives (3a-i) in Vitro a
Compound
CC50 b) (μg/mL)
EC50c) (μg/mL)
TId)
3a
3b
3c
3d
3e
3f
96.05
>154.56
>200
18.67
22.76
47.12
9.50
5.16
>6.79
>4.28
>19.98
>27.15
7.97
>189.87
>185.46
9.58
6.83
1.50
3g
3h
3i
3.14
3.31
0.97
98.18
4.35
49.45
26.07
10.94
0.00335
2.41
AZTe
1730.28
516,501.49
aValues are means of two separate experiments.
bCC50 (50% cytotoxic concentration), concentration of drug that causes 50% reduction in total C8166 cell number.
cEC50 (50% effective concentration), concentration of drug that reduces syncytia formation by 50%.
dTherapeutic Index (TI) is a ratio of the CC50 value/EC50 value.
eAZT was used as a positive control.
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CONFLICT OF INTEREST
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The author(s) confirm that this article content has no con-
flicts of interest.
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ACKNOWLEDGEMENTS
This work was financially supported in part by grants
from New Century Excellent University Talents, State Edu-
cation Ministry of China (NCET-06-0868), and the Key Pro-
ject of Chinese Ministry of Education (No. 107105). We also
would like to acknowledge the National Basic Research Pro-
gram of China (2009CB522306), the Eleventh Five-Year
Key Scientific and Technological Program of China
(2009ZX09501-029, 2008ZX10005-005), and Scientific and
Technological Projects of Yunnan (2007BC006).
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Received: August 12, 2011
Revised: April 16, 2012
Accepted: April 16, 2012